WO2022167157A1

WO2022167157A1 - Eribulin-balixafortide combinations for treating cancer

Info

Publication number: WO2022167157A1
Application number: PCT/EP2022/025045
Authority: WO
Inventors: Francois RINGEISEN; Remco DIAB; Achim Wach
Original assignee: Spexis Ag
Priority date: 2021-02-05
Filing date: 2022-02-07
Publication date: 2022-08-11

Abstract

The present invention relates to pharmaceutical combinations comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4 and Cys11, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject.

Description

ERIBULIN-BALIXAFORTIDE COMBINATIONS FOR TREATING CANCER

Field of the invention

The present invention relates to pharmaceutical combinations comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala- ^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject.

Background of the invention

Despite the ever increasing number of cancer therapies in general, and combination cancer therapies in particular, cancer is still the third most common cause of death worldwide after cardiovascular diseases and infectious/parasitic diseases; in absolute numbers, this corresponds to 7.6 million deaths (ca. 13% of all deaths) in any given year. The WHO estimates deaths due to cancer to increase to 13.1 million by 2030.

Metastatic breast cancer (mBC) remains an incurable disease. Hormonal therapy is the initial course of treatment for those breast cancers that are estrogen receptor positive. Unfortunately, most of these patients become resistant to hormone therapy, and like those patients that are hormone receptor negative, they must then rely upon cytotoxic chemotherapy to control their disease. Despite new targeted therapies and cytotoxic agents that have recently been added to the treatment armamentarium, most patients with metastatic breast cancer develop resistance within months and overall survival remains poor. One of the most recently registered new cytoreductive agents is eribulin (Halaven®). Recently published data regarding the use of eribulin in relapsed mBC patients in 3rd line and beyond, demonstrated that progression-free survival (PFS) and overall survival (OS) could be prolonged 3.7 months and 13.1 months, respectively, and these data formed the basis for registration of this novel chemotherapeutic agent. Despite the recent addition of new therapeutic options, there is a distinct need for new treatment modalities for the treatment of breast cancer, in particular advanced breast cancer. Summary of the invention

It has now unexpectedly been found that a particular dose regimen of a combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, such as e.g. eribulin mesylate and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof such as e.g. the acetate salt of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro- Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, is useful for the prevention, delay of progression or treatment of cancer, in particular breast cancer

Taking these findings into account, the present invention is herewith provided in its following aspects.

In one aspect the present invention provides a pharmaceutical combination comprising:

(a) a compound of formula I

formula I which has the chemical name 2-(3-amino-2-hydroxypropyl)hexacosahydro-3-methoxy-26- methyl-20, 27-bis(methylene)ll, 15-18, 21-24, 28-triepoxy-7,9-ethano-12,15-methano- 9/7,15/7-furo(3,2-/)furo(2',3'-5,6)pyrano(4,3-b)(l,4)dioxacyclopentacosin-5-(4/7)-one, or a pharmaceutically acceptable salt thereof; (b) cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof; and optionally

(c) one or more pharmaceutically acceptable diluents, excipients or carriers, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, wherein each of the compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is independently administered to the subject on days 1 and 8 of a 21-day cycle administration.

Detailed description of the invention

As outlined above, the present invention provides pharmaceutical combinations comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer.

Thus, in one aspect the present invention provides a pharmaceutical combination comprising:

(a) a compound of formula I

formula I which has the chemical name 2-(3-amino-2-hydroxypropyl)hexacosahydro-3-methoxy-26- methyl-20, 27-bis(methylene)ll, 15-18, 21-24, 28-triepoxy-7,9-ethano-12,15-methano- 9/7,15/7-furo(3,2-/)furo(2',3'-5,6)pyrano(4,3-b)(l,4)dioxacyclopentacosin-5-(4/7)-one, or a pharmaceutically acceptable salt thereof;

(b) cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and optionally

For the purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. The terms "comprising", "having", and "including" are to be construed as open-ended terms (i.e. meaning "including, but not limited to,") unless otherwise noted.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

The terms "individual," "subject" or "patient" are used herein interchangeably. In certain embodiments, the subject is a mammal. Mammals include, but are not limited to primates (including human and non-human primates). In a preferred embodiment, the subject is a human.

The term "about" as used herein refers to +/- 10% of a given measurement.

The term "dose" as used herein refers to the total amount of an active ingredient (e.g., the compound of formula I, or a pharmaceutically acceptable salt thereof, or cyclo(-Tyr-His-Ala- Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, to be taken each time by a subject (e.g. a human).

The term "objective response rate" (ORR) as used herein refers to the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period. Response duration usually is measured from the time of initial response until documented tumor progression. Generally, the FDA has defined ORR as the sum of partial responses plus complete responses. When defined in this manner, ORR is a direct measure of drug antitumor activity, which can be evaluated in a single-arm study.

The ORR refers to the sum of complete response (CR) and partial response (PR).

The term "clinical benefit rate" (CBR) as used herein refers to the sum of complete response (CR), partial response (PR) and stable disease (SD) >6 months.

The term "complete response" (CR) as used herein in relation to target lesions refers to disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to <10 mm. The term complete response (CR) as used herein in relation to non-target lesions refers to disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).

The term "partial response" (PR) as used herein in relation to target lesions refers to at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

The term "progressive disease" (PD) as used herein in relation to target lesions refers to at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions. The term progressive disease (PD) as used herein in relation to non-target lesions refers to appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

The term "stable disease" (SD) as used herein in relation to target lesions refers to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

The terms "cancer" and "cancerous" as used herein refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancer include, but are not limited to, kaposi sarcoma, endometrial cancer, head and neck cancer, oesophageol cancer, breast cancers, lung cancer, pancreatic cancer, prostate cancer, colon cancer, ovarian cancer, and gastric cancer.

The term "breast cancer" as used herein means cancer that forms in tissues of the breast. The most common type of breast cancer is ductal carcinoma, which begins in the lining of the milk ducts. Another type of breast cancer is lobular carcinoma, which begins in the lobules (milk glands) of the breast. Invasive breast cancer is breast cancer that has spread from where it began in the breast ducts or lobules to surrounding normal tissue.

The term "metastatic breast cancer" as used herein means the state of breast cancer where the cancer cells are transmitted from the original site to one or more sites elsewhere in the body, by the blood vessels or lymphatics, to form one or more secondary tumors at one or more sites or organs besides the original site or organ. According to the criteria of the American Joint Committee on Cancer (AJCC, 8^th edition) metastatic breast cancer is staged as stage IV breast cancer.

The terms "locally advanced breast cancer" and "locally recurrent breast cancer" are used synonymously herein and therefore have the same meaning, "locally advanced breast cancer" and "locally recurrent breast cancer" mean the most advanced stage breast cancer that is still potentially curable with surgery, radiation, and systemic therapy. In general, cancers of the breast are considered to be locally advanced if they are large and/or have infiltrated into adjacent tissues (the overlying skin or underlying muscles) and/or are found to have extensive locoregional lymph node involvement. Locally advanced breast cancer does not represent a single clinical entity but rather a heterogeneous group of breast tumors that share a common theme of extensive locoregional spread without overt evidence of distant metastatic disease According to the criteria of the American Joint Committee on Cancer (AJCC, 8^th edition) locally advanced breast cancer is staged as stage III breast cancer.

The term "advanced breast cancer" as used herein includes metastatic breast cancer and locally advanced breast cancer, as used herein. The compound of formula I

formula I has the chemical name 2-(3-amino-2-hydroxypropyl)hexacosahydro-3-methoxy-26-methyl- 20, 27-bis(methylene)ll, 15-18, 21-24, 28-triepoxy- 7, 9-ethano-12,15-methano-9/7, 15/7- furo(3,2-/)furo(2',3'-5,6)pyrano(4,3-b)(l,4)dioxacyclopentacosin-5-(4/7)-one and is also referred to in the literature as (15,35,65,95,125,14/?,16/?,185,20/?,21/?,225,26/?,295,31/?,325,35/?,365)-20-[(25)-3-amino-2- hydroxypropyl]-21-methoxy- 14-methyl-8,15-bis(methylene)-2,19,30,34,37,39,40,41- octaoxanonacyclo[24.9.2.1³'³².l³'³³.l⁶'⁹.l¹²'¹⁶.0¹⁸'²².0²⁹'³⁶.0³¹'³⁵]hentetracontan-24-one;

11,15:18, 21:24, 28-Triepoxy- 7,9-ethano-12,15-methano-9H,15H-furo[3,2-/]furo[2^,,3^,:5,6] pyrano[4,3-b][l,4]dioxacyclopentacosin-5(4/7)-one, 2-[(25)-3-amino-2- hydroxypropyl]hexacosahydro-3-methoxy- 26-methyl-20,27-bis(methylene)-, (2R, 3R, 3a5, 7R, 8a5, 95, 10a/?, 115, 12/?, 13a/?, 13b5, 155, 185, 215, 245, 26/?, 28/?, 29a5); or eribulin (CAS Registry Number: 253128-41-5). Where the compound of formula I is in the form of a pharmaceutically acceptable salt, the amounts, concentrations and doses provided herein are all calculated on the basis of the respective free base. The amounts and concentrations are calculated for a 70 kg patient. In a preferred embodiment, the compound of formula I is the compound of formula la

formula la

The compound of formula la has the chemical name 2-(3-amino-2- hydroxypropyl)hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)ll, 15-18, 21- 24,28-triepoxy-7,9-ethano-12,15-methano-9/7,15/7-furo(3,2-/)furo(2',3'-5,6)pyrano(4,3- b)(l,4)dioxacyclopentacosin-5-(4/7)-one methanesulfonate and is also referred to in the literature as ( IS, 35,65,95, 125,14/?, 16/?, 185,20/?, 21/?, 225,26/?, 295,31/?, 325,35/?, 365)-20-[(25)- 3-amino-2-hydroxypropyl]-21-methoxy-14-methyl-8,15-bis(methylene)- 2,19,30,34,37,39,40,41- octaoxanonacyclo[24.9.2.1³'³².l³'³³.l⁶'⁹.l¹²'¹⁶.0¹⁸'²².0²⁹'³⁶.0³¹'³⁵]hentetracontan-24-one methanesulfonate (1:1); 11,15:18, 21:24, 28-Triepoxy- 7,9-ethano-12,15-methano-9/7,15/7- furo[3,2-/]furo[2',3':5,6] pyrano[4,3-b][l,4]dioxacyclopentacosin-5(4/7)-one, 2-[(25)-3-amino- 2-hydroxypropyl]hexacosahydro-3-methoxy- 26-methyl-20,27-bis(methylene)-, (2/?, 3/?, 3aS, 7R, 8aS, 95, 10a/?, 115, 12/?, 13a/?, 13b5, 155, 185, 215, 245, 26/?, 28/?, 29a5)-, methanesulfonate; or eribulin mesylate (CAS Registry Number: 441045-17-6).

Eribulin mesilate is a non-taxane inhibitor of microtubule dynamics of the halichondrin class of antineoplastic drugs. It is a structurally modified synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. It has a novel mode of action that is distinct from those of other tubulin-targeting agents: inhibiting the microtubule growth phase without affecting the shortening phase, resulting in tubulin sequestration into non-productive aggregates. The compound is approved for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Eribulin mesilate is marketed under the tradename Halaven®.

Cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll is also referred as POL6326 herein or balixafortide. POL6326 is a cyclic synthetic peptide consisting of 16 amino acids and an antagonist of the highly conserved chemokine receptor CXCR4 and is being developed as an IV treatment in combination with chemotherapy in patients with leukemias (autologous transplantation). In vitro receptor binding studies demonstrated a significant affinity of POL6326 for the human CXCR4 receptor, as well as a general lack of significant binding to other potential target receptors. Where cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll is in the form of a pharmaceutically acceptable salt, the amounts, concentrations and doses provided herein are all calculated on the basis of the respective free base. The amounts and concentrations are calculated for a 70 kg patient.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxy-benzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-enel-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e. g. an alkaline metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

Particularly suitable pharmaceutically acceptable salts of the compound of formula I are e.g. methane- or ethane-sulfonate. Most preferred is the methanesulfonate salt of the compound of formula I i.e. the compound of formula la.

Particularly suitable pharmaceutically acceptable salts of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro- Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll to be useful in the context of the present invention include the acetates, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4- aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonate, 2-hydroxyethanesulfonic acid, ethane-l,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N- cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or other organic protonic acids, such as ascorbic acid. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Most preferred is the acetate salt of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll.

The compound of formula I, or a pharmaceutically acceptable salt thereof, is comprised by the pharmaceutical combination of the present invention. Preferably the pharmaceutical combination of the present invention comprises a pharmaceutically acceptable salt of the compound of formula I. More preferably the pharmaceutical combination of the present invention comprises the compound of formula la (eribulin mesylate). Cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll or pharmaceutically acceptable salts thereof are comprised by the pharmaceutical combination of the present invention. Preferably the pharmaceutical combination of the present invention comprises cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll in free form. More preferably the pharmaceutical combination of the present invention comprises cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll as acetate salt. Thus, the most preferred pharmaceutical combination of the present invention for use in a method for the prevention, delay of progression or treatment of cancer in a subject as described herein is a pharmaceutical combination comprising the compound of formula la (eribulin mesylate) and the acetate salt of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll.

Combinations

As outlined above, the invention relates to a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein. A pharmaceutical combination according to the invention is for example a combined preparation or a pharmaceutical composition, for simultaneous, separate or sequential use.

The term "combined preparation" as used herein defines especially a "kit of parts" in the sense that the compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, can be dosed independently, either in separate form or by use of different fixed combinations with distinguished amounts of the active ingredients. In a preferred embodiment, the pharmaceutical combination according to the invention is a combined preparation. In a more preferred embodiment the pharmaceutical combination according to the invention is a combined preparation wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, are dosed independently from each other, i.e. are dosed in separate form.

The ratio of the amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, to be administered in the combined preparation can be varied, e.g. in order to cope with the needs of a patient sub-population to be treated or the needs of a single patient, which needs can be different due to age, sex, body weight, etc. of a patient. The individual parts of the combined preparation (kit of parts) can be administered simultaneously or sequentially, i.e. chronologically staggered, e.g. at different time points and with equal or different time intervals for any part of the kit of parts.

The term "pharmaceutical composition" refers to a fixed-dose combination (FDC) that includes the compound of formula I and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr- Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, combined in a single dosage form, having a predetermined combination of respective dosages.

The pharmaceutical combination further may be used as add-on therapy. As used herein, "add-on" or "add-on therapy" means an assemblage of reagents for use in therapy, the subject receiving the therapy begins a first treatment regimen of one or more reagents prior to beginning a second treatment regimen of one or more different reagents in addition to the first treatment regimen, so that not all of the reagents used in the therapy are started at the same time. A preferred add-on therapy of the present invention, comprises adding a compound of formula I therapy to a patient already receiving cyclo(-Tyr-His-Ala-Cys-Ser-Ala- ^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) therapy. The amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, respectively, to be administered will vary depending upon factors such as the particular compound, disease condition and its severity, according to the particular circumstances surrounding the case, including, e.g., the route of administration, the condition being treated, the target area being treated, and the subject or host being treated.

In one embodiment, the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, are present in a therapeutically effective amount.

The expression "effective amount" or "therapeutically effective amount" as used herein refers to an amount capable of invoking one or more of the following effects in a subject receiving the combination of the present invention: (i) increase of objective response rate (ORR); (ii) inhibition or arrest of tumor growth, including, reducing the rate of tumor growth or causing complete growth arrest; (iii) reduction in the number of tumor cells; (iv) reduction in tumor size; (v) reduction in tumor number; (vi) inhibition of metastasis (i.e. reduction, slowing down or complete stopping) of tumor cell infiltration into peripheral organs; (vii) enhancement of antitumor immune response, which may, but does not have to, result in the regression or elimination of the tumor; (viii) relief, to some extent, of one or more symptoms associated with cancer; (ix) increase in progression-free survival (PFS) and/or; overall survival (OS) of the subject receiving the combination. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. In some embodiments, a therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof and/or cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll or a pharmaceutically acceptable salt thereof, may (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent, and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (e.g., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) delay occurrence and/or recurrence of a tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer. In various embodiments, the amount is sufficient to ameliorate, palliate, lessen, and/or delay one or more of symptoms of cancer.

The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one ordinary skilled in the art.

In one embodiment, the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, are present in an amount producing an additive therapeutic effect.

As used herein, the term "additive" means that the effect achieved with the pharmaceutical combinations of this invention is approximately the sum of the effects that result from using the anti-cancer agents, namely the compound of formula I and cyclo(-Tyr-His-Ala-Cys-Ser- Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, as a monotherapy.

Advantageously, an additive effect provides for greater efficacy at the same doses, and may lead to longer duration of response to the therapy.

In one embodiment, the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein said compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, are present in an amount producing a synergistic therapeutic effect.

As used herein, the term "synergistic" means that the effect achieved with the pharmaceutical combinations of this invention is approximately higher than the sum of the effects that result from using the anti-cancer agents, namely the compound of formula I and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, as a monotherapy.

In one embodiment, the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein the amount of said compound of formula I, or a pharmaceutically acceptable salt thereof, in the combination is from about 0.1 to about 50 mg or from about 0.1 to about 20 mg or from about 0.1 to about 10 mg or from about 0.5 to about 8 mg or from about 0.5 to about 6 mg or from about 0.5 to about 4 mg or from about 0.75 to about 3 mg or from about 1.1 to about 2.4 mg, preferably from about 0.5 to about 4 mg, more preferably from about 0.75 to about 3 mg, even more preferably from about 1.1 to about 2.4 mg,.

In one embodiment, the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein the amount of said compound of formula I, or a pharmaceutically acceptable salt thereof, in the combination is about 1 mg, about 1.2 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg.

In one embodiment, the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein the amount of said cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr- Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, in the combination is from about 385 to about 2240 mg or from about 385 to about 1610 mg or from about 385 to about 1155 mg, preferably from about 770 to about 2240 mg or from about 770 to about 1610 mg or from about 770 to about 1155 mg.

In one embodiment, the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein the amount of said cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr- Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, in the combination is about 385 mg, about 770 mg, about 1155 mg, about 1610 mg, or about 2240 mg, preferably about 770 mg, about 1155 mg, about 1610 mg, or about 2240 mg,.

In one embodiment, the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein the amount of said compound of formula I, or a pharmaceutically acceptable salt thereof, in the combination is from about 0.1 to about 50 mg or from about 0.1 to about 20 mg or from about 0.1 to about 10 mg or from about 0.5 to about 8 mg or from about 0.5 to about 6 mg or from about 0.5 to about 4 mg or from about 0.75 to about 3 mg or from about 1.1 to about 2.4 mg, preferably from about 0.5 to about 4 mg, more preferably from about 0.75 to about 3 mg, even more preferably from about 1.1 to about 2.4 mg, and wherein the amount of said cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys- Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, in the combination is from about 385 to about 2240 mg or from about 385 to about 1610 mg or from about 385 to about 1155 mg, preferably from about 770 to about 2240 mg or from about 770 to about 1610 mg or from about 770 to about 1155 mg.

In a preferred embodiment, the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, wherein the amount of said compound of formula I, or a pharmaceutically acceptable salt thereof, in the combination is about 1 mg, about 1.2 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10 mg; and wherein the amount of said cyclo(-Tyr-His-Ala-Cys-Ser- Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, in the combination is about 385 mg, about 770 mg, about 1155 mg, about 1610 mg, or about 2240 mg, preferably about 770 mg, about 1155 mg, about 1610 mg, or about 2240 mg.

In a particularly preferred embodiment, the invention provides a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, wherein the amount of said compound of formula I, or a pharmaceutically acceptable salt thereof, in the combination is from about 1.1 to about 2.4 mg; and wherein the amount of said cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro- Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, in the combination is from about 385 to about 2240 mg, preferably from about 770 to about 2240 mg, more preferably about 385 mg, about 770 mg, about 1155 mg, about 1610 mg, or about 2240 mg, even more preferably about 770 mg, about 1155 mg, about 1610 mg, or about 2240 mg.

As indicated above, the invention also relates to a pharmaceutical combination comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable diluents, excipients or carriers for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein.

The term "pharmaceutically acceptable diluent, excipient or carrier" as used herein refers to a carrier or excipient or diluent that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. It can be a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the subject. In a further aspect the present invention provides a pharmaceutical combination comprising:

(a) a compound of formula I

formula I which has the chemical name 2-(3-amino-2-hydroxypropyl)hexacosahydro-3-methoxy-26- methyl-20, 27-bis(methylene)ll, 15-18, 21-24, 28-triepoxy-7,9-ethano-12,15-methano- 9/7,15/7-furo(3,2-/)furo(2',3'-5,6)pyrano(4,3-b)(l,4)dioxacyclopentacosin-5-(4/7)-one or a pharmaceutically acceptable salt thereof;

(b) cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof; and optionally

(c) one or more pharmaceutically acceptable diluents, excipients or carriers, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject at an amount from about 0.1 to about 10 mg and cyclo(-Tyr- His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered at an amount from about 770 to about 2240 mg.

Amounts of the compound of formula I, or a pharmaceutically acceptable salt thereof,, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, respectively, administered to the subject, are as mentioned above.

Formulations and modes of administration

The formulation and route of administration chosen may be tailored to the individual subject, the nature of the condition to be treated in the subject, and generally, the judgment of the attending practitioner.

The pharmaceutical compositions or combined preparations of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal, transmucosal, transdermal, by intra-arterial injection, by infusion, intravenously, intraperitoneally, parenterally, intramuscularly, orally, topically, as e.g. an inhalant via pulmonary adminstration, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.

One mode for administration is administration by injection or infusion, preferably intravenous administration by infusion. The forms in which the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, may be incorporated for administration by injection or infusion include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline may also conventionally be used for injection or infusion, preferably physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer are used as aqueous solutions. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compound according to the present disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. In certain embodiments, for parenteral administration, sterile injectable solutions are prepared containing a therapeutically effective amount, e.g., 0.1 to 1000 mg, of the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or cyclo(-Tyr-His-Ala-Cys-Ser- Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

A pharmaceutical combination for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein according to the invention is, preferably, suitable for injection, e.g. intravenous, intramuscular, intrathecal or intraperitoneal injection, or infusion, more preferably suitable for intravenous injection or infusion, and usually comprises a therapeutically effective amount of the active ingredients and one or more suitable pharmaceutically acceptable diluent, excipient or carrier. Thus, in a preferred embodiment the pharmaceutical combination is administered to the subject intravenously, i.e. the compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, are administered to the subject intravenously, in particular by intravenous infusion.

Pharmaceutical compositions or combined preparations in separate form comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, may be manufactured by means of conventional mixing, dissolving, granulating, coated tabletmaking, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions or combined preparations in separate form may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxilliaries which facilitate processing of the active ingredient into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen.

For topical administration the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation as known in the art.

For oral administration, the compounds can be readily formulated by combining the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, with pharmaceutically acceptable carriers well known in the art. Such carriers enable the the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion by a patient to be treated. For oral formulations such as, for example, powders, capsules and tablets, suitable excipients include fillers such as sugars, e. g. lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose; granulating agents; and binding agents. If desired, desintegrating agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate. If desired, solid dosage forms may be sugar-coated or enteric-coated using standard techniques.

For oral liquid preparations such as, for example, suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc. In addition, flavoring agents, preservatives, coloring agents and the like may be added.

For buccal administration, the composition may take the form of tablets, lozenges, etc. formulated as usual.

For administration by inhalation, the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln- Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, are conveniently delivered in form of an aeorosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluromethane, carbon dioxide or another suitable gas. In the case of a pressurized aerosol the dose unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compounds of the invention and a suitable powder base such as lactose or starch.

The compounds may also be formulated in rectal or vaginal compositions such as suppositories together with appropriate suppository bases such as cocoa butter or other glycerides. In addition, other pharmaceutical delivery systems may be employed such as liposomes and emulsions well known in the art. Certain organic solvents such as dimethylsulfoxide may also be employed. Additionally, the compound of formula I, or a pharmaceutically acceptable salt thereof, and/or cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, may be delivered using a sustained-release system, such as semipermeable matrices of solid polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for protein stabilization may be employed.

Using the combinations of the invention to treat cancer

The present invention provides a pharmaceutical combination as described herein, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, preferably for use in a method for the delay of progression or treatment of cancer in a subject, more preferably for use in a method for the treatment of cancer in a subject.

Also provided is the use of a pharmaceutical combination as described herein for the manufacture of a medicament for the prevention, delay of progression or treatment of cancer in a subject, as described herein preferably for the manufacture of a medicament for the delay of progression or treatment of cancer in a subject, more preferably for the manufacture of a medicament for the treatment of cancer in a subject.

Also provided is the use of a pharmaceutical combination as described herein for the prevention, delay of progression or treatment of cancer in a subject, preferably for the delay of progression or treatment of cancer in a subject, more preferably for the treatment of cancer in a subject. Also provided is a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, preferably a method for the delay of progression or treatment of cancer in a subject, more preferably a method for the treatment of cancer in a subject, comprising administering to said subject a pharmaceutical combination as described herein e.g. administering to said subject a therapeutically effective amount of a pharmaceutical combination as described herein.

As used herein, the term "prevention"/"preventing" e.g. preventive treatments comprise prophylactic treatments. In preventive applications, the pharmaceutical combination of the invention is administered to a subject suspected of having, or at risk for developing cancer.

As used herein, the term "delay of progression"/"delaying of progression" means increasing the time to appearance of a symptom of a cancer or a mark associated with a cancer or slowing the increase in severity of a symptom of a cancer. Further, "delay of progression" as used herein includes reversing or inhibition of disease progression. "Inhibition" of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.

The terms "treatment"/"treating" as used herein includes: (1) delaying the appearance of clinical symptoms of the state, disorder or condition developing in an animal, particularly a mammal and especially a human, that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof; and/or (3) relieving the condition (i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment.

In therapeutic applications, the pharmaceutical combination is usually administered to a subject such as a patient already suffering from cancer, in an amount sufficient to cure or at least partially arrest the symptoms of the disease. Amounts effective for this use will depend on the severity and course of the disease, previous therapy, the subject's health status and response to the drugs, and the judgment of the treating physician.

In the case wherein the subject's condition does not improve, the pharmaceutical combination of the invention may be administered chronically, which is, for an extended period of time, including throughout the duration of the subject's life in order to ameliorate or otherwise control or limit the symptoms of the subject's disease or condition.

In the case wherein the subject's status does improve, the pharmaceutical combination may be administered continuously; alternatively, the dose of drugs being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").

Once improvement of the patient's condition has occurred, a maintenance dose of the pharmaceutical combination of the invention is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is optionally reduced, as a function of the symptoms, to a level at which the improved disease is retained.

In one embodiment of the invention, there is provided a pharmaceutical combination according to the invention, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, as described herein, preferably for use in a method for the delay of progression or treatment of cancer in a subject, more preferably for use in a method for the treatment of cancer in a subject, wherein the cancer is breast cancer, preferably advanced breast cancer, more preferably advanced breast cancer selected from the group consisting of metastatic breast cancer and locally advanced breast cancer, even more preferably metastatic breast cancer or locally advanced breast cancer. Usually the cancer to be treated by the method for the prevention, delay of progression or treatment of cancer of the present invention expresses CXCR4. Methods of assessment of CXCR4 expression of a cancer have been reported in the scientific literature and are known to the skilled person. CXCR4 expression of a cancer can be assessed by e,g, immunohistochemistry on tumour tissue (archival primary tumour, metastatic tissue, or from a fresh biopsy). Any level of expression of CXCR4 of the cancer to be treated by the method of the present invention is considered as cancer expressing CXCR4 in the context of the invention. Also provided is the use of a pharmaceutical combination as described herein for the manufacture of a medicament for the prevention, delay of progression or treatment of cancer in a subject, preferably for the manufacture of a medicament for the delay of progression or treatment of cancer in a subject, more preferably for the manufacture of a medicament for the treatment of cancer in a subject, wherein the cancer is breast cancer, preferably advanced breast cancer, more preferably advanced breast cancer selected from the group consisting of metastatic breast cancer and locally advanced breast cancer, even more preferably metastatic breast cancer or locally advanced breast cancer.

Also provided is the use of a pharmaceutical combination as described herein for the prevention, delay of progression or treatment of cancer in a subject, preferably for the delay of progression or treatment of cancer in a subject, more preferably for the treatment of cancer in a subject, wherein the cancer is breast cancer, preferably advanced breast cancer, more preferably advanced breast cancer selected from the group consisting of metastatic breast cancer and locally advanced breast cancer, even more preferably metastatic breast cancer or locally advanced breast cancer.

Also provided is a method for the prevention, delay of progression or treatment of cancer in a subject, preferably a method for the delay of progression or treatment of cancer in a subject, more preferably a method for the treatment of cancer in a subject, comprising administering to said subject a pharmaceutical combination as described herein e.g. administering to said subject a therapeutically effective amount of a pharmaceutical combination as described herein, wherein the cancer is breast cancer, preferably advanced breast cancer, more preferably advanced breast cancer selected from the group consisting of metastatic breast cancer and locally advanced breast cancer, even more preferably metastatic breast cancer or locally advanced breast cancer.

In a preferred embodiment the breast cancer is selected from the group consisting of HER2- negative estrogen receptor negative progesterone receptor negative (HER2-ER-PR-) breast cancer, HER2-negative estrogen receptor positive progesterone receptor negative (HER2- ER+PR-) breast cancer, HER2- negative estrogen receptor negative progesterone receptor positive (HER2-ER-PR+) breast cancer, HER2- negative estrogen receptor positive progesterone receptor positive (HER2-ER+PR+) breast cancer.

In a further preferred embodiment the advanced breast cancer is selected from the group consisting of HER2-negative estrogen receptor negative progesterone receptor negative (HER2-ER-PR-) advanced breast cancer, HER2-negative estrogen receptor positive progesterone receptor negative (HER2-ER+PR-) advanced breast cancer, HER2- negative estrogen receptor negative progesterone receptor positive (HER2-ER-PR+) advanced breast cancer, HER2- negative estrogen receptor positive progesterone receptor positive (HER2- ER+PR+) advanced breast cancer

In a further preferred embodiment the locally advanced breast cancer is selected from the group consisting of HER2-negative estrogen receptor negative progesterone receptor negative (HER2-ER-PR-) locally advanced breast cancer, HER2-negative estrogen receptor positive progesterone receptor negative (HER2-ER+PR-) locally advanced breast cancer, HER2- negative estrogen receptor negative progesterone receptor positive (HER2-ER-PR+) locally advanced breast cancer, HER2- negative estrogen receptor positive progesterone receptor positive (HER2-ER+PR+) locally advanced breast cancer.

In a further preferred embodiment the metastatic breast cancer is selected from the group consisting of HER2-negative estrogen receptor negative progesterone receptor negative (HER2-ER-PR-) metastatic breast cancer, HER2-negative estrogen receptor positive progesterone receptor negative (HER2-ER+PR-) metastatic breast cancer, HER2- negative estrogen receptor negative progesterone receptor positive (HER2-ER-PR+) metastatic breast cancer, HER2- negative estrogen receptor positive progesterone receptor positive (HER2- ER+PR+) metastatic breast cancer.

In one embodiment the subject who has cancer is (i) refractory to at least one chemotherapy treatment, or (ii) is in relapse after treatment with chemotherapy, or a combination thereof. In some embodiments, the subject is refractory to at least two, at least three, or at least four anti-cancer therapy (including, for example, standard or experimental chemotherapies), preferably the subject is refractory to one to three or one to two anti-cancer therapies (including, for example, standard or experimental chemotherapies), more preferably the subject is refractory to one to three or one to two anti-cancer therapies for the treatment of locally recurrent breast cancer or metastatic breast cancer.

In some embodiments, the subject who is in relapse after treatment with chemotherapy has received at least two, at least three, or at least four anti-cancer therapy (including, for example, standard or experimental chemotherapies), preferably the subject who is in relapse after treatment with chemotherapy has received one to three or one to two anticancer therapies (including, for example, standard or experimental chemotherapies), more preferably the subject who is in relapse after treatment with chemotherapy has received one to three or one to two anti-cancer therapies for the treatment of locally recurrent breast cancer or metastatic breast cancer.

A subject who is refractory to at least one anti-cancer therapy and/or is in relapse after treatment with at least one anti-cancer therapy, as described above, may have undergone one or more prior therapies. In some embodiments, such subjects have undergone one, two, three, or four, or five, or at least one, at least two, at least three, at least four, or at least five, or between one and ten, between one and nine, between one and eight, between one and seven, between one and six, between one and five, or between one and four, or between one and three, between four and six or between seven and ten anti-cancer therapies prior to treatment using the methods described herein (e.g., prior to the administration of the compound of formula I, or a pharmaceutically acceptable salt thereof and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof ).

Dosing regimen

The present invention provides a pharmaceutical combination as described herein, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, wherein each of the compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is independently administered to the subject on days 1 and 8 of a 21-day cycle administration. The administration of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro- Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and of the compound of formula I, or a pharmaceutically acceptable salt thereof, may deviate by ± 1 day. Thus administration might occur on day 1 or 2 and on day 7, 8 or 9 of a 21-day cycle administration.

The dosing regimen of the compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln- Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, in the methods provided herein may vary depending upon the indication, route of administration, and severity of the condition, for example. Depending on the route of administration, a suitable dose can be calculated according to body weight, body surface area, or organ size. The final dosing regimen can be determined by the attending physician in view of good medical practice, considering various factors that modify the action of drugs, e.g., the specific activity of the compound, the identity and severity of the disease state, the responsiveness of the patient, the age, condition, body weight, sex, and diet of the patient, and the severity of any infection. Additional factors that can be taken into account include time and frequency of administration, drug combinations, reaction sensitivities, and tolerance/response to therapy. Further refinement of the doses appropriate for treatment involving any of the formulations mentioned herein is done routinely by the skilled practitioner without undue experimentation, especially in light of the dosing information and assays disclosed, as well as the pharmacokinetic data observed in human clinical trials. Appropriate doses can be ascertained through use of established assays for determining concentration of the agent in a body fluid or other sample together with dose response data.

The amount, e.g. the therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt thereof, may be provided in a single dose or multiple doses to achieve the desired treatment endpoint.

The frequency of dosing will depend on the pharmacokinetic parameters of the compound administered, the route of administration, and the particular disease treated. The dose and frequency of dosing may also depend on pharmacokinetic and pharmacodynamic, as well as toxicity and therapeutic efficiency data. For example, pharmacokinetic and pharmacodynamic information about the compound of formula I, or a pharmaceutically acceptable salt thereof and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, can be collected through preclinical in vitro and in vivo studies, later confirmed in humans during the course of clinical trials. Thus, for the ccompound of formula I, or a pharmaceutically acceptable salt thereof and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, used in the methods provided herein, a therapeutically effective dose can be estimated initially from biochemical and/or cell-based assays. Then, dosage can be formulated in animal models to achieve a desirable circulating concentration range. As human studies are conducted further information will emerge regarding the appropriate dosage levels and duration of treatment for various diseases and conditions.

Toxicity and therapeutic efficacy of the compound of formula I, or a pharmaceutically acceptable salt thereof and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the "therapeutic index", which typically is expressed as the ratio LD50/ED50. Compounds that exhibit large therapeutic indices, i.e. the toxic doses are substantially higher than the effective doses, are preferred. The data obtained from such cell culture assays and additional animal studies can be used in formulating a range of dosage for human use. The doses of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/kg, even more preferably of about 0.5 mg/kg, followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 3.5 to about 32 mg/kg.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 9 to about 32 mg/kg.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.2 to about 1 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg. In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10.5 to about 32. mg/kg. In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10.5 to about 32. mg/kg.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 5 mg/kg.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 10.5 mg/kg. In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 16 mg/kg

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 22.5 mg/kg.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 31.5 mg/kg. In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/kg, even more preferably of about 0.5 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 3.5 to about 32 mg/kg for 2 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 9 to about 32 mg/kg for 2 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-

Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.2 to about 1 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg for 2 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg for 2 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg for 2 to about 6 hours. In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/kg, even more preferably of about 0.5 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 3.5 to about 32 mg/kg for 2 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 9 to about 32 mg/kg for 2 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.2 to about 1 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg for 2 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg for 2 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg for 2 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10.5 to about 32 mg/kg for 2 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10.5 to about 32 mg/kg for 2 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10.5 to about 32 mg/kg for 2 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10.5 to about 32 mg/kg for 2 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 5 mg/kg for about 2 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 10.5 mg/kg for about 3.5 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 16 mg/kg for about 3.5 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 22.5 mg/kg for about 3.5 to about 6 hours. In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hours followed by b) a second phase comprising infusion of a dose of of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro- Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 31.5 mg/kg for about 3.5 to about 6 hours.

Exemplary doses of the compound of formula I, or a pharmaceutically acceptable salt thereof, above, e.g. for a human subject, may be from about 0.1 to about 50 mg/m² or from about 0.1 to about 20 mg/m² or from about 0.1 to about 10 mg/m² or from about 0.5 to about 8 mg/m² or from about 0.5 to about 6 mg/m² or from about 0.5 to about 1.6 mg/m² or from about 0.5 to about 1.5 mg/m² about 0.6 mg/m² or about 0.7 mg/m², about 0.8 mg/m², about 0.9 mg/m², about 1 mg/m², about 1.1 mg/m², about 1.2 mg/m², about 1.3 mg/m², about 1.4 mg/m², about 1.5 mg/m², about 2 mg/m², about 3 mg/m², about 4 mg/m², about 5 mg/m², about 6 mg/m², about 7 mg/m², about 8 mg/m², about 9 mg/m² or about 10 mg/m² and are preferably from about 0.1 to about 10 mg/m², more preferably from about 0.5 to about 1.5 mg/m², even more preferably from about 0.6 to about 1.4 mg/m², in particular about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m² .

In some embodiments the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject after the end of the second phase of administration of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, as described above, wherein the doses of the compound of formula I, or a pharmaceutically acceptable salt thereof, are from about 0.1 to about 50 mg/m² or from about 0.1 to about 20 mg/m² or from about 0.1 to about 10 mg/m² or from about 0.5 to about 8 mg/m² or from about 0.5 to about 6 mg/m² or from about 0.5 to about 1.6 mg/m² or from about 0.5 to about 1.5 mg/m² or about 0.7 mg/m², about 0.8 mg/m², about 0.9 mg/m², about 1 mg/m², about 1.1 mg/m², about 1.2 mg/m², about 1.3 mg/m², about 1.4 mg/m², about 1.5 mg/m², about 2 mg/m², about 3 mg/m², about 4 mg/m², about 5 mg/m², about 6 mg/m², about 7 mg/m², about 8 mg/m² about 9 mg/m² or about 10 mg/m² and are preferably from about 0.1 to about 10 mg/m², more preferably from about 0.5 to about 1.5 mg/m², even more preferably from about 0.6 to about 1.4 mg/m², in particular about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m² .

In one embodiment the administration of the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject about 30 to about 60 minutes, preferably about 45 minutes after the end of the administration of cyclo(-Tyr-His-Ala-Cys- Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof.

In one embodiment the administration of the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject about 30 to about 60 minutes, preferably about 45 minutes after the end of the second phase of administration as described above of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro- Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof.

The dosing regimen of the above embodiments relating to a first and a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln- Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof and the compound of formula I, or a pharmaceutically acceptable salt thereof, are usually administered to the subject on days 1 and 8 of a 21-day cycle administration. The administration of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys- Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof and of the compound of formula I, or a pharmaceutically acceptable salt thereof, may deviate by ± 1 day. Thus, administration might occur on day 1 or 2 and on day 7, 8 or 9 of a 21-day cycle administration.

In one embodiment the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject (e.g. a human) usually over about 1 to about 60 minutes, preferably over about 2 to about 30 minutes, more preferably over about 2 to about 10 minutes, most preferably over about 2 to about 5 minutes.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/kg, even more preferably of about 0.5 mg/kg, followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 3.5 to about 32 mg/kg followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m².

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 9 to about 32 mg/kg followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m².

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.2 to about 1 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m².

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m².

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m².

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10.5 to about 32 mg/kg followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m². In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10.5 to about 32 mg/kg followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m².

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll , or a pharmaceutically acceptable salt thereof, of about 5 mg/kg followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m².

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-

^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 10.5 mg/kg followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m².

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 16 mg/kg followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m².

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 22.5 mg/kg followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m².

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, followed by b) a second phase comprising infusion of a dose of of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro- Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 31.5 mg/kg followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m².

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/kg, even more preferably of about 0.5 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 3.5 to about 32 mg/kg for 2 and about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 9 to about 32 mg/kg for 2 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.2 to about 1 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg for 2 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg for 2 to about 6 hours, followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg for 2 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/kg, even more preferably of about 0.5 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 3.5 to about 32 mg/kg for 2 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes. In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 9 to about 32 mg/kg for 2 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.2 to about 1 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg for 2 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes. In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg for 2 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10 to about 32 mg/kg for 2 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m²mg/m², for 2 to about 10 minutes. In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll , or a pharmaceutically acceptable salt thereof, from about 10.5 to about 32 mg/kg for 2 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10.5 to about 32 mg/kg for 2 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes. In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.4 to about 0.6 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10.5 to about 32 mg/kg for 2 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysl , or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 10.5 to about 32 mg/kg for 2 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes. In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 5 mg/kg for about 2 to about 6 hours. c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 10.5 mg/kg for about 3.5 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes. In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 16 mg/kg for about 3.5 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 22.5 mg/kg for about 3.5 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes. In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hours followed by b) a second phase comprising infusion of a dose of of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro- Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 31.5 mg/kg for about 3.5 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In one embodiment the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject about 30 to about 60 minutes, preferably about 45 minutes after the end of the second phase of administration as described above of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof.

The dosing regimen of the above embodiments relating to a first and a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln- Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof and a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, are usually administered to the subject on days 1 and 8 of a 21-day cycle administration. The administration of cyclo(-Tyr- His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof and of the compound of formula I, or a pharmaceutically acceptable salt thereof, may deviate by ± 1 day. Thus, administration might occur on day 1 or 2 and on day 7, 8 or 9 of a 21-day cycle administration.

An exemplary treatment regimen entails administration once daily, twice daily, three times daily, every day, every second day, every third day, every fourth day, every fifth day, every sixth day, twice per week, once per week. The combination of the invention is usually administered on multiple occasions. Intervals between single dosages can be, for example, less than a day, a day, two days, three days, four days, five days, six days or a week. The combination of the invention may be given as a continous uninterrupted treatment. The combination of the invention may also be given in a regimen in which the subject receives cycles of treatment (administration cycles) interrupted by a drug holiday or period of nontreatment. Thus, the combination of the invention may be administered according to the selected intervals above for a continuous period of one week or a part thereof, for two weeks, for three weeks for four weeks, for five weeks or for six weeks and then stopped for a period of one week, or a part thereof, for two weeks, for three weeks, for four weeks, for five weeks, or for six weeks or for even more weeks. The combination of the treatment interval and the non-treatment interval is called a cycle. The cycle may be repeated one or more times. Two or more different cycles may be used in combination for repeating the treatment one or more times. A preferred administration cycle in the methods of the present invention is a period of three weeks i.e. a 21-day cycle. In one embodiment, the cycle is repeated one or more times, usually one, two, three, for, five, six, seven, eight , nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or twenty one times, preferably at least two, at least three, at least four, at least five, at least six seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, at least twenty or at least twenty one times, more preferably at least two times. In a particular preferred embodiment the cycle is repeated at least two times, so that the treatment comprises at least three 21-day cycles. In a further aspect the present invention provides a pharmaceutical combination comprising:

(a) a compound of formula I

(c) one or more pharmaceutically acceptable diluents, excipients or carriers, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose from about 0.1 to about 10 mg/m² and cyclo(-Tyr- His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered at a dose from about 11 to about 32 mg/kg.

Doses of the compound of formula I, or a pharmaceutically acceptable salt thereof,, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, respectively, administered to the subject, are as mentioned above.

In a further aspect the present invention provides a pharmaceutical combination comprising:

(a) a compound of formula I

(c) one or more pharmaceutically acceptable diluents, excipients or carriers, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, wherein cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/kg, even more preferably of about 0.5 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 3.5 to about 32 mg/kg for 2 to about 6 hours.

In some embodiments relating to this aspect the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 9 to about 32 mg/kg for about 2 to about 6 hours.

In some embodiments relating to this aspect the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 5 mg/kg for about 2 to about 6 hours. In some embodiments relating to this aspect the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 10.5 mg/kg for about 3.5 to about 6 hours.

In some embodiments relating to this aspect the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 16 mg/kg for about 3.5 to about 6 hours.

In some embodiments relating to this aspect the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 22.5 mg/kg for about 3.5 to about 6 hours.

In some embodiments relating to this aspect the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 31.5 mg/kg for about 3.5 to about 6 hours.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, preferably from about 0.2 to about 1 mg/kg, more preferably from about 0.4 to about 0.6 mg/kg, even more preferably of about 0.5 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 3.5 to about 32 mg/kg for 0.5 to about 4 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof,, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In one embodiment the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 9 to about 32 mg/kg for 0.5 to about 4 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for between about 2 to about 10 minutes.

In some embodiments relating to this aspect the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 5 mg/kg for about 2 to about 6 hours. c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof,, from about 0.5 to about 1.5mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In some embodiments relating to this aspect the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 10.5 mg/kg for about 3.5 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In some embodiments relating to this aspect the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 16 mg/kg for about 3.5 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5 mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In some embodiments relating to this aspect the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 22.5 mg/kg for about 3.5 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

In some embodiments relating to this aspect the cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, and the compound of formula I, or a pharmaceutically acceptable salt thereof, are administered in a dosing regimen comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hours followed by b) a second phase comprising infusion of a dose of of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro- Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll , or a pharmaceutically acceptable salt thereof, of about 31.5 mg/kg for about 3.5 to about 6 hours followed by c) a third phase comprising infusion of a dose of the compound of formula I, or a pharmaceutically acceptable salt thereof, from about 0.5 to about 1.5mg/m², preferably about 0.6 mg/m², about 1.1 mg/m² or about 1.2 mg/m², for 2 to about 10 minutes.

Additonal combination therapies

Provided herein are also methods of treatment in which the compound of formula I, or a pharmaceutically acceptable salt thereof, in combination with cyclo(-Tyr-His-Ala-Cys-Ser-Ala- ^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered to a subject (e.g. a human) in additional combination with one or more additional therapies. Thus, in some embodiments, the method for treating cancer in a subject (e.g. a human), comprises administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, together with one or more additional therapies, which can be useful for treating the cancer. The one or more additional therapies may involve the administration of one or more therapeutic agents, preferably therapeutic anticancer agents.

Examples

The present examples are intended to illustrate the present invention without restricting it.

Example 1

For patients with pretreated unresectable locally advanced (LA) or metastatic, HER2- negative breast cancer (BC) who have failed at least one chemotherapeutic regimen for advanced breast cancer, current treatment options are modestly effective. More therapeutic options with demonstrable improvement in clinical outcomes without the addition of significant, cumulative toxicity are strongly needed.

Balixafortide, a potent and highly selective antagonist of the CXCR4, a key molecule involved in tumor growth and metastasis, in combination with eribulin — a highly potent anticancer agent approved for use in pretreated metastatic breast cancer (MBC) — produced a higher response rate (RR) than published data for eribulin alone in a similar patient population when administered at a dose of 5.5 mg/kg on days 1-3 and 8-10 in a 21-day cycle. However, this dose regimen is inconvenient, time consuming, and cumbersome.

In a study of healthy hematopoietic stem cell (HSC) donors, all doses of balixafortide were assessed as well tolerated.

A total of 54 adverse events (AEs) was reported during treatment with balixafortide by 22/27 (81.5%) treated subjects. There were no severe adverse events). No subjects were withdrawn from the study or from study treatment prematurely.

The most common infusion-related reactions (IRR) which started at doses of 1 mg/kg balixafortide and were seen in all six volunteers/donors receiving 2 mg/kg of balixafortide by continuous infusion. These events included erythema, pruritus, hypoesthesia, flushing, and urticaria which were mostly confined to head and torso. The majority of these events were of mild intensity and symptoms resolved within minutes after intravenous (IV) administration of anti-histaminergic agents (50 mg ranitidine, or 2 mg clemastin).

The ESMO Guideline on Infusion Reactions of 2017 (S. Rosello, I. Blasco, L. Garcia Fabregat, A. Cervantes and K. Jordan, on behalf of the ESMO Guidelines Committee: Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines, Annals of Oncology 28 [Supplement 4], ivl00-ivll8; 2017doi: 10.1093/annonc/mdx216) states: signs and symptoms of infusion-related reactions (IRR) vary from patient to patient. Typical IRR manifestations include mucocutaneous symptoms in up to 90% of patients (flushing, urticaria, pruritus), respiratory in 40% (wheezing), circulatory in 30%-35% (hypotension) and abdominal symptoms (nausea, vomiting, cramps, diarrhea), minutes to hours after exposure to the drug.

The IRR observed with balixafortide at the therapeutic dose of 5.5 mg/kg are mainly localized at the infusion site and of mild to moderate nature. The most common occurring adverse events reported to have occurred in conjunction with an IRR are, e.g., acute infusion related reactions, injection site erythema, injection site pain, injection site pruritus, scalppruritus, whole body-pruritus, rash, rash at the chest, rash on the extremities, anaphylactoid skin reactions, flushing, facial edema, tight throat, tight upper chest wall, dyspnea, bronchospasm, edema, sensation of warmth, perioral numbness, paresthesia, "periorbital"- headache and urticaria (incl. large body surface areas).

Description of the study

This is a multicenter Phase lb/ll, open-label, dose-escalation study to optimize balixafortide in combination with eribulin in patients with locally recurrent or metastatic HER2-negative BC.

Inclusion criteria for phase lb

Eribulin-Balixafortide combination:

• Female patients, age > 18 years, with HER2-negative advanced breast cancer (ABC) and any estrogen receptor (ER)/progesteron receptor (PgR) status who have previously received at least 1 and up to 3 chemotherapeutic regimens for the treatment of locally recurrent or metastatic BC. Unless contra-indicated for safety reasons, prior therapy should have included an anthracycline and/or a taxane in either the adjuvant or metastatic setting.

HER2-negative advanced breast cancer should include locally advanced stages IIIB/C or metastatic stage IV disease by American Joint Committee on Cancer (AJCC) criteria (8th edition).

Prior therapies should have included at least 1 but no more than 3 prior chemotherapy-based lines of treatment for advanced or metastatic disease.

• Patients who are hormone receptor-positive (HR+) (ER+ and/or PgR+) should have received at least one line of hormonal therapy, unless contraindicated.

• (Neo)adjuvant chemotherapy will be considered as one prior regimen for advanced disease, if the development of unresectable locally recurrent or metastatic disease occurred within 12-months after completion of prior (neo)adjuvant therapy.

• Evidence of either measurable or evaluable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v.) 1.1 is mandatory, with at least one site of disease amenable to biopsy.

Inclusion criteriea for phase II

Eribulin-Balixafortide combination:

• Female patients, age > 18 years, with HER2-negative ABC and any ER/PgR status who have previously received at least 1 and up to 2 chemotherapeutic regimens for the treatment of locally recurrent or metastatic BC. Unless contra-indicated for safety reasons, prior therapy will have included an anthracycline and/or a taxane in either the adjuvant or metastatic setting.

Prior therapies should have included at least 1 but no more than 2 prior chemotherapy-based lines of treatment for advanced or metastatic disease.

• Patients who are HR+ (ER+ and/or PgR+), should have received at least one line of hormonal therapy and CDK4/6 inhibitors, unless contraindicated or not accessible.

• (Neo)adjuvant chemotherapy is considered as one prior regimen for advanced disease, if the development of unresectable locally advanced or metastatic disease occurred within 12-months after completion of prior (neo)adjuvant therapy. • Evidence of either measurable or evaluable disease as per RECIST v.1.1 is mandatory, with at least one site of disease amenable to biopsy.

The study has 2 parts: a phase Ib-part and a phase ll-part.

Part I of the study (Phase lb)

This is a modified 3+3 design, open label and dose escalation part. After signing informed consent form (ICF) and confirmed eligibility, patients will be assigned to receive eribulin in combination with balixafortide based on local investigator assessment and slots availability. Patients will be enrolled in groups of 3.

The dose escalation scheme illustrating the stepwise dose increases of balixafortide is described below.

Balixafortide + eribulin

Patients will be treated on 21-day cycles.

Patients will be administered a fixed eribulin dose of 1.23 mg/m² (equivalent to 1.4 mg/m² eribulin mesylate) combined with increasing doses of balixafortide starting at a dose of 5.5 mg/kg. Both drugs will be administered on day 1 and 8 of each 21-day cycle (+/- 1 day), see table below.

Balixafortide will be administered intravenously (IV) following a biphasic regimen (4.5% of balixafortide dose during the first 30 minutes of treatment, 95.5% of balixafortide dose during the following 3 hours and 30 minutes for a total of 4 hours; e.g. a balixafortide dose of 11 mg/kg will be administered as follow: 0,5 mg/ kg during the first 30 minutes and the remaining 10.5 mg/kg during the following 3 hours and 30 minutes.

Eribulin will be both administered IV over 2 to 5 minutes. Up to 4 additional cohorts (balixafortide dose: 11 mg/kg, 16.5 mg/kg, 23 mg/kg, 32 mg/kg) are to be introduced to evaluate and establish the optimum exposure of balixafortide combined with eribulin, see table below.

Part II of the study (Phase II)

After signing IGF and confirmed eligibility, patients will receive the combination of eribulin and balixafortide.

Balixafortide + eribulin

Maximum tolerated dose (MTD)/ recommended dose for the phase II (RDP2) balixafortide (from phase lb) will be administered over 4-hour IV infusion (biphasic regimen as detailed above/ phase lb) followed by 1.4 mg/m² eribulin over 5 minutes IV infusion on days 1 and 8 in 21-day cycles (+/- 1 day).

Though the dose of eribulin is expected to be the same during the phase lb and phase II part of the study, it could be adjusted in response to safety observations during phase lb of the study and in line with the instructions for dose adjustment given in the eribulin summary of product characteristics (SmPC).

All patients will receive treatment until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason.

Claims

1) A pharmaceutical combination comprising:

(a) a compound of formula I

(c) one or more pharmaceutically acceptable diluents, excipients or carriers, for use in a method for the prevention, delay of progression or treatment of cancer in a subject, wherein each of the compound of formula I or a pharmaceutically acceptable salt thereof and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is independently administered to the subject on days 1 and 8 of a 21-day cycle administration. 2) A pharmaceutical combination for use according to claim 1, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered to the subject at a dose from about 0.1 to about 10 mg/m² and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose from about 5.5 to about 32 mg/kg.

3) A pharmaceutical combination for use according to claim 1 or 2, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose from about 0.5 to about 1.5 mg/m² and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dose from about 11 to about 32 mg/kg.

4) A pharmaceutical combination for use according to claim 1, wherein cyclo(-Tyr-His-Ala- Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 3.5 to about 32 mg/kg

5) A pharmaceutical combination for use according to claim 1, wherein cyclo(-Tyr-His-Ala- Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 3.5 to about 32 mg/kg for about 2 to about 6 hours.

6) A pharmaceutical combination for use according to claim 1, wherein cyclo(-Tyr-His-Ala- Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 0.1 to about 2 mg/kg, for less than 1 hour followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, from about 9 to about 32 mg/kg for about 2 to about 6 hours.

7) A pharmaceutical combination for use according to claim 1, wherein cyclo(-Tyr-His-Ala- Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 5 mg/kg for about 2 to about 6 hours. 8) A pharmaceutical combination for use according to claim 1, wherein cyclo(-Tyr-His-Ala- Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 10.5 mg/kg for about 3.5 to about 6 hours.

9) A pharmaceutical combination for use according to claim 1, wherein cyclo(-Tyr-His-Ala- Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 16 mg/kg for about 3.5 to about 6 hours.

10) A pharmaceutical combination for use according to claim 1, wherein cyclo(-Tyr-His-Ala- Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 22.5 mg/kg for about 3.5 to about 6 hours.

11) A pharmaceutical combination for use according to claim 1, wherein cyclo(-Tyr-His-Ala- Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is administered in a dosing regime comprising: a) a first phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg- Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 0.5 mg/kg, for about 0.5 hours followed by b) a second phase comprising infusion of a dose of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab- Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, of about 31.5 mg/kg for about 3.5 to about 6 hours.

12) A pharmaceutical combination according to any one of claims 1 to 11, wherein cyclo(- Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll, or a pharmaceutically acceptable salt thereof, is the acetate salt of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-DPro-Pro-) having a disulfide bond between Cys4 and Cysll. 13) A pharmaceutical combination according to any one of claims 1 to 12, wherein said compound of formula I is the compound of formula la

formula la which has the chemical name 2-(3-amino-2-hydroxypropyl)hexacosahydro-3-methoxy-26- methyl-20, 27-bis(methylene)ll, 15-18, 21-24, 28-triepoxy-7,9-ethano-12,15-methano- 9/7,15/7-furo(3,2-/)furo(2',3'-5,6)pyrano(4,3-b)(l,4)dioxacyclopentacosin-5-(4/7)-one methanesulfonate.

14) A pharmaceutical combination for use according to any one of claims 1 to 13, wherein the cancer is breast cancer.

15) A pharmaceutical combination for use according to any one of claims 1 to 13, wherein the cancer is advanced breast cancer.

16) A pharmaceutical combination for use according to any one of claims 1 to 13, wherein the cancer is metastatic breast cancer.

17) A pharmaceutical combination for use according to any one of claims 1 to 13, wherein the cancer is locally advanced breast cancer. 18) A pharmaceutical combination for use according to any one of claims 1 to 17, wherein the administration to the subject of the compound of formula I or a pharmaceutically acceptable salt thereof and cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys- ^DPro-Pro-) having a disulfide bond between Cys4 and Cysll or a pharmaceutically acceptable salt thereof, starts with a 21-day cycle which is repeated at least two times.

19) A pharmaceutical combination for use according to any one of claims 1 to 18, wherein administration of the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject about 30 to about 60 minutes after the end of the administration of cyclo(-Tyr-His-Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysllor a pharmaceutically acceptable salt thereof.

20) A pharmaceutical combination for use according to any one of claims 1 to 19, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered about 1 to about 10 minutes .

21) A pharmaceutical combination for use according to any one of claims 1 to 20, wherein the compound of formula I or a pharmaceutically acceptable salt thereof and cyclo(-Tyr-His- Ala-Cys-Ser-Ala-^DPro-Dab-Arg-Tyr-Cys-Tyr-Gln-Lys-^DPro-Pro-) having a disulfide bond between Cys4 and Cysll or a pharmaceutically acceptable salt thereof, are administered to the subject intravenously.

22) A pharmaceutical combination for use according to any one of claims 1 to 21, wherein the subject who has cancer is (i) refractory to at least one chemotherapy treatment, or (ii) is in relapse after treatment with chemotherapy, or a combination thereof.