WO2005117833A2

WO2005117833A2 - Methods for dose selection of liposomal encapsulated sn38

Info

Publication number: WO2005117833A2
Application number: PCT/US2005/019834
Authority: WO
Inventors: James Hussey; Jeff Sherman; Stephen Wanaski; Stephen Gately
Original assignee: Neopharm, Inc.
Priority date: 2004-06-05
Filing date: 2005-06-06
Publication date: 2005-12-15
Also published as: WO2005117833A3

Abstract

The present invention is directed to methods for determining pharmaceutically effective amounts of a liposomal formulation containing SN-38 (LE-SN38) by detecting polymorphisms within a uridine diphosphate glucuronosyltransferase (UGT1A1) gene. In accordance with the inventive method, LE-SN38 is administered at dosages of up to about 35 mg/m2 for individuals having at least one wild-type copy of the UGT1A1 allele and at dosages between about 20 mg/m2 to about 35 mg/m2 for individuals with no wild type UGT1A1 allele, such as dosages between about 20 mg/m2 to about 30 mg/m2.

Description

METHODS FOR DOSE SELECTION OF LIPOSOMAL ENCAPSULATED SN38

CROSS REFERENCE TO RELATED PATENT APPLICATIONS

[0001] This application claims priority to United States Provisional Application No. 60/577,414 filed on June 5, 2004. The disclosure of this application is incorporated herein in its entirety by reference thereto.

FIELD OF THE INVENTION

[0002] This invention pertains to methods for determining and optimizing liposomal encapsulated SN38 (LE-SN38) drug dosages.

BACKGROUND OF THE INVENTION

[0003] The compound known as 7-ethyl-lO-hydroxycarnptothecin (SN38) and more formally as ((+)-(4S)-4,l l-diethyl-4,9-dihydroxy-lH-pyrano[3',4':6,7]-indolizino[l,2-b ]quinoline-3,14(4H,12H)-dione, first disclosed in U.S. Patent 4,473,692, is an active metabolite of irinotecan, a derivative of camptothecin.

[0004] The metabolic conversion of irinotecan to SN38 occurs primarily in the liver by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and a dipiperidino side chain. Subsequently, this derivative undergoes conjugation to form the glucuronide metabolite. The prodrug irinotecan is converted into its active moiety, SN38, with wide interpatient variability, due in part to differential expression of cellular carboxylesterases responsible for prodrug hydrolysis. Carboxylesterases, such as the enzyme UDP-glucuronosyltransferase (UGT), convert SN38 to its inactive metabolite, SN38 glucuronide (SN38G). Presence of polymoφhisms in the UGTIAI gene or its promoter, such as the UGTIAI *28 allele, can lead to decreased expression of the enzyme, which, in turn, decreases SN38 glucuronidation and is associated with increased risk of severe diarrhea and neutropenia following irinotecan administration (see, e.g., Ando et al., Cancer Res., 60, 6921-26 (2000); Iyer et al., Clin. Pharmacol. Ther., 65, 576-82 (1999); Iyer et al, Pharmacogenomics J., 2, 43-47 (2002); Innocenti et al., Proc. Am. Soc. Clin. Oncol., 22, 124 (Abstract 495 (2003)). SUMMARY OF THE INVENTION

[0005] The present invention is directed to methods for determining pharmaceutically effective amounts of a liposomal formulation containing SN-38 (LE-SN38) by detecting polymoφhisms within a uridine diphosphate glucuronosyltransferase (UGTIAI) gene. In accordance with the inventive method, LE-SN38 is administered at dosages of up to about 35 mg/m² for individuals having at least one wild- type copy of the UGTIAI allele and at dosages between about 20 mg/m² to about 35 mg/m², such as dosages between about 20 mg/m²and about 30 mg/m² , for individuals with no wild type UGTIAI allele. Advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Figure 1 presents data concerning the mean plasma concentrations of SN38 following infusion of LE-SN38 to cancer patients in Stratum A (WT/WT genotype).

[0007] Figure 2 presents data concerning the mean plasma concentrations of SN38 following infusion of LE-SN38 to cancer patients in Stratum B (WT/*28 genotype).

[0008] Figure 3 presents data concerning the mean plasma concentrations of SN38 following infusion of LE-SN38 to cancer patients in Stratum C (*28 /*28 genotype).

[0009] Figure 4 presents data concerning the mean plasma concentrations of SN38 following a 10 mg/m² infusion of LE-SN38 to cancer patients across Strata A (WT/WT),

B (WT/*28), and C (*28/*28).

[0010] Figure 5 presents data concerning the mean plasma concentrations of SN38 following 10 mg/m² infusion of LE-SN38 to cancer patients across Strata A (WT/WT), B

(WT/*28), and C (*28/*28), 0-48 hours.

[0011] Figure 6A presents data relating to the mean SN-38 AUC by dose level.

[0012] Figure 6B presents data comparing the area under the concentration curve

(AUC) levels of SN38 for the three different genotypes after administration of LE-SN38 at 10 mg/m² and 20 mg/m².

[0013] Figure 7 presents data concerning plasma SN-38 and SN-38G in UGTIAI

WT/WT (Stratum A) patients at 10.0 mg/m².

[0014] Figure 8 presents data concerning plasma SN-38 and SN-38G in UGT 1 A 1

WT/*28 (Stratum B) patients at 10.0 mg/m². [0015] Figure 9 presents data concerning plasma SN-38 and SN-38G in UGTIAI

*28/*28 (Stratum C) patients at 10.0 mg/m².

[0016] Figure 10 presents data demonstrating incidences of adverse events by dose level and severity in WT/WT Stratum A patients.

[0017] Figure 11 presents data demonstrating incidences of adverse events by dose level and severity in WT/*28 Stratum B patients.

[0018] Figure 12 presents data demonstrating incidences of adverse events by dose level and severity in * 28/* 28 Stratum B patients.

[0019] Figure 13 presents data demonstrating incidences of the six most frequent adverse events for the three different genotypes

DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention pertains to a method for treating a disease in a human patient by administering a pharmaceutically-acceptable liposomal formulation containing SN-38 (LE-SN38) to the patient. The LE-SN38 for use in the present invention can be any suitable formulation, such as formulations known to those of ordinary skill in the art. Suitable formulations for use in the present invention, and their manner of manufacture, are described in United States Patent Application 10/424,258 (Published on November 20, 2003 as United States Patent Publication 2003/0215492) and also International Patent Publication Nos. WO 02/058622, WO 2004/017940, and WO 2004/035032. These publications are incoφorated herein by reference.

[0021] Preferably, the LE-SN38 formulation for use in the invention contains, as one lipid constituent, cardiolipin. Also, preferably, at least about 90% of the SN-38 present in the formulation is encapsulated in the liposomes.

[0022] In accordance with the inventive method, the dosage of LE-SN38 is determined by assessing the genotype of the patient. Specifically, the patient is assessed to determine whether (s)he has at least one wild-type copy of the uridine diphosphate glucuronosyltransferase I (UGTIAI) gene or promoter. Most preferably, the patient is assessed to determine whether (s)he has at least one wild- type copy of the UGTIAI allele or is heterozygous for the UGTl Al *28 allele, or is homozygous for the UGTIAI *28 allele. [0023] Assessment of the genotype of the patient can be accomplished using any suitable method, such as those known to those of skill in the art. For example, genetic material from the patient (e.g., blood, oral epithelial tissue, saliva, hair, etc.) can be subjected to a standard PCR reaction to assess the polymoφhisms. United States Patent 6,395,481 discloses methods for assessing polymoφhisms in the UGTIAI allele that can be suitably employed in the context of the present inventive method. [0024] In accordance with the inventive method, homozygous UGTIAI polymoφhic individuals will typically receive a smaller dosage of LE-SN38 than heterozygotes or individuals homozygous for the wild-type allele. In some protocols, heterozygous individuals will receive less of a dose than patients homozygous for the wild-type allele. [0025] Preferably, in accordance with the inventive method, patients that have at least one wild- type copy of the UGTIAI allele are given a dose of LE-SN38 of up to about 35 mg/m². Individuals with no wild type UGTIAI allele are given a dose of LE-SN38 of between about 20 mg/m² to about 35 mg/m², such as dosages between about 20 mg/m²and about 30 mg/m².

[0026] In accordance with the inventive method, the LE-SN38 preferably is formulated for injection and is delivered to patients intravenously. However, the invention is not limited to such route of administration. The LE-SN38 can be thus administered over any suitable time course, but typically is delivered by continuous administration for more than about 10 minutes. Typically, the LE-SN38 is administered by continuous intravenous injection over a period of between about 30 minutes and about 120 minutes, and preferably about 90 minutes.

[0027] Preferably, the dosage of LE-SN38 is administered to the patient by intravenous delivery over about a 90 minute period once in a single day. However, it is desired for this treatment to be repeated, such as every day for a treatment period, or every other day, or every third day, or otherwise as deemed suitable. Most preferably, the treatment is repeated daily for a period of about 21 days, but this period can be longer or shorter as desired. For example, some patients can be treated in accordance with the inventive method daily for a period of at least one week (and more preferably for at least two weeks). Other patients can be treated for longer than about 21 days, such as for at least about four weeks or even for at least about six weeks. [0028] The inventive method can be used to treat patients having diseases that can be treated with camptothecins, and especially SN-38. Thus, the inventive method can be used to treat patients suffering from diseases such as cancer, viral infections, or multiple sclerosis. Typically, the inventive method is used to treat patients suffering from cancers such as lung cancers (especially non-small cell lung cancer), breast cancers, testicular cancers, ovarian cancers, gastrointestinal cancers (e.g., colon, rectal, pancreatic, gastric cancers, and the like), hepatocellular carcinoma, head and neck cancers, prostate cancers, renal cell carcinoma, adenocarcinomas, sarcomas, lymphomas, leukemias, mycosis fugoides, melanomas, gliomas (especially high grade gliomas), glioblastomas, brain cancers, and the like. Such cancers can manifest as solid tumors or metastatic cancer. [0029] The inventive method can be used by itself or in conjunction with other therapeutic regimens. Thus, for example, for treatment of viral infection, the inventive method can be used in conjunction (or adjunctively) with antiviral agents. Furthermore, for treatment of cancers, the inventive method can be used in conjunction (or adjunctively) with other chemotherapeutic regimens or agents or in conjunction (or adjunctively) with radiation therapy. For adjunctive use, the inventive method can be used concurrently, prior to, or following the other treatment regimen, as desired. [0030] It is within the ordinary skill of the art to assess the effectiveness in giving the therapeutic treatment. For example, treatment of multiple sclerosis can be assessed by noting the retardation of the progression of the disease or its remission. Treatment of viral infection can be assessed by a decrease in viral load, circulating antibodies to the virus in question, or a decrease in the symptoms of viral infection. Treatment of cancers can be monitored by assessing stability of tumor growth (for example, using radiography).

[0031] It should be noted that the inventive method need not result in a complete cure or remission of the disease (e.g., cancer) within the patient to be shown to be successfully employed. Thus, for example, the method can be successfully employed if, by using the inventive method, the progress of the disease is slowed or retarded in the patient. Alternatively, the inventive method is deemed to have been used successfully in the treatment of the disease if, for adjunctive uses, the inventive composition renders the disease more amenable to other treatment or demonstrates an additive, but not necessarily synergistic, therapeutic potential as compared to monotherapy using the other treatment regimen (although in some embodiments, synergistic therapeutic potential can be achieved). However, in some embodiments, the inventive method can lead to remission or cure of cancer or other disease.

[0032] The following example further illustrates the invention, but it should not be taken as limiting its scope.

EXAMPLE 1

[0033] This example demonstrates the use of the inventive liposomal SN38 (LE-

SN38) formulations in the treatment of patients with advanced cancer.

[0034] A study was conducted to assess the maximum tolerated dose and f toxicity of liposomal SN38, to determine the pharmacokinetics of SN38 after administration of LE-

SN38, and to observe the antitumor effects of LE-SN38.

[0035] The LE-SN38 was prepared as described in International Patent Publication

WO 04/017940 by reconstitution with 5mL of lOmM lactate buffer and was stable for up to 8 hours refrigerated at 2-8 °C or at room temperature, 20-25 °C. After dilution with normal saline, LE-SN38 was administered intravenously over 90 minutes on day 1 of a

21 day cycle. The first cycle consisted of a pre-dose, 15 & 45 min after infusion start, end-of-infusion; and a post-infusion at 5, 15 & 30 min; 1, 2, 3, 4, 6, 8, 12 & 24 h; 2, 4, 7,

14 & 21 days.

[0036] Patients involved in the study were individuals with advanced solid tumors who had failed conventional therapy. These consisted of three strata according to genotype: Stratum A: Patients with UGTIAI wt allele (homozygous) Stratum B: Patients with UGTIAI *28 allele (heterozygous) Stratum C: Patients with UGTIAI *28 allele (homozygous)

[0037] Dosages of from 2.5 mg/m² to 40 mg/m² are employed in this study according to Table 1. Table 1

Starting dose level *28/*28 stratum *Final dose level *28/*28 stratum ^§MTD for WT/WT stratum ^πDLTs occurred in WT/WT stratum

[0038] A dose level of LE-SN38 had to be tolerated by Stratum A patients before enrollment began at that dose level for Stratum B patients, and a dose level LE-SN38 had to be tolerated by Stratum B patients before enrollment began at that dose level for Stratum C patients. There were between 3 and 7 patients/cohort/strata. Total plasma SN38 concentration and plasma SN38-glucoronide concentration were assessed for each patient. Tumor progression was monitored radiographically after every second cycle. [0039] It was determined that genotype frequencies, for the UGTA1 Al allele, are about 42.4% wt/wt, about 45.1% wt/*28, and about 10.9% *28/*28. [0040] Figure 1 presents data concerning mean plasma concentrations of SN38 following infusion of LE-SN38 to cancer patients in Stratum A (WT/WT genotype). Table 2 presents data concerning the pharmacokinetic parameters of SN38 after IV Infusion of LE-SN38 at 2.5, 5, 10, 20, 30, 35 and 40 mg/m² to patients with advanced cancer in Stratum A. Table 3 presents data concerning Mean (SD) SN38 C_max and AUC_0- _inf after CPT1 l^a administration or after LE-SN38 administration. Table 2 Mean PK Parameters of SN-38 After LE-SN38 Infusion

Table 3

[0041] For Stratum B (WT/*28 genotype), Figure 2 presents data concerning mean plasma concentrations of SN38 following infusion of LE-SN38 to cancer patients. In addition, Table 2 presents data concerning the pharmacokinetic parameters of SN38 after IV infusion of LE-SN38, at 2.5, 5, 10, 20, 30, 35 and 40 mg/m², to Stratum B patients. [0042] For Stratum C (*28 /*28 genotype), Table 2 presents data concerning the pharmacokinetic parameters of SN38 after IV infusion of LE-SN38 at 10 mg m² and 20 mg/m², and Figure 3 presents data concerning mean plasma concentrations of SN38 following infusion of LE-SN38.

[0043] Figure 4 presents data concerning mean plasma concentrations of SN38 following 10 mg/m² infusion of LE-SN38 to cancer patients across Strata A (WT/WT), B (WT/*28), and C (*28/*28). Figure 5 presents data concerning the mean plasma concentrations of SN38 following 10 mg/m² infusion of LE-SN38 to cancer patients across Strata A (WT/WT), B (WT/*28), and C (*28/*28), 0-48 hours. Figure 6A presents data relating to the mean SN-38 AUC by dose level. Figure 6B presents data comparing the area under the concentration curve (AUC) levels of SN38 for different genotypes after administration of LE-SN38 at 10 mg/m² and 20 mg/m². Figure 7 presents data concerning plasma SN-38 and SN-38G in UGTIAI wild-type (Stratum A) patients at 10.0 mg/m². Figure 8 presents data concerning plasma SN-38 and SN-38G in UGTIAI wild-type/*28 (Stratum B) patients at 10.0 mg/m². Figure 9 presents data concerning plasma SN-38 and SN-38G in UGTIAI *28/*28 (Stratum C) patients at 10.0 mg/m². [0044] Incidences of adverse events with a grade greater than or equal to three for Stratum A, B and C patients are presented in Table 4. Incidences of adverse events by dose level and severity for Stratum A, B and C are presented in Figures 10, 11 and 12 respectively. Incidences of the most frequent adverse events, regardless of attribution, are presented in Figure 13. Furthermore, incidences of dose limiting toxicities are presented in Table 5. Table 4 Grade > 3 Adverse Events Related to Study Drug WT/WT WT/*28 *28/*28 Adverse Event (n=34) (n=35) (n=6) Gr 3 Gr 4 Gr 5 Gr 3 Gr 4 Gr 3 Hematologic Neutropenia 2 3 - 2 - Febrile Neutropenia - 2* - - - Anemia , 2 - - 1 - Leukopenia - - - 1 - Gastrointestinal Diarrhea 1 - - 1 - Vomiting 1 - - 1 - Other Anorexia 2 - - - - Fatigue 2 - - - - Asthenia 1 - - - - Hypokalaemia - - - - 1 Increased ALP Levels - - - 1 - Exertional Dyspnea⁵¹ - - 1 - -

*Each adverse event is attributed to a given patient only once (at the maximum severity reported). ^Occurred in patient with underlying lung cancer at dose of 5 mg/m²; relationship to study drug uncertain.

Table 5

*Two DLTs in patients with <3 prior chemotherapy regimens

*One patient received 9 prior treatment regimens; revised protocol limited prior treatment to <3 regimens

[0045] From this study, it has been observed that LE-SN38 is well tolerated for both UGTIAI WT/WT and WT*/28 patients at 35 mg/m². Across all genotypes, the most frequent adverse effects were fatigue, nausea, anorexia, diarrhea, and vomiting. Importantly, diarrhea was generally mild and self-limiting, and no late onset diarrhea was reported. Dose limiting toxicity of neutropenia/febrile neutropenia in WT/WT patients at 40 mg/m² resulted in a MTD of 35 mg/m². ^x

[0046] The PK profiles are similar for UGT 1 A 1 wt/wt and UGT 1 A 1 wt/*28 patients. Drug pharmacokinetic parameters appeared to be linear over the doses assessed. At the 10 mg/m² LE-SN38 dose level, greatest SN-38 systemic exposure occurred in homozygous variant patients. For 28*/28* patients, PK results showed 2-3 fold greater drug exposure that WT/*28 or WT/WT patients at the same doses. Thus, the preferred MTD for 28*/28* patients is between about 20 mg/m² to about 35 mg/m², such as dosages between about 20 mg/m²and about 30 mg/m².

[0047] Stable disease (4 or more cycles of treatment) was observed in approximately 36% of the patients in this study (Table 6).

Table 6 Stable Progressive Disease* Disease T/WT 15 19 WT/*28 10 25 *28/*28 2 4 27 48 Total (36%) (64%) *Received >4 cycles of treatment [0048] All references, including publications, patent applications, and patents, cited herein are hereby incoφorated by reference to the same extent as if each reference were individually and specifically indicated to be incoφorated by reference and were set forth in its entirety herein.

[0049] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incoφorated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0050] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

WHAT IS CLAIMED IS: 1. A method for treating a disease in a human patient having at least one wild- type copy of the UGTIAI allele, the method comprising administering a pharmaceutically-acceptable liposomal formulation containing SN-38 (LE-SN38), wherein the formulation is administered to the patient so as to provide a dosage of SN-38 of up to about 35 mg/m².

2. The method of claim 1, wherein the dosage is between about 30 mg/m² and about 35 mg/m².

3. The method of claim 1, wherein the dosage is about 35 mg/m².

4. The method of any of claims 1 -3, wherein the patient experiences no dose limiting adverse events subsequent to the administration of the liposomal formulation containing SN-38.

5. The method of claim 4, wherein the adverse event is selected from a group consisting of diarrhea, neutropenia and combination thereof.

6. A method for treating disease in a human patient not having a wild-type UGTIAI allele, the method comprising administering a pharmaceutically-acceptable liposomal formulation containing SN-38 (LE-SN38), wherein the formulation is administered to the patient so as to provide a dosage of SN-38 between about 20 mg/m² and about 35 mg/m².

7. The method of claim 6, wherein the dosage is between about 20 mg/m² to about 30 mg/m².

8. The method of any of claims 6-7, wherein the patient is homozygous for the UGTl A 1*28 allele.

9. The method of any of claims 6-8, wherein the patient experiences no dose limiting adverse events subsequent to the administration of the liposomal formulation containing SN-38.

10. The method of claim 9, wherein the adverse event is selected from a group consisting of diarrhea, neutropenia and combination thereof.

11. The method of any of claims 1-10, wherein the LE-SN38 is administered to said patient intravenously.

12. The method of claim 11, wherein the LE-SN38 is administered to said patient by continuous intravenous injection for a period of between about 30 and about 120 minutes.

13. The method of claim 12, wherein the LE-SN38 is administered to said patient over a period of about 90 minutes.

14. The method of any of claims 1-13, wherein the treatment is repeated.

15. The method of claim 14, wherein the treatment is repeated each day.

16. The method of claim 15, wherein the treatment is repeated for at least about 21 consecutive days.

17. The method of any of claims 1-16, wherein the disease is a cancer, a viral infection, or multiple sclerosis.

18. The method of claim 17, wherein the cancer is selected from a group consisting of lung cancer; a breast cancer; a testicular cancer; an ovarian cancer; a gastrointestinal cancers, hepatocellular carcinoma; a head and neck cancer; a prostate cancer; a renal cell carcinoma; an adenocarcinoma; a sarcoma; a lymphoma; a leukemia; mycosis fugoides; a melanoma; a high grade glioma, a glioblastoma, and brain cancer.

19. The method of claim 18, wherein the lung cancer is non-small cell lung cancer.

20. The method of claim 18, wherein the gastrointestinal cancer is selected from a group consisting of colon, rectal, pancreatic, and gastric cancers.