WO2013192367A1

WO2013192367A1 - Neuroendocrine tumor treatment

Info

Publication number: WO2013192367A1
Application number: PCT/US2013/046690
Authority: WO
Inventors: Samit Hirawat; Alessandro Riva
Original assignee: Novartis Ag
Priority date: 2012-06-22
Filing date: 2013-06-20
Publication date: 2013-12-27
Also published as: TW201402120A

Abstract

A method for treating a neuroendocrine tumor, particularly pancreatic neuroendocrine tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with at least one therapeutic agent, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor; uses of said compounds for the preparation of a medicament for use in the treatment of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor; uses of said compound for treating said disease; and related pharmaceutical compositions and pharmaceutical package thereof.

Description

Case 55171A

Neuroendocrine tumor treatment

Field of the Invention

The present invention relates to a method for treating a neuroendocrine tumor, particularly pancreatic neuroendocrine tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with at least one therapeutic agent, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor; uses of said compounds for the preparation of a medicament for use in the treatment of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor; uses of said compound for treating said disease; and related pharmaceutical compositions and pharmaceutical package thereof.

Background of the Invention

Neuroendocrine tumors (NET) are a heterogeneous group of malignancies that can arise from neuroendocrine cells throughout the body. These tumors are classically divided into two groups: functioning (secreting hormones resulting in symptoms) and non-functioning (non- secreting). An annual incidence of neuroendocrine tumors in the United States is 5.25 cases per 100,000 population. The overall incidence of this disease appears to be increasing, probably due to improved diagnostic techniques (Howlader et al, J. Natl Cancer Inst. 102(20): 1584-98 (Oct 20, 2010)).

Pancreatic NET (pNET) specifically arises from the pancreatic islets of Langerhans and is a rare malignancy. pNETs constitute a distinct subgroup of NETs characterized by a different genetic profile, more aggressive clinical evolution, and a different pattern of response to cytotoxic chemotherapy. The overall incidence of pNET is less than 1 case per 100,000 per year and it accounts for 9% of all NETs. Pancreatic NET accounts for less than 2% of all digestive malignant tumors and less than 1 % of endocrine tumors. Since pNET can initially be slow- growing and indolent, patients tend to present for treatment at a late stage with advanced disease. At least 60% of patients present with liver metastases, and the most common cause of death in patients with pNET is hepatic failure. Advanced (unresectable or metastatic) pNETs are incurable with a median overall survival (OS) reported to be between 17 and 24 months from the time of diagnosis (Halfdanarson et al., Ann Oncol. 19(10):1727-33 (Oct 2008), Yao et al., J. Clin. Oncol. 26(18): 3063-72 (June 20, 2008a)). The phosphatidylinositol 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathway plays a central role in cell metabolism. PI3K is activated by growth factors, cytokines, and other stimulatory factors in association with their receptors. Activated PI3K in turn initiates signaling transduction to Akt-mTOR and leads to regulation of cell growth, proliferation, and apoptosis. mTOR modulates translation of specific mRNAs via the regulation of the phosphorylation state of several different translation proteins, mainly 4E-PB1 , P70S6K (p70S6 kinase 1 ) and eEF2. Dysregulation of the PI3K/ mTOR pathway is widely seen in different types of human cancers, including neuroendocrine tumors.

Patients suffering from pNET have limited options for treatment. The only curative treatment option is complete surgical resection in regional or localized disease. Cytotoxic treatment has been the standard of care for advanced pNET, but is of limited value for the treatment of low proliferating NETs (Oberg and Jelic, Ann. Oncol., 20 Suppl. 4: 150-3 (May 2009)). There is no established treatment for pNET after chemotherapy failure at this time.

Everolimus, an mTOR inhibitor also known as Afinitor®, has been recently approved by FDA and EMA for the treatment of advanced pNET based on the RADIANT-3 study. Although everolimus provides clinical benefit for patients with pNET, both de novo and acquired resistance to this agent exists. There continues to be a need for treatment for patients suffering from neuroendocrine tumors, particularly pancreatic neuroendocrine tumors, resistant or refractory to treatment with at least one mTOR inhibitor.

It is now found that the dual phosphatidylinositol 3-kinase inhibitor and mTOR inhibitor compound of formula (I) or a pharmaceutically acceptable salt thereof is effective for the treatment of a neuroendocrine tumor, particularly pancreatic neuroendocrine tumor, resistant to treatment with at least one mTOR inhibitor.

Summary of the Invention

The present invention relates to a method for treating a neuroendocrine tumor comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with at least one additional therapeutic compound, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor. The present invention further relates to a method for inhibiting growth of a neuroendocrine tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to a method for inducing neuroendocrine tumor regression, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to a method for preventing metastatic spread of neuroendocrine tumors or for preventing or inhibiting growth of micrometastasis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to the use of compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to the use of compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in inhibiting growth of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to the use of compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in inducing regression of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to the use of compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in preventing metastatic spread of neuroendocrine tumors or for preventing or inhibiting growth of micrometastasis, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to the use of compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to the use of compound of formula (I) or a pharmaceutically acceptable salt thereof for inhibiting growth of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to the use of compound of formula (I) or a pharmaceutically acceptable salt thereof for inducing regression of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to the use of compound of formula (I) or a pharmaceutically acceptable salt thereof for preventing metastatic spread of neuroendocrine tumors or for preventing or inhibiting growth of micrometastasis, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to any of the methods or uses above wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered or used in combination with at least one additional therapeutic compound,

The present invention further relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with at least one pharmaceutically acceptable excipient for use in the treatment of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to a pharmaceutical package comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and instructions for administration for the treatment of a neuroendocrine tumor, particularly pNET, resistant or refractory to treatment with at least one mTOR inhibitor; Detailed Description of the Invention

The present invention relates to a method for treating a neuroendocrine tumor comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with at least one additional therapeutic compound, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor.

The general terms used herein are defined with the following meanings, unless explicitly stated otherwise:

The terms "comprising" and "including" are used herein in their open-ended and non- limiting sense unless otherwise noted.

The terms "a" and "an" and "the" and similar references 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. Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.

The term "a phosphatidylinositol 3-kinase inhibitor" or "PI3K inhibitor" is defined herein to refer to a compound which targets, decreases or inhibits PI 3-kinase. PI 3-kinase activity has been shown to increase in response to a number of hormonal and growth factor stimuli, including insulin, platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, colony-stimulating factor, and hepatocyte growth factor, and has been implicated in processes related to cellular growth and transformation.

The term "mammalian target of rapamycin inhibitor" or "mTOR inhibitor" is defined herein to refer to compounds which target, decrease or inhibit the activity/function of mammalian target of rapamycin (mTOR) kinase. The term "pharmaceutical composition" is defined herein to refer to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human, in order to prevent or treat a particular disease or condition affecting the subject thereof.

The term "pharmaceutically acceptable" is defined herein to refer to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues a subject, e.g., a mammal or human, without excessive toxicity, irritation allergic response and other problem complications commensurate with a reasonable benefit / risk ratio.

The term "treating" or "treatment" as used herein comprises a treatment relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a disease. For example, treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer. Within the meaning of the present invention, the term "treat" also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.

The term "prevent" or "preventing" as used herein includes the prevention of at least one symptom associated with or caused by the state, disease or disorder being prevented.

The term "pharmaceutically effective amount" of a combination of therapeutic agents is an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the disorder treated with the combination.

The term "subject" or "patient" as used herein includes animals, which are capable of suffering from or afflicted with at least one neuroendocrine tumor or any disorder involving, directly or indirectly, a neuroendocrine tumor. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits rats and transgenic non- human animals. In the preferred embodiment, the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from a neuroendocrine tumor. A "subject in need thereof" or "patient in need thereof" as hused herein includes a subject or patient suffering from or afflicted with the identified neuroendocrine tumor or any disorder involving, directly or indirectly, said neuroendocrine tumor. The term about" or "approximately" shall have the meaning of within 10%, more preferably within 5%, of a given value or range.

WO2006/122806 and WO2008/103636 describe imidazoquinoline derivatives, which have been found to inhibit the activity of phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR). Specific imidazoquinoline derivatives which are suitable for the present invention, their preparation and suitable pharmaceutical formulations containing the same are described in WO2006/122806 and WO2008/103636 and include compounds of formula (I)

wherein

R-i is naphthyl or phenyl wherein said phenyl is substituted by one or two substituents independently selected from the group consisting of Halogen; lower alkyl unsubstituted or substituted by halogen, cyano, imidazolyl or triazolyl; cycloalkyl; amino substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkyl sulfonyl, lower alkoxy and lower alkoxy lower alkylamino; piperazinyl unsubstituted or substituted by one or two substituents independently selected from the group consisting of lower alkyl and lower alkyl sulfonyl; 2-oxo-pyrrolidinyl; lower alkoxy lower alkyl; imidazolyl; pyrazolyl; and triazolyl;

R₂ is O or S;

R₃ is lower alkyl; R₄ is pyridyl unsubstituted or substituted by halogen, cyano, lower alkyl, lower alkoxy or piperazinyl unsubstituted or substituted by lower alkyl; pyrimidinyl unsubstituted or substituted by lower alkoxy; quinolinyl unsubstituted or substituted by halogen; or quinoxalinyl;

R₅ is hydrogen or halogen;

n is 0 or 1 ;

R₆ is oxido;

with the proviso that if n=1 , the N-atom bearing the radical R₆ has a positive charge; R₇ is hydrogen or amino.

The radicals and symbols as used in the definition of a compound of formula (I) have the meanings as disclosed in WO2006/122806 and WO2008/103636, which publications are both hereby incorporated into the present application by reference in its entirety, and include:

The prefix "lower" denotes a radical having up to and including a maximum of 7, especially up to and including a maximum of 4 carbon atoms, the radicals in question being either linear or branched with single or multiple branching.

Where the plural form is used for compounds, salts, and the like, this is taken to mean also a single compound, salt, or the like.

In a preferred embodiment, "alkyl" has up to a maximum of 12 carbon atoms and is especially lower alkyl.

"Lower alkyl" is preferably alkyl with from and including 1 up to and including 7, preferably from and including 1 to and including 4, and is linear or branched; preferably, lower alkyl is butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl, ethyl or preferably methyl.

"Cycloalkyl" is preferably cycloalkyl with from and including 3 up to and including 6 carbon atoms in the ring; cycloalkyl is preferably cyclopropyl, cyclobutyl , cyclopently or cyclohexyl.

"Alkyl which is substituted by halogen" is preferably perfluoro alkyl such as

trifluoromethyl. "Halogen" is especially fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine.

The compound of formula (I) may be present in the form of the free base or a

pharmaceutically acceptable salt thereof. Suitable salts of the compounds of formula (I) include those formed, for example, as acid addition salts, preferably with organic or inorganic acids. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, 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, malonic 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-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1 ,2-disulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, 2-naphthalenesulfonic acid, 1 ,5-naphthalene-disulfonic acid, 2- or 3-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.

Preferred compounds of formula (I) for use in the present invention are 2-methyl-2-[4-(3- methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile ("COMPOUND A") or its monotosylate salt and 8-(6-methoxy-pyridin-3-yl)-3-methyl-1 -(4- piperazin-1 -yl-3-trifluoromethyl-phenyl)-1 ,3-dihydro-imidazo[4,5-c]quinolin-2-one ("COMPOUND B"). The synthesis of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5- c]quinolin-1 -yl)-phenyl]-propionitrile and its monotosylate is for instance described in

WO2006/122806 as Examples 7 and 152-3 respectively. The synthesis of 8-(6-methoxy- pyridin-3-yl)-3-methyl-1 -(4-piperazin-1 -yl-3-trifluoromethyl-phenyl)-1 ,3-dihydro-imidazo[4,5- c]quinolin-2-one is for instance described in WO2006/122806 as Example 86. In a particularly preferred embodiment, the compound of formula (I) is 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin- 3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile ("COMPOUND A") or its monotosylate salt. In accordance with the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, alone or in combination with other therapeutic agents, is useful for the treatment of a neuroendocrine tumor, particularly pancreatic neuroendocrine tumor, which is resistant or refractory to treatment with at least one mTOR inhibitor.

Neuroendocrine tumors suitable for treatment in accordance with the present invention are those resistant or refractory to treatment at least one mTOR inhibitor (i.e, an mTOR inhibitor in the absence of a phosphatidylinositol-3-kinase (PI3K) inhibitor). Neuroendocrine tumors arise from neuroendocrine cell. If resistant or refractory to treatment with at least one mTOR inhibitor as singe agent, neuroendocrine tumors suitable for treatment in accordance with the present invention include, but not limited to, carcinoid tumors, pancreatic neuroendocrine tumors, pheochromocytoma, Merkel cell cancer, MEN1 , and MEN2. Preferably, the

neuroendocrine tumor is a carcinoid tumor or a pancreatic neuroendocrine tumor. Most preferably, the neuroendocrine tumor is a pancreatic neuroendocrine tumor.

Carcinoid tumors belong to the family of neuroendocrine tumors which derive from the neuroendocrine cell system. In the intestinal tract, these tumors develop deep in the mucosa, growing slowly and extending into the underlying submucosa and mucosal surface. This results in the formation of small firm nodules, which bulge into the intestinal lumen.

Carcinoid tumors have historically been classified, according to their point of origin in embryonic development, as arising from the foregut (e.g., bronchial, pulmonary or gastric carcinoid), midgut (e.g., small intestine or appendiceal carcinoid), or hindgut (e.g., rectal carcinoid), see e.g. Kulke M., Cancer Treatment Reviews 2003;29:363-370.

Primary foregut tumors e.g., bronchial, pulmonary or gastric carcinoids, e.g. including primary foregut tumors confined to the thymus, lung, stomach, and duodenum; e.g. carcinoid tumors of the Gl tract, e.g. located in the colon, stomach or small intestine, e.g. small-intestinal carcinoids,

Midgut carcinoids e.g., small intestine or appendiceal carcinoids, e.g. located in the distal ileum, cecum, and proximal colon, or

Hindgut tumors e.g, distal colon and rectal carcinoids. Data suggest that the incidence of pulmonary and gastric carcinoid has increased in the past two decades.

According to histopathologic criteria, carcinoids can be divided into typical (TC) and atypical (AC) carcinoids. Carcinoids can be placed in a spectrum of neuroendocrine tumors, ranging from low-grade malignant TC to intermediate AC to high-grade large-cell

neuroendocrine carcinoma and small-cell lung carcinoma.

Carcinoid lung tumors as indicated herein e.g. include neuroendocrine carcinoma, Kulchitsky cell carcinoma (KCC) (Kulchitsky cells, argentaffin cells), bronchial carcinoid tumors, bronchial adenomas, e.g. including bronchial adenomas such as a small cell carcinoma and large cell neuroendocrine tumors, typical carcinoids or atypical carcinoids associated with large bronchopulmonary carcinoid tumors or small-cell carcinomas, pulmonary carcinoids, neuroendocrine lung tumors, large-cell neuroendocrine carcinoma of the lung, (primary) pulmonary neoplasms, bronchopulmonary carcinoid tumors, lung neoplasms, lung cancers, pulmonary cancers, intrabronchial mass.

Typical carcinoid tumors of the lung represent the most well differentiated and least biologically aggressive type of pulmonary neuroendocrine tumor. These tumors

characteristically grow slowly and tend to metastasize infrequently. Atypical carcinoid tumors have a more aggressive histologic and clinical picture. They metastasize at a considerably higher rate than do typical carcinoid tumors. Carcinoid syndrome has been reported in association with very large bronchopulmonary carcinoid tumors or in the presence of metastatic disease. It is noted much less frequently in association with carcinoids of pulmonary origin than those originating within the gastrointestinal tract.

Large-cell neuroendocrine carcinoma of the lung is a newly recognized clinicopathologic entity, which is distinct from small-cell carcinoma and has a poor prognosis.

Bronchial carcinoid tumors belong to a group of neuroendocrine tumors, which cover a range of tumors ranging from bronchial carcinoid at one of the spectrum, with a small cell carcinoma, or possibly large cell neuroendocrine tumors at the other end. They demonstrate a wide range of clinical and biologic behaviors, including the potential to synthesize and secrete peptide hormones and neuroamines, particularly adrenocorticotropic hormone (ACTH), serotonin, somatostatin, and bradykinin. Bronchial carcinoid tumors (previously classified as bronchial adenomas) may originate from the neurosecretory cells of bronchial mucosa. Bronchial carcinoids are now classed as low-grade malignant neoplasms because of their potential to cause local invasion, their tendency for local recurrence, and their occasional metastases to extrathoracic sites.

Bronchial carcinoid tumors may arise from Kulchitsky cells (argentaffin cells) within the bronchial mucosa. The predominant distribution of cells are believed to occur at the bifurcation of the lobar bronchi. These cells are neurosecretory cells, which belong to the amine precursor uptake and decarboxylation (APUD) system. They have the capacity to synthesize serotonin (5- hydroxytryptamine), 5-hydroxytryptophan, ACTH, norepinephrine, bombesin, calcitonin, antidiuretic hormone (ADH), and bradykinin.

Carcinoid tumors of the Gl tract may display an aggressive biology similar to that of adenocarcinomas, particularly when they are located in the colon, stomach, and small intestine, see e.g. Modlin IM et al, Gastroenterology 2005; 128:1717-1751. For small-intestinal carcinoids, which are the most frequent cause of carcinoid syndrome due to metastatic disease in the liver, the incidence of metastasis increases proportionally with the size of the primary tumor

(Tomassetti et al 2001 , ibidem).

Carcinoid syndrome is caused by hypersecretion of numerous hormone products by the tumor cells, including kinins, prostaglandins, substance P, gastrin, corticotrophin and chromogranin A (see e.g. Davis et al, Gynecology & Obstetrics 1973;137:637-644). Various endocrine or neuroendocrine syndromes can be initial clinical manifestations of either typical or atypical pulmonary carcinoid tumors. Carcinoid syndrome, hypercortisolism and Cushing syndrome, inappropriate secretion of ADH, increased pigmentation secondary to excess MSH, and ectopic insulin production resulting in hypoglycemia are some of the endocrinopathies that can be produced by a pulmonary carcinoid tumor in a patient who is otherwise asymptomatic.

Pancreatic neuroendocrine tumors (islet cell tumors), which were formerly classified as

APUDomas (tumors of the amine precursor uptake and decarboxylation system), comprise less than half of all neuroendicrine tumors and only 1-2% of all pancreatic tumors. Pancreatic NETs can arise either in the pancreas (insulinomas, glucagonomas, nonfunctioning pancreatic NETs, pancreatic NETs causing hypercalcemia) or at both pancreatic and extrapancreatic sites (gastrinomas, VIPomas, somatostatinomas, GRFomas). The hormones secreted by pancreatic NETs depend upon the cell of origin and are physiologically involved in a network of autocrine, paracrine, endocrine and neurotransmitter communication. While hormone secretion is not observed in all cases of pancreatic NET, the apparently "nonfunctioning" (i.e., non-secreting) pancreatic NETs tend to be more aggressive and present with symptoms of tumor bulk (see e.g. Barakat et al, Endocrine-related cancer 2004;1 1 :1-18 and Tomassetti et al, Ann Oncol

2001 ; 12(Suppl 2):S95-S99).

Pancreatic neuroendocrine tumors as indicated herein e.g. include islet cell tumors, APUDomas, insulinomas, glucagonomas, nonfunctioning pancreatic NETs, pancreatic NETs associated with hypercalcemia, gastrinomas, VIPomas, somatostatinomas, GRFomas.

Further examples of neuroendocrine tumors include: pheochromocytoma, Merkel cell cancer, Multiple Endocrine Neoplasia Type 1 (MEN1 ), Multiple Endocrine Neoplasia Type 2 (MEN2).

Where hereinbefore and subsequently a tumor, a tumor disease, a carcinoma or a cancer is mentioned, also metastasis in the original organ or tissue and/or in any other location are implied alternatively or in addition, whatever the location of the tumor and/or metastasis is.

The compounds of the present invention are particularly useful for the treatment of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor. A tumor "resistant or refractory to treatment with at least one mTOR inhibitor" as used herein refers to a tumor that either fails to respond favorably to treatment with at least one compound which directly inhibits the mammalian target of rapaymycin (mTOR) kinase, or alternatively, recurs or relapses after responding favorably to treatment with at least one compound which directly inhibits the mammalian target of rapaymycin (mTOR) kinase. Said compound which directly inhibits the mammalian target of rapaymycin (mTOR) kinase (an MTOR inhibitor) in the absence of a PI3K inhibitor.

In this context of the neuroendocrine tumor "resistant or refractory to treatment with at least one mTOR inhibitor", absent PI3K inhibitors may include but are not limited to: 2-methyl-2- [4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile; 8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1 -yl-3-trifluoromethyl-phenyl)-1 ,3-dihydro- imidazo[4,5-c]quinolin-2-one, 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2- ylamine (described in WO 2007/084786); 4-[2-(1 H-lndazol-4-yl)-6-[[4-(methylsulfonyl)piperazin- 1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT Publication Nos. WO 09/036082 and WO 09/055730); Tozasertib (VX680 or MK-0457, CAS 639089-54-6); (5Z)-5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione (GSK1059615); (1 E,4S,4aR,5R,6aS,9aR)-5-(Acetyloxy)-1 -[(di-2-propenylamino)methylene]- 4,4a,5,6,6a,8,9,9a-octahydro-1 1 -hydroxy-4-(methoxymethyl)-4a,6a-dimethyl- cyclopenta[5,6]naphtho[1 ,2-c]pyran-2,7, 10(1 H)-trione (PX866); 8-Phenyl-2-(morpholin-4-yl)- chromen-4-one (LY294002); XL765; CAL101 ; and XL-147. The tumor may be resistant or refractory at the beginning of treatment or it may become resistant or refractory during treatment. In a preferred embodiment of the present invention, the tumor fails to respond, or alternatively, recurs or relapses after responding favorably to treatment either while on treatment with at least one mTOR inhibitor or within 3 months of treatment discontinuation.

Examples of mTOR inhibitor include, but is not limited to, compounds, proteins or antibodies which target/inhibit members of the mTOR kinase family, e.g., RAD, rapamycin (sirolimus) and derivatives/analogs thereof such as everolimus or RAD001. Sirolimus is also known by the name RAPAMUNE^®, and everolimus (or RAD001 ) by the name AFINITOR^®.

Other compounds, proteins or antibodies which target/inhibit members of the mTOR kinase family include CCI-779, ABT578, SAR543, and ascomycin which is an ethyl analog of FK506. Also included are AP23573 and AP23841 from Ariad. Further examples of mTOR inhibitors include, but not limited to, I. Rapamycin which is an immunosuppressive lactam macrolide that is produced by

Streptomyces hygroscopicus.

II. Rapamycin derivatives such as:

a. substituted rapamycin e.g. a 40-O-substituted rapamycin e.g. as described in US 5,258,389, WO 94/09010, WO 92/05179, US 5, 1 18,677, US 5, 1 18,678, US 5, 100,883, US 5,151 ,413, US 5,120,842, WO 93/1 1 130, WO 94/02136, WO 94/02485 and WO 95/14023 all of which are incorporated herein by reference;

b. a 16-O-substituted rapamycin e.g. as disclosed in WO 94/02136, WO 95/16691 and WO 96/41807, the contents of which are incorporated herein by reference; c. a 32-hydrogenated rapamycin e.g. as described in WO 96/41807 and US 5 256 790, incorporated herein by reference.

d. Preferred rapamycin derivatives are compounds of formula (II)

wherein

Ri is CH₃ or C_3-6alkynyl,

R₂ is H or -CH₂-CH₂-OH, 3-hydroxy-2-(hydroxymethyl)-2-methyl-propanoyl or tetrazolyl, and X is =0, (H,H) or (Η,ΟΗ)

provided that R₂ is other than H when X is =0 and R-i is CH₃,

or a prodrug thereof when R₂ is -CH₂-CH₂-OH, e.g. a physiologically hydrolysable ether thereof.

Compounds of formula (II) are disclosed e.g. in WO 94/09010, WO 95/16691 or WO 96/41807, which are incorporated herein by reference. They may be prepared as disclosed or by analogy to the procedures described in these reference. Preferred compounds are 32- deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S)-dihydro- rapamycin, 16-pent-2-ynyloxy-32(S)-dihydro-40-O-(2-hydroxyethyl)-rapamycin and, more preferably, 40-0-(2-hydroxyethyl)-rapamycin, disclosed as Example 8 in WO 94/09010.

Particularly preferred rapamycin derivatives of formula (II) are 40-O-(2-hydroxyethyl)-rapamycin, 40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]-rapamycin (also called CCI779), 40-epi- (tetrazolyl)-rapamycin (also called ABT578), 32-deoxorapamycin, 16-pent-2-ynyloxy-32(S)- dihydro rapamycin, or TAFA-93. e. Rapamycin derivatives also include so-called rapalogs, e.g. as disclosed in WO 98/02441 and WO 01/14387, e.g. AP23573, AP23464, or AP23841.

III. Ascomycin, which is an ethyl analog of FK506.

IV. AZD08055 and OSI127, which are compounds that inhibit the kinase activity of mTOR by directly binding to the ATP-binding cleft of the enzyme.

In a preferred embodiment, the mTOR inhibitor is everolimus (RAD001 ).

In a further preferred embodiment, the neuroendocrine tumor treated in accordance with the present invention is a carcinoid tumor or pancreatic NET (pNET) resistant or refractory to treatment with everolimus (RAD001 ) or a pharmaceutically acceptable salt thereof as single agent.

In a particularly preferred embodiment, the neuroendocrine tumor treated in accordance with the present invention is a pancreatic NET (pNET) resistant or refractory to treatment with everolimus (RAD001 ) or a pharmaceutically acceptable salt thereof as single agent.

To detect a neuroendocrine tumor resistant or refractory to at least one mTOR inhibitor, a patient undergoing initial treatment can be carefully monitored for signs of resistance, non- responsiveness, progressing or recurring tumors. This can be accomplished by monitoring the patient's tumor's response to the initial treatment with the mTOR inhibitor. The response, lack of response, or relapse of the tumor compared to the initial tumor can be determined by any suitable method practiced in the art. For example, this can be accomplished by the assessment of tumor size and number. An increase in tumor size or, alternatively, tumor number, indicates that the tumor is not responding to the treatment with the mTOR inhibitor or that a relapse has occurred. The determination can be done according to the "RECIST" criteria as described in detail in Therasse et at, J. Natl. Cancer Inst. 92:205-216 (2000). In accordance with the present invention, a patient having a neuroendocrine tumor resistant or refractory to the mTOR inhibitor may be treated by administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof to said patient in need thereof. In accordance with the particular findings, the present invention further provides in several aspects:

1.1 A method for inhibiting growth of a neuroendocrine tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor.

1.2 A method for inducing neuroendocrine tumor regression, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor.

1.3 A method for preventing metastatic spread of neuroendocrine tumors or for preventing or inhibiting growth of micrometastasis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to the use of compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of a neuroendocrine tumor, particularly a carcinoid tumor or a pancreatic

neuroendocrine tumor, resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to the use of compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of a pancreatic neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to the use of compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a neuroendocrine tumor, particularly a carcinoid tumor or a pancreatic neuroendocrine tumor, resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to the use of compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a pancreatic neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to the use of compound of formula (I) or a pharmaceutically acceptable salt thereof for preventing metastatic spread of neuroendocrine tumors or for preventing or inhibiting growth of micrometastasis, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor. The present invention further relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a neuroendocrine tumor, particularly a carcinoid tumor or a pancreatic neuroendocrine tumor, resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a pancreatic neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in inhibiting growth of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in inducing regression of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

The present invention further relates to a compound of formula (I) or a pharmaceutically acceptable salt for use in preventing metastatic spread of neuroendocrine tumors or for preventing or inhibiting growth of micrometastasis, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor.

In a further aspect of the present invention, the compound of formula (I) may also be used or administered in combination with at least one additional therapeutic compounds for the treatment of a neuroendocrine tumor, particularly a carcinoid tumor or a pancreatic

neuroendocrine tumor, resistant or refractory to treatment with at least one mTOR inhibitor. It is understood that the compound of formula (I) may be used or administered in combination with at least one additional therapeutic compounds for any of the methods and uses disclosed above. Potential suitable additional therapeutic agents for use in said combination include but are not limited to somatostatin analogs, including but not limited to octreotide, lanreotide, and SOM230; proton pump inhibitors; diazoxide; pancrealipase (lipase, protease, and amylase); anti-diarrheals, including but not limited to Imodium or Lomotil, opiates, etc.; antiemetics, including but not Imited to aprepitant (Emend®) or ondansetron (Zofran®); bisphosphonates; erithropoietin replacement; cortocosteroids administered by topical, inhalation, eye drops or local injection only; anticoagulants (excluding warfarin/ coumarin derivatives or anti-aggregation agents), and radiotherapy, or a combination thereof. Preferably, the neuroendocrine tumor is a pancreatic neuroendocrine tumor.

Examples of somatostatin analogues which may be used in the present invention include, but are not limited to, compounds which target, treat or inhibit the somatostatin receptor such as octreotide, lanreotide, and SOM230.

Examples of proton pump inhibitors which may be used in the present invention include, but are not limited to, omeprazole (Prilosec®), lansoprazole (Prevacid®), dexlansoprazole (Dexilant®), and pantoprazole (Protonix®).

Examples of bisphosphonates which may be used in the present invention include, but are not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. "Etridonic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark DIDRONEL. "Clodronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONEFOS. "Tiludronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark SKELID. "Pamidronic acid" can be administered, e.g. in the form as it is marketed, e.g. under the trademark AREDIA™.

"Alendronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX. "Ibandronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONDRANAT. "Risedronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the trademark ACTON EL. "Zoledronic acid" can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZOMETA.

Radiation may include approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4^th Edition, Vol. 1 , pp. 248-275 (1993). In a preferred embodiment, the compound of formula (I) is administered in combination with a somatostatin analogue, particularly octreotide, lanreotide, and SOM230.

In one embodiment, the present invention relates to a method for treating a

neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with at least one additional therapeutic agent.

In a further embodiment, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with at least one additional therapeutic compound for the manufacture of a medicament for use the treatment of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

In a further embodiment, the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof which is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent for use in the treatment of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor, wherein the at least one additional therapeutic agent selected from the group consisting of somatostatin analogs, proton pump inhibitors, diazoxide, pancrealipase (lipase, protease, and amylase), anti-diarrheals, antiemetics, bisphosphonates; erithropoietin replacement; cortocosteroids administered by topical, inhalation, eye drops or local injection only; anticoagulants (excluding warfarin/ coumarin derivatives or anti-aggregation agents), and radiotherapy, or a combination thereof.

By "combination", there is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the formula (I) and a combination partner may be administered independently, at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g.

synergistic effect.

A compound of formula (I) can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed

combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.

A combination partner may be administered in combination therapy as appropriate, e.g. according to a method as conventional, e.g. analogously to administration indications given for a specified drug for single treatment.

Said combination partner may be administered by any conventional route, for example enterally, e.g. including nasal, buccal, rectal, oral, administration; parenterally, e.g. including intravenous, intraarterial, intramuscular, intracardiac, subcutanous, intraosseous infusion, transdermal (diffusion through the intact skin), transmucosal (diffusion through a mucous membrane), inhalational administration; topically; e.g. including epicutaneous, intranasal, intratracheal administration; intraperitoneal (infusion or injection into the peritoneal cavity);

epidural (peridural) (injection or infusion into the epidural space); intrathecal (injection or infusion into the cerebrospinal fluid); intravitreal (administration via the eye); or via medical devices; For example, in form of coated or uncoated tablets, capsules, (injectable) solutions, infusion solutions, solid solutions, suspensions, dispersions, solid dispersions; e.g. in the form of ampoules, vials, in the form of creams, gels, pastes, inhaler powder, foams, tinctures, lip sticks, drops, sprays, or in the form of suppositories.

In one embodiment, the present invention relates to a combination comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) at least one additional therapeutic agent, for use in the treatment of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

In one embodiment, the present invention relates to a combination comprising (a) 2- methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1 -yl)-phenyl]- propionitrile (COMPOUND A) or a pharmaceutically acceptable salt thereof, and (b) at least one additional therapeutic agent, for use in the treatment of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

In one embodiment, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in combination with at least one therapeutic agent for any use as indicated above. In another aspect of the present invention, a compound of formula (I) may a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically accepable salt thereof in association with at least one pharmaceutically acceptable excipient, e.g. appropriate carrier and/or diluent, e.g. including fillers, binders, disintegrants, flow conditioners, lubricants, sugars or sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers, for use in the treatment of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

The dosage of the active ingredient depends upon a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound employed. A physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.

The dose of a compound of the formula (I) or a pharmaceutically acceptable salt thereof to be administered to subject in need thereof, for example humans of approximately 70 kg body weight, is preferably from approximately 3 mg to approximately 5 g, more preferably from approximately 10 mg to approximately 1.5 g, most preferably from about 100 mg to about 1000 mg per person per day, divided preferably into 1 to 3 single doses which may, for example, be of the same size. Usually, children receive half of the adult dose.

The compounds of the invention may be administered by any conventional route, in particular parenterally, for example in the form of injectable solutions or suspensions, enterally, e.g. orally, for example in the form of tablets or capsules, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form. Topical administration is e.g. to the skin. A further form of topical administration is to the eye. Pharmaceutical compositions comprising a compound of the invention in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent.

The pharmaceutical compositions are comprising an amount effective in the treatment of one of the above-mentioned neuroendocrine tumors, of a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with at least one pharmaceutically acceptable carrier that is suitable for topical, enteral, for example oral or rectal, or parenteral administration and that may be inorganic or organic, solid or liquid. There are pharmaceutical compositions used for oral administration especially tablets or gelatin capsules that comprise the active ingredient together with diluents, for example lactose, dextrose, manitol, and/or glycerol, and/or lubricants and/or polyethylene glycol. Tablets may also comprise binders, for example magnesium aluminum silicate, starches, such as corn, wheat or rice starch, gela^tin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. It is also possible to use the pharmacologically active compounds of the present invention in the form of parenterally administrable compositions or in the form of infusion solutions. The pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilizers, wetting compounds and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical compositions, which may, if desired, comprise other pharmacologically active substances are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising lyophilizing processes, and comprise approximately from 1 % to 99%, especially from approximately 1 % to approximately 20%, active ingredient(s).

In another aspect, the present invention provides:

.1 A pharmaceutical package comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and instructions for administration for the treatment of a

neuroendocrine tumor, particularly carcinoid tumors or pNET, resistant or refractory to treatment with at least one mTOR inhibitor; 2.2 A pharmaceutical package comprising a first drug substance which is a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent, beside instructions for combined administration;

2.2 A pharmaceutical package comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof beside instructions for combined administration with at least one additional therapeutic agent;

2.3 A pharmaceutical package comprising at least one second therapeutic agent beside

instructions for combined administration with a compound of formula (I) or a

pharmaceutically acceptable salt thereof; e.g. for use in any method of above.

In each case where citations of patent applications or scientific publications are given, the subject-matter relating to the compounds is hereby incorporated into the present application by reference, e.g. comprised are likewise the pharmaceutical acceptable salts thereof, the corresponding racemates, diastereoisomers, enantiomers, tautomers as well as the

corresponding crystal modifications of above disclosed compounds where present, e. g.

solvates, hydrates and polymorphs, which are disclosed therein. The compounds used as active ingredients in the combinations of the invention may be prepared and administered as described in the cited documents or in the product description, respectively. Also within the scope of this invention is the combination of more than two separate active ingredients as set forth above, i. e. a pharmaceutical combination within the scope of this invention could include three active ingredients or more. Further, both the first agent and the co-agent are not the identical ingredient.

The structure of the drug substances identified by code numbers, generic or trade names may be taken from the Internet, actual edition of the standard compendium "The Merck Index" or from databases, e.g., Patents International, e.g., IMS World Publications, or the publications mentioned above and below. The corresponding content thereof is hereby incorporated by reference. In a preferred embodiment, the present invention relates to the use of the compound 2- methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1 -yl)-phenyl]- propionitrile ("COMPOUND A") or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment of pancreatic neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

In a preferred embodiment, the present invention relates to the use of the compound 2- methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1 -yl)-phenyl]- propionitrile ("COMPOUND A") or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment of pancreatic neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

In the preferred embodiment, the present invention relates to the use of the compound 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]- propionitrile ("COMPOUND A") or a pharmaceutically acceptable salt thereof for use in the treatment of pancreatic neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

In the preferred embodiment, the present invention relates to a compound 2-methyl-2-[4- (3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1 -yl)-phenyl]-propionitrile ("COMPOUND A") or a pharmaceutically acceptable salt thereof for use in the treatment of pancreatic neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

Utility of the compounds of formula (I) in treating a neuroendocrine tumor, particularly pancreatic NET, resistant or refractory to treatment with at least one mTOR inhibitor as hereinabove specified, may be demonstrated in vitro, in animal test methods as well as in clinic studies. For example in the utility of the compounds of formula (I) in accordance with the present invention may be demonstrated in accordance with the methods hereinafter described:

Example 1 - Clinical Trial A clinical study using Compound A or its monotosylate salt in an amount of 400 mg twice daily (b.i.d.) Compound A in monotherapy for treatment of patients with advanced pancreatic neuroendocrin tumors (pNET) after failure of mTOR inhibitor therapy is investigated.

A prospective, global, multi-center, two stage study of Compound A or the monotosylate salt of Compound A is conducted in adult patients who are diagnosed with a advanced

(unresectable or metastatic) pancreatic neuroendocrine tumor (pNET) which is refractory to treatment with at least one mTOR inhibitor. For the clinical trial, refractory is defined as progression while on treatment or within 3 months of treatment discontinuation.

Inclusion criteria:

Patients eligible for inclusion in this study must provide written informed consent prior to any screening procedures and meet all of the following criteria:

1. Patient must have advanced (unresectable or metastatic), histologically confirmed low or intermediate grade pancreatic pNET according to the World Health Organization (WHO) 2010 classification (grade 1 or 2) and show radiological evidence of disease progression since last treatment.

2. Patients' disease is refractory to treatment with mTOR inhibitor. Patients must not have taken another treatment between mTOR inhibitor and Compound A or its monotosylate salt.

3. Measurable disease per RECIST Version 1 .1 using Computed Tomography (CT) or Magnetic Resonance Imaging (MRI). Any lesions which have been subjected to percutaneous therapies, or radiotherapy are not considered measurable, unless they have clearly progressed since the procedure;

4. Prior or concurrent therapy with a somatostatin analogue (SSA) is permitted;

however, for concurrent therapy with SSA while on study, patients must be on a stable dose at least 2 months prior to study start and must continue on the stable dose while receiving study treatment.

5. Adequate bone marrow function or organ function as shown by:

• Absolute Neutrophil Count (ANC)≥ 1.5 x 10⁹/L, Platelets≥ 100 x 10⁹/L (non-transfused),

Hemoglobin > 9 g/dL (in case of blood transfusions, hemoglobin must be stable for at least 2 weeks before first dose of study medication),

• INR < 2.0,

Serum creatinine < 1.5 x ULN,

Total serum bilirubin < 1.5 x ULN (or in patients with known Gilbert Syndrome, a total bilirubin < 3.0 x ULN, with direct bilirubin < 1 .5 x ULN),

ALT and AST < 3 x ULN (or < 5x ULN in patients with liver metastases),

Fasting plasma glucose (FPG) < 140 mg/dL or < 7.8 mmol/L,

• HbA1 c < 8%.

6. WHO PS≤1 .

7. Adult male or female patients≥ 18 years of age.

8. Written informed consent obtained before any trial related activities and according to local guidelines.

Excluded from the study are: patients having received previous treatment with any PI3K inhibitor or AKT inhibitor for treatment of pNET, patients having discontinued prior mTOR inhibitor therapy due to toxicity, and patients having poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid and small cell carcinoma. Additional criteria for exclusion include:

1. Patient has received cytotoxic chemotherapy, targeted therapy, immunotherapy, radiotherapy, or major surgery within 4 weeks prior to enrolment in the study.

2. Patient has been treated with hepatic artery embolization within the last 6 months (1 month if there are other sites of measurable disease), or cryoablation/ radiofrequency ablation of hepatic metastasis within 2 months of enrollment. 3. Patients with more than 3 prior systemic treatment regimens.

4. Patient is being treated at start of study treatment with any of the following drugs: (a) Drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A4 including herbal medications (list of prohibited CYP3A4 inhibitors and inducers to be provided in final protocol). The patient must have discontinued strong inducers and/or strong inhibitors two weeks before the treatment is initiated. Switching to a different medication prior to starting study treatment is allowed. Or (b) Drugs with a known risk to induce Torsades de Pointes, Or (c) Warfarin and coumarin analogues

5. Patient is consuming Seville oranges, grapefruit, grapefruit hybrids, pummelos and exotic citrus fruits (as well as their juices) during the last 7 days prior to start of treatment.

Regular orange juice is permitted.

6. Patient who has any severe and/or uncontrolled medical conditions, for example: active or uncontrolled severe infection,

cirrhosis, chronic active hepatitis or chronic persistent hepatitis,

· severely impaired lung function inadequately controlled hypertension (i.e., SBP>180 mmHg or DBP>100mmHg),

active bleeding diathesis.

7. Patient has any of the following cardiac abnormalities: symptomatic congestive heart failure, myocardial infarction < 6 months prior to enrollment; unstable angina pectoris; serious uncontrolled cardiac arrhythmia; symptomatic pericarditis; history of documented congestive heart failure (New York Heart Association functional classification lll-IV), documented cardiomyopathy; abnormal Left Ventricular Ejection Fraction (LVEF) as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO); QTcF > 480 msec on the screening ECG (using the QTcF formula); or currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. 8. Patient has impairment of gastrointestinal (Gl) function or Gl disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

9. Patient is receiving chronic high dose treatment with corticosteroids (e.g. total daily dose of prednisone at 1 mg per kg of body weight, or approximately 60 milligrams a day or equivalent dose of other corticosteroid) or another immunosuppressive agent that would cause the patient to be immunocompromised.

10. Patient is immunocompromised, including known seropositivity for HIV.

1 1 . Patient has other prior or concurrent malignancy (except for the following:

adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any other cancer from which the patient has been disease free for≥ 3 years).

12. Patient has a history of non-compliance to medical regimen or is considered potentially unreliable or is unable to grant consent.

13. Patient is a pregnant or nursing (lactating) woman, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mlU/mL). Patients with elevated hCG at baseline that is judged to be related to the tumor are eligible if hCG levels do not show the expected doubling when repeated 5-7 days later, or pregnancy has been ruled out by vaginal ultrasound.

14. Patient who does not apply highly effective contraception during the study and through the duration after the final dose of study treatment.

Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective contraception during the study and through 12 weeks after the final dose of study treatment. "Highly effective contraception" is defined as either:

1. Total abstinence

2. Female sterilization:

3. Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject. 4. Use a combination of the following (both a+b):

a Placement of an intrauterine device (IUD) or intrauterine system (IUS) b Barrier methods of contraception: Condom or Occlusive cap (OC) (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. c Note: Hormonal contraception methods (e.g. oral, injected, implanted) are not allowed.

Women are considered post-menopausal and not of child bearing potential if: they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms), or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

Sexually active males must use a condom during the study period and up to 12 weeks after the end of treatment.

In the first stage of the clinical trial, approximately 10-30 patients are enrolled in an open-label single arm stage study to assess the efficacy of oral 400 mg B.I.D. dosing of Compound A or the monotosylate salt of Compound A. Potential patients are screened for a period of 28 days to assess eligibility. Screening radiological tumor assessments are used as baseline if completed within 4 weeks prior to treatment start for the first stage), with the exception of bone scans which may be obtained within 6 weeks of treatment start.

Patients are orally administered 400 mg B.I.D. Compound A in the form of its free base or its monotosylate salt. For each patient, a maximum of 2 dose reductions are allowed. Dose per administration may be reduced to 300 mg B.I.D. Compound A and then to 200 mg B.I.D. Compound A. Doses below 200 mg per administration (400 mg total daily dose) are not permitted. For patients who experience any intolerable toxicity, the study treatment is withheld until the toxicity resolves to Grade 1 or better. Patients are permitted to receive additional Best Supportive Care treatment during the study treatment. Best Supportive Care includes all care provided to patients deemed necessary by the treating physician, such as, the use of somatostatin analogs; proton pump inhibitor for gastrinoma; diazoxide, short course of steroids or feeding tube for insulinoma; Pancrealipase (lipase, protease, and amylase) for patients with pancreatic exocrine insufficiency; and nonspecific anti-diarrheals, such as, imodium or lomotil (containing loperamide), opiates, etc. Best Supportive care excludes the use of anti-tumor therapies such as interferon, targeted/biological agent (e.g. sunitinib, sorafenib, bevacizumab), cytotoxic agent (e.g. streptozocin) tumor ablative procedures, and curative radiation therapy. This concomitant therapy may further include: (a) antiemetics once patient experiences nausea or vomiting and at discretion of investigator, bisphosphonates if patient has been on stable doses for at least 2 weeks prior to screening procedures, erithropoietin replacemet if initiated greater than 2 weeks prior to treatment, cortocosteroids as topical, inhaled, eye drops or local injection only, anticoagulants other than warfarin/ coumarin derivatives or anti-aggregation agents, or radiotherapy. Patients are not permitted to be treated with (a) other investigational therapies; (b) anticancer therapy (e.g, antineoplastic therapy, hormonal agents); (c) moderate and strong inhibitors of CYP3A4/5; (d) Drugs with a known risk for Torsades de Pointes; or (e) herbal medications; (f) warfarin and coumarin derivatives.

Patients are followed for at least 16 weeks or until disease progression, death, or start of new antineoplastic therapy is reported for all patients. If the Progression-Free Survival (PFS) rate at 16 weeks is 60% or greater, then the second stage of the clinical trial is beginning. The primary endpoint is the PFS rate at 16 weeks as per modified RECIST v. 1 .1 criteria.

In the second stage of the clinical trial, approximately 80-99 patients are registered in a double-blind study and randomized in a 2:1 ratio to receive either (a) daily 400 B.I.D. Compound A in the form of its free base or its monotosylate salt or (b) a daily B.I.D. matching placebo. This study does not include fixed treatment duration. Randomization will be stratified by (a) current somatostatin analogue therapy (yes/no) and (b) elevated CgA > 2xULN and/or NSE > ULN. Prior to randomization, potential patients are screened upon registration in the IRT system for a period of 28 days to assess eligibility. Screening radiological tumor assessments are used as baseline if completed within 4 weeks prior to randomization (for second stage), with the exception of bone scans which may be obtained within 6 weeks of randomization.

Patients are orally administered 400 mg B.I.D. Compound A in the form of its free base or its monotosylate salt.

Primary analysis of this second stage is performed when approximately 50 progression free survivals are observed in this second stage. A complete treatment cycle is defined as a period of 28 days (+ 4 days). Following study inclusion and initiation of study treatment, the patient is encouraged to visit the site on Day 1 , 8, 15, and 22 for the first cycle and every 14 days thereafter during the treatment phase. Patients will have their first dose of study drug at Visit 2 (Day 1 , Cycle 1 ).

Patients receiving placebo may be permitted to cross-over to Compound A treatment if one of the following criteria are met: (a) In Stage 1 , the PFS rate at 16 weeks is > 75%, or (b) If criterion (a) is not fulfilled, the estimate hazard ratio (HR) based on an interim analysis of the second stage after approximately 30 events are observed), is < 0.6. Before crossing over, patients are re-evaluated to ensure eligibility for the trial.

Patients are assessed for efficacy via radiographic tumor assessments every 8 weeks (+1 week) fro the date of initiation of study treatment in Stage 1 and from the randomization date in Stage 2 until documented disease progression or start of new anti-neoplastic therapy, whichever occurs first. Additional tumor assessments may be performed if there is symptomatic evidence suggesting the possibility of disease progression based on clinical symptoms or physical examination.

Patients are receiving study treatment until disease progression or any of the following criteria for discontinuation from study are met:

• General criteria: voluntary withdraw by patient, adverse events, lost to follow-up, non-compliance with study treatment, physician decision, pregnancy, progressive disease, protocol deviation, study terminated by sponsor, technical problems, subject/ guarian decision, or death. • Specific criteria: Study treatment modification that results in discontinuation, interruption of study treatment for more than 21 days, use of prohibited medications, or start of antineoplastic therapy other than Compound A.

The primary endpoint is the PFS rate as per modified RECIST v. 1 .1 criteria. Overall tumor response and disease progression are assessed locally according to modified RECIST v. 1 .1 criteria. In addition to the RECIST v. 1.1 criteria, the following criteria is applied when determining tumor status:

• Up to 10 lesions in total and 5 per organ can be selected as Target lesions, · New lesions are required to have a minimum of 10 mm in the longest diameter,

• If more than one equivocal lesion is found at any particular timepoint, the minimum size of 10 mm in the longest diameter is not required to determine progressive disease,

• Presence of new unequivocal non-measurable disease (e.g., new bone lesions).

All patients are required to undergo chest, abdomen and pelvis CT or MRI scans for baseline assessments and post-base-line assessments. If bone metastases are suspected or known at baseline, a whole body bone scan should be acquired. If brain metastases are suspected or known at screening, brain CT or MRI scans should be acquired at screening and continued at subsequent visits. Color photographs should be acquired for skin mestastases. Other efficacy assessments include CgA and NSE which will be performed on Day 1 of every cycle except the baseline visit.

Safety assessments and PK assessments are routinely performed. Safety assessments consist of monitoring, by investigators, and recording of all adverse events (non-serious and serous) and concomitant medications, and the regular monitoring of laboratory tests, physical examinations, weight, vital signs, cardiac health and WHO Performance Status (PS).

Performance status (PS) will be assessed according to the WHO PS and will be documented at Screening, Day 1 of each cycle, and End-of-treatment visit. The WHO Performance Status Scale is as follows:

Score PS

0 Fully active, able to carry on all pre-disease performance without restriction.

1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work.

2 Ambulatory and capable of all self-care but unable to carry out any work

activities. Up and about more than 50% of waking hours.

3 Capable of only limited self-care, confined to bed or chair more than 50% of

waking hours.

4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.

5 Death

These assessments are performed + 3 days of the scheduled day of assessments except for adverse events that are evaluated continuously through study. Additional physical examinations and vital sign (body temperature, sitting blood pressure, and sitting pulse) are assessed in the study. Further laboratory evaluations will be conducted in the study as part of the screening evaluations and within 7 days of the first dose of study drug and include: hematology

(hemoglobin, hematocrit, platelet counts, total red blood cells, total white blood cells and a WBC differential including neutrophils, lymphocytes, monocytes, eosinophils and basophils), clinical chemistry, cooagultion, C-peptide and HbA1 c analysis, fasting plasma glucose, urinalysis, serum lipid profile and optionally thyroid activity.

All patients who discontinue treatment have a safety follow-up visit to follow adverse events or serious adverse events that may have occurred after discontinuation of treatment. This safety follow-up occurs for at least 30 days after the last dose of Compound A or placebo.

All patients who discontinue treatment prior to progression of disease will continue to have tumor assessments performed every 8 weeks (+ 1 week) from initiation of study treatment in Stage 1 and from the randomization in Stage 2 until radiologically documented disease progression or until start of new anti-neoplastic therapy.

All patients are followed for survival after discontinuation of treatment. All patients who discontinue study treatment and are no longer followed radiologically are contacted every 12 weeks (+ 7 days) from the time of end of treatment visit or, where applicable, from the last visit in the efficacy follow-up period until death.

End of post-treatment electronic case report/ record form (study phase completion) is completed once a patient has discontinued study treatment, completed safety follow-up and can no longer perform efficacy assessment.

Safety and efficacy of the use of the monotosylate salt of Compound A may be assessed and/or determined through use of interim study data.

Pursuant to this clinical study procedure, the following preliminary results have been obtained as of April 2013:

1 1 patients were enrolled into the first phase of the study based upon the inclusion and exclusion criteria set forth above. 2 patients discontinued treatment after receiving treatment with 400 mg BID Compound A in the monotosylate salt form ("Compound A monotosylate salt) for 3 days and 8 days respectively. 1 patient discontinued treatment after receiving treatment with 400 mg BID Compound A monotosylate salt for 4 days and then with 300 mg BID

Compound A monotosylate salt for 39 days. These 3 patients discontinued treatment after experiencing toxicity.

1 patient had stable disease on treatment with 200 mg BID Compound A monotosylate salt for 95 days after receiving prior treatment with 400 mg BID Compound A monotosylate salt for 4 days and then 300 mg BID Compound A monotosylate salt for 21 days. This patient discontinued treatment following 95 days of treatment after experiencing toxicity.

1 patient had partial regression on treatment with 300 mg BID Compound A

monotosylate salt after receiving treatment with 400 mg BID Compound A monotosylate salt for 22 days. This patient had partial regression within the first 47 days of treatment with 300 mg BID Compound A monotosylate salt and receives ongoing treatment at this dose. 1 patient had received treatment with 400 mg BID Compound A in the monotosylate salt form for 56 days and discontinued treatment after disease progression.

Further, 5 patients are receiving ongoing treatment at the dosage of 400 mg BID Compound A in the monotosylate salt form ("Compound A monotosylate salt"), including (a) 2 patients receiving ongoing treatment with 400 mg BID Compound A monotosylate salt for 50 day, (b) 1 patient receiving ongoing treatment with 400 mg BID Compound A monotosylate salt for 8 days, and (c) 2 patients receiving ongoing treatment with 400 mg BID Compound A monotosylate salt for 3 days. Additionally, 1 patient is receiving ongoing treatment at the dosage of 200 mg BID Compound A monotosylate salt for 15 days after receiving treatment with 400 mg BID Compound A monotosylate salt for 3 days and then with 300 mg BID Compound A monotosylate salt for 3 days.

This preliminary data demonstrates that Compound A in free form or its monotosylate salt form may be useful for the treatment of advanced pNET after failure of mTOR inhibitor therapy. It is understood that additional data from this study may provide additional support this finding but not required to demonstrate this finding to one of skilled in the art.

Example 2 - Clinical Trial

A clinical study using Compound A or its monotosylate salt in an amount of 300 mg twice daily (b.i.d.) Compound A in monotherapy for treatment of patients with advanced pancreatic neuroendocrine tumors (pNET) after failure of mTOR inhibitor therapy is

investigated.

Inclusion criteria:

Patients eligible for inclusion in this study must provide written informed consent prior to any screening procedures and meet all of the following criteria: 1. Patient must have advanced (unresectable or metastatic), histologically confirmed low or intermediate grade pancreatic pNET according to the World Health Organization (WHO) 2010 classification (grade 1 or 2) and show radiological evidence of disease progression since last treatment.

2. Patients' disease is refractory to treatment with mTOR inhibitor. Patients must not have taken another antineoplastic treatment between mTOR inhibitor and Compound A or its monotosylate salt. Refractory disease is defined as progression while on mTOR inhibitor treatment or within 3 months of treatment discontinuation. An mTOR inhibitor treatment must be the last systemic treatment received prior to study entry with the last dose administered within 4 weeks of study treatment start.

4. Prior or concurrent therapy with a somatostatin analogue (SSA) is permitted;

5. Adequate bone marrow function or organ function as shown by:

· Absolute Neutrophil Count (ANC)≥ 1.5 x 10⁹/L,

Platelets≥ 100 x 10⁹/L (non-transfused),

• INR < 2.0,

· Serum creatinine < 1.5 x ULN,

ALT and AST < 3 x ULN (or < 5x ULN in patients with liver metastases), Fasting plasma glucose (FPG) < 140 mg/dL or < 7.8 mmol/L,

6. WHO PS≤1 .

7. Adult male or female patients≥ 18 years of age.

1. Patient has received radiotherapy, or major surgery within 4 weeks prior to study treatment start.

2. Patient has been treated with hepatic artery embolization, or cryoablation/ radiofrequency ablation of hepatic metastasis within 2 months of study treatment start.

3. Patients with more than 3 prior systemic treatment regimens.

Regular orange juice is permitted. 6. Patient who has any severe and/or uncontrolled medical conditions, for example: active or uncontrolled severe infection,

cirrhosis, chronic active hepatitis or chronic persistent hepatitis,

severely impaired lung function inadequately controlled hypertension (i.e., SBP>180 mmHg or DBP>100mmHg),

active bleeding diathesis.

7. Patient has any of the following cardiac abnormalities: symptomatic congestive heart failure, myocardial infarction < 6 months prior to enrollment; unstable angina pectoris; serious uncontrolled cardiac arrhythmia; symptomatic pericarditis; history of documented congestive heart failure (New York Heart Association functional classification lll-IV), documented cardiomyopathy; abnormal Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO); QTcF > 480 msec on the screening ECG (using the QTcF formula); or currently receiving treatment with medication that has a known risk to prolong the QT interval or inducing Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug.

8. Patient has impairment of gastrointestinal (Gl) function or Gl disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

10. Patient is immunocompromised, including known seropositivity for HIV.

12. Patient has a history of non-compliance to medical regimen or is considered potentially unreliable or is unable to grant consent. 13. Patient is a pregnant or nursing (lactating) woman, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mlU/mL). Patients with elevated hCG at baseline that is judged to be related to the tumor are eligible if hCG levels do not show the expected doubling when repeated 5-7 days later, or pregnancy has been ruled out by vaginal ultrasound.

1. Total abstinence

2. Female sterilization:

3. Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject.

4. Use a combination of the following (both a+b):

a. Placement of an intrauterine device (IUD) or intrauterine system (IUS) b. Barrier methods of contraception: Condom or Occlusive cap (OC) (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. c. Note: Hormonal contraception methods (e.g. oral, injected, implanted) are not allowed.

Women are considered post-menopausal and not of child bearing potential if: they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms), or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. Sexually active males must use a condom during the study period and up to 12 weeks after the end of treatment.

In the first stage of the clinical trial, approximately 10-30 patients are enrolled in an open-label single arm stage study to assess the efficacy of oral 300 mg B.I.D. dosing of Compound A or the monotosylate salt of Compound A. Potential patients are screened for a period of 28 days to assess eligibility. Screening radiological tumor assessments are used as baseline if completed within 4 weeks prior to treatment start for the first stage), with the exception of bone scans which may be obtained within 6 weeks of treatment start.

Patients are orally administered 300 mg B.I.D. Compound A in the form of its free base or its monotosylate salt. For each patient, a maximum of 2 dose reductions are allowed. Dose per administration may be reduced to 200 mg B.I.D. Compound A and then to 100 mg B.I.D. Compound A. Doses below 100 mg B.I.D. are not permitted. For patients who experience any intolerable toxicity, the study treatment is withheld until the toxicity resolves to Grade 1 or better.

Patients are permitted to receive additional Best Supportive Care treatment during the study treatment. Best Supportive Care includes all care provided to patients deemed necessary by the treating physician, such as, the use of somatostatin analogs; proton pump inhibitor for gastrinoma; diazoxide, short course of steroids or feeding tube for insulinoma; Pancrealipase (lipase, protease, and amylase) for patients with pancreatic exocrine insufficiency; and non- specific anti-diarrheals, such as, imodium or lomotil (containing loperamide), opiates, etc. Best Supportive care excludes the use of anti-tumor therapies such as interferon, targeted/biological agent (e.g. sunitinib, sorafenib, bevacizumab), cytotoxic agent (e.g. streptozocin) tumor ablative procedures, and curative radiation therapy. This concomitant therapy may further include: (a) antiemetics once patient experiences nausea or vomiting and at discretion of investigator, bisphosphonates if patient has been on stable doses for at least 2 weeks prior to screening procedures, erithropoietin replacement if initiated greater than 2 weeks prior to treatment, cortocosteroids as topical, inhaled, eye drops or local injection only, anticoagulants other than warfarin/ coumarin derivatives or anti-aggregation agents, or radiotherapy. Patients are not permitted to be treated with (a) other investigational therapies; (b) anticancer therapy (e.g, antineoplastic therapy, hormonal agents); (c) moderate and strong inhibitors of CYP3A4/5; (d) Drugs with a known risk for Torsades de Pointes; or (e) herbal medications; (f) warfarin and coumarin derivatives.

Patients are followed for at least 16 weeks or until disease progression, withdrawal, death, or start of new antineoplastic therapy is reported for all patients. If the Progression-Free Survival (PFS) rate at 16 weeks is 60% or greater and the posterior probability that PFS rate at 16 weeks is > 40% is at least 90%, then the second stage of the clinical trial is beginning. The primary endpoint is the PFS rate at 16 weeks as per modified RECIST v. 1 .1 criteria. The PFS rate at 16 weeks is defines as the number of progression free patients divided by the total number of patients in the full analysis set. The posterior probability is derived from the Bayesian posterior distribution of the PFS rate.

In the second stage of the clinical trial, approximately 80-99 patients are registered in a double-blind study and randomized in a 2:1 ratio to receive either (a) daily 300 B.I.D.

Compound A in the form of its free base or its monotosylate salt or (b) a daily B.I.D. matching placebo. This study does not include fixed treatment duration. Randomization will be stratified by (a) current somatostatin analogue therapy (yes/no) and (b) elevated CgA > 2xULN and/or NSE > ULN. Prior to randomization, potential patients are screened upon registration in the IRT system for a period of 28 days to assess eligibility. Screening radiological tumor assessments are used as baseline if completed within 4 weeks prior to randomization (for second stage), with the exception of bone scans which may be obtained within 6 weeks of randomization.

Patients are orally administered 300 mg B.I.D. Compound A in the form of its free base or its monotosylate salt. It may be permitted to allow a maximum of 2 dose reductions. Dose per administration may be reduced to 200 mg B.I.D. Compound A and then to 100 mg B.I.D. Compound A. Doses below 100 mg B.I.D. are not permitted.

Primary analysis of this second stage is performed when approximately 50 progression free survivals are observed in this second stage. The study result may be considered positive if a Hazard Ratio (HR) of 0.60 or better is observed and the probability that the HR is less than 1 is at least 95%. A complete treatment cycle is defined as a period of 28 days (+ 4 days).

Following study inclusion and initiation of study treatment, the patient is encouraged to visit the site on Day 1 , 8, 15, and 22 for the first cycle and every 14 days thereafter during the treatment phase. Patients will have their first dose of study drug at Visit 2 (Day 1 , Cycle 1 ).

Patients receiving placebo may be permitted to cross-over to Compound A treatment if one of the following criteria are met: (a) In Stage 1 , the PFS rate at 16 weeks is > 75%, or (b) If criterion (a) is not fulfilled, the estimate hazard ratio (HR) based on an interim analysis of the second stage after approximately 30 events are observed), is < 0.6Before crossing over, patients are re-evaluated to ensure eligibility for the trial.

Patients are assessed for efficacy via radiographic tumor assessments every 8 weeks (+1 week) from the date of initiation of study treatment in Stage 1 and from the randomization date in Stage 2 until documented disease progression, discontinuation according to criteria set forth below, or start of new anti-neoplastic therapy, whichever occurs first. Additional tumor assessments may be performed if there is symptomatic evidence suggesting the possibility of disease progression based on clinical symptoms or physical examination.

• General criteria: voluntary withdraw by patient, adverse events, lost to follow-up, non-compliance with study treatment, physician decision, pregnancy, progressive disease, protocol deviation, study terminated by sponsor, technical problems, subject/ guardian decision, or death.

• Specific criteria: Study treatment modification that results in discontinuation, interruption of study treatment for more than 21 days, use of prohibited medications, or start of antineoplastic therapy other than Compound A.

The primary endpoint is the PFS rate as per modified RECIST v. 1.1 criteria. Overall tumor response and disease progression are assessed locally according to modified RECIST v. 1.1 criteria. In addition to the RECIST v. 1 .1 criteria, the following criteria is applied when determining tumor status:

• Up to 10 lesions in total and 5 per organ can be selected as Target lesions, • New lesions are required to have a minimum of 10 mm in the longest diameter,

• If more than one equivocal lesion is found at any particular timepoint, the

minimum size of 10 mm in the longest diameter is not required to determine progressive disease,

Score PS

2 Ambulatory and capable of all self-care but unable to carry out any work

activities. Up and about more than 50% of waking hours.

3 Capable of only limited self-care, confined to bed or chair more than 50% of

waking hours.

5 Death

All patients who discontinue treatment prior to progression of disease will continue to have tumor assessments performed every 8 weeks (+ 1 week) from initiation of study treatment in Stage 1 and from the randomization in Stage 2 until radiologically documented disease progression or until start of new anti-neoplastic therapy. All patients are followed for survival after discontinuation of treatment. All patients who discontinue study treatment and are no longer followed radiologically are contacted every 12 weeks (+ 7 days) from the time of end of treatment visit or, where applicable, from the last visit in the efficacy follow-up period until death.

Claims

What is Claimed:

1. A method for treating a neuroendocrine tumor comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I),

wherein

Ri is naphthyl or phenyl wherein said phenyl is substituted by one or two substituents independently selected from the group consisting of Halogen; lower alkyl unsubstituted or substituted by halogen, cyano, imidazolyl or triazolyl; cycloalkyl; amino substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkyl sulfonyl, lower alkoxy and lower alkoxy lower alkylamino; piperazinyl unsubstituted or substituted by one or two substituents independently selected from the group consisting of lower alkyl and lower alkyl sulfonyl; 2-oxo-pyrrolidinyl; lower alkoxy lower alkyl; imidazolyl; pyrazolyl; and triazolyl;

R₂ is O or S;

R₅ is hydrogen or halogen; n is 0 or 1 ; R₆ is oxido; with the proviso that if n=1 , the N-atom bearing the radical R₆ has a positive charge; R₇ is hydrogen or amino;

or a pharmaceutically acceptable salt thereof, wherein said neuroendocrine tumor is resistant or refractory to treatment with at least one mTOR inhibitor.

A method according to claim 1 , wherein the compound of formula (I) is 2-Methyl-2-[4-(3- methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile or its monotosylate salt.

A method according to claim 1 , wherein the compound of formula (I) is 8-(6-methoxy- pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1 ,3-dihydro-imidazo[4,5- c]quinolin-2-one (COMPOUND B) or a pharmaceutically acceptable salt thereof.

A method according to any one of claims 1 to 3, wherein the neuroendocrine tumor is pancreatic neuroendocrine tumors.

A method according to any one of claims 1 to 4, comprising administering in addition a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of somatostatin analogs, proton pump inhibitors, diazoxide, pancrealipase (lipase, protease, and amylase), anti-diarrheals, antiemetics,

bisphosphonates; erithropoietin replacement; cortocosteroids administered by topical, inhalation, eye drops or local injection only; anticoagulants (excluding warfarin/ coumarin derivatives or anti-aggregation agents), and adiotherapy, or a combination thereof.

The use of a compound of formula (I) according to any one of claims 1 to 3 or

pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in treatment of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

7. The use according to claim 6, wherein the neuroendocrine tumor is pancreatic

neuroendocrine tumors. 8. The use according claim 6 or 7, wherein the compound of formula (I) is used in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of somatostatin analogs, proton pump inhibitors, diazoxide, pancrealipase (lipase, protease, and amylase), anti-diarrheals, antiemetics,

9. A compound of formula (I) according to any one of claims 1 to 3 or a pharmaceutically

acceptable salt thereof for use in the treatment of a neuroendocrine tumor resistant or refractory to treatment with at least one mTOR inhibitor.

10. A compound according to claim 9, wherein the neuroendocrine tumor is pancreatic

neuroendocrine tumors. 1 1 . A compound according to claim 9 or 10, wherein the compound of formula (I) is

administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of somatostatin analogs, proton pump inhibitors, diazoxide, pancrealipase (lipase, protease, and amylase), anti- diarrheals, antiemetics, bisphosphonates; erithropoietin replacement; cortocosteroids administered by topical, inhalation, eye drops or local injection only; anticoagulants (excluding warfarin/ coumarin derivatives or anti-aggregation agents), and adiotherapy, or combination thereof.