A Phase 2 Study of the MET Kinase Inhibitor INC280 in Papillary Renal Cell Cancer

Background: Papillary Renal Cell Cancer (RCC) is the second most common histologic subtype of kidney cancer, accounting for approximately 10-15% of cases Type 1 papillary RCC occurs in both sporadic and hereditary forms, which are histologically identical. Non familial type 1 papillary RCC can present as both solitary renal tumors and as bilateral, multifocal disease There are no standard agents of proven efficacy for patients with advanced papillary RCC. Patients with disease localized to the kidney are managed surgically while patients with advanced/unresectable disease are usually managed in the community with vascular endothelial growth factor (VEGF) pathway antagonists or mechanistic target of rapamycin (mTOR) inhibitors. Activating mutations of mesenchymal epithelial transition (MET) were identified in the germline of affected hereditary papillary renal cancer (HPRC) patients, who have a predilection for the development of bilateral, multifocal type 1 papillary RCC. Somatic MET mutations have been found in a subset of patients with non-inherited, sporadic papillary renal carcinoma The investigational agent Capmatinib (INC280) is a selective MET inhibitor lacking activity against the VEGF pathway This is a proof-of-concept study using INC280 in patients with papillary RCC to test the idea that effectively blocking the hepatocyte growth factor (HGF)/MET pathway will lead to clinical activity in patients with papillary renal cell cancer Objectives: Primary Objective: -To determine the overall response rate (Response Evaluation Criteria in Solid Tumors (RECIST) 1.1) in patients with papillary renal cell carcinoma treated with single agent INC280 Eligibility: Diagnosis of hereditary papillary renal carcinoma (HPRC) or sporadic papillary renal cell carcinoma (RCC) Patients with bilateral multifocal disease can have tumors localized to the kidney or have metastatic disease Patients with sporadic papillary RCC (but without multifocal disease) should have advanced disease that is considered unresectable Eastern Cooperative Oncology Group (ECOG) 0-2 Measurable disease Adequate organ function No active brain metastases Prior therapy No more than 3 prior lines of systemic therapy Prior therapy with a MET inhibitor is allowed as long as the patient has not had progressive disease while receiving the agent Design: This is a phase 2 single center non-randomized trial. The study will be conducted using a Simon 2 stage minimax design. Initially 13 evaluable subjects will be recruited. If there are no responses to therapy, the study will be terminated. If there is at least 1 response an additional 7 evaluable subjects will be accrued. The two-stage minimax design is based on assuming an ineffective response rate of 5% and a targeted effective response rate of 25%. We also assume that the probability of accepting an ineffective treatment and the probability of rejecting an effective treatment are each 10%. Subjects will be dosed orally at a starting dose of 600 mg twice daily. The overall response rate (complete response + partial response) will be determined.

Background: Papillary Renal Cell Cancer (RCC) is the second most common histologic subtype of kidney cancer, accounting for approximately 10-15% of cases Type 1 papillary RCC occurs in both sporadic and hereditary forms, which are histologically identical. Non familial type 1 papillary RCC can present as both solitary renal tumors and as bilateral, multifocal disease There are no standard agents of proven efficacy for patients with advanced papillary RCC. Patients with disease localized to the kidney are managed surgically while patients with advanced/unresectable disease are usually managed in the community with vascular endothelial growth factor (VEGF) pathway antagonists or mechanistic target of rapamycin (mTOR) inhibitors. Activating mutations of mesenchymal epithelial transition (MET) were identified in the germline of affected HPRC patients, who have a predilection for the development of bilateral, multifocal type 1 papillary RCC. Somatic MET mutations have been found in a subset of patients with non-inherited, sporadic papillary renal carcinoma The investigational agent Capmatinib (INC280) is a selective MET inhibitor lacking activity against the VEGF pathway This is a proof-of-concept study using INC280 in patients with papillary RCC to test the idea that effectively blocking the hepatocyte growth factor (HGF)//MET pathway will lead to clinical activity in patients with papillary renal cell cancer Objectives: Primary Objective: -To determine the overall response rate (Response Evaluation Criteria in Solid Tumors (RECIST) 1.1) in patients with papillary renal cell carcinoma treated with single agent INC280 Eligibility: Diagnosis of hereditary papillary renal carcinoma (HPRC) or sporadic papillary renal cell carcinoma (RCC) Patients with bilateral multifocal disease can have tumors localized to the kidney or have metastatic disease Patients with sporadic papillary RCC (but without multifocal disease) should have advanced disease that is considered unresectable Eastern Cooperative Oncology Group (ECOG) 0-2 Measurable disease Adequate organ function No active brain metastases Prior therapy No more than 3 prior lines of systemic therapy Prior therapy with a MET inhibitor is allowed as long as the patient has not had progressive disease while receiving the agent Design: This is a phase 2 single center non-randomized trial. The study will be conducted using a Simon 2 stage minimax design. Initially 13 evaluable subjects will be recruited. If there are no responses to therapy, the study will be terminated. If there is at least 1 response an additional 7 evaluable subjects will be accrued. The two-stage minimax design is based on assuming an ineffective response rate of 5% and a targeted effective response rate of 25%. We also assume that the probability of accepting an ineffective treatment and the probability of rejecting an effective treatment are each 10%. Subjects will be dosed orally at a starting dose of 400 mg twice daily. The overall response rate (complete response + partial response) will be determined.

Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.

OS is the time between the first day of treatment and day of death or last follow up calculated by Kaplan Meier analysis.

Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

INCLUSION CRITERIA 2.1.1.1 Patients must have histologically or cytologically confirmed papillary Renal Cell Cancer (RCC). Patients with bilateral multifocal disease can have tumors localized to the kidney or have metastatic disease Patients with sporadic papillary RCC (but without multifocal disease) should have advanced disease that is considered unresectable 2.1.1.2 Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions). Nodal lesions must be 15mm by computed tomography (CT) scan or magnetic resonance imaging (MRI). Non nodal lesions must be >10 mm with CT scan or MRI. 2.1.1.3 Patients must have normal organ and marrow function as defined below: Hemoglobin > 9 g/dL (SI Units: 90 g/L) Platelet count greater than or equal to 75 x 10 (9)/L Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10(9)/L without growth factor support Total bilirubin less than or equal to 2 x upper limit of normal (ULN) Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT)/serum glutamate-pyruvate transaminase (SGPT) less than or equal to 2.5 x upper limit of normal (ULN) Serum creatinine less than or equal to 1.5 x ULN Asymptomatic serum amylase less than or equal to 2 x ULN; patients with > ULN but less than or equal to 2 x ULN serum amylase at study start must be confirmed to have no signs and/or symptoms suggestion pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.) Serum lipase less than or equal to ULN Fasting serum triglyceride level less than or equal to 500 mg/dL 2.1.1.4 Patients may have had no more than 3 prior lines of systemic therapy. Prior therapy with a mesenchymal epithelial transition (MET) inhibitor is allowed as long as the patient has not had progressive disease while receiving the agent 2.1.1.5 Patient must be able to swallow and retain oral medication 2.1.1.6 Age greater than or equal to18 years. 2.1.1.7 Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2. 2.1.1.8 Patients must provide written informed consent prior to any study procedures. 2.1.1.9 Patients must be willing and able to comply with scheduled visits, treatment plan and laboratory tests EXCLUSION CRITERIA 2.1.2.1 Patients who are receiving any other investigational agents for treatment of their kidney cancer. 2.1.2.2 History of allergic reactions attributed to compounds of similar chemical or biologic composition to Capmatinib (INC280). Excipients in the current formulation include microcrystalline cellulose, mannitol, sodium starch glycolate, magnesium stearate and colloidal silicon dioxide 2.1.2.3 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements or potentially affect the interpretation of study data. 2.1.2.4 Subjects with significant or uncontrolled cardiovascular disease (e.g., uncontrolled hypertension, peripheral vascular disease, congestive heart failure, cardiac arrhythmia, or acute coronary syndrome) within 6 months prior to starting study treatment or heart attack within 12 months prior to starting study treatment 2.1.2.5 Patients receiving any medications that are known to be strong inducers or inhibitors of cytochrome P450 3A4 (CYP3A4), or sensitive substrates of CYP3A4, cytochrome P450 1A2 (CYP1A2), cytochrome P450 family 2 subfamily C member 9 (CYP2C9), cytochrome P450 2C19 (CYP2C19) or P-glycoprotein (P-gp) with a narrow therapeutic index. 2.1.2.6 Symptomatic central nervous system (CNS) metastases that are neurologically unstable or requiring > 5 mg/day of dexamethasone (or equivalent) to control CNS disease. Note: Patients with controlled CNS metastases are allowed. Radiotherapy or surgery for CNS metastases must have been completed >2 weeks prior to study entry. Patients must be neurologically stable, having no new neurologic deficits on clinical examination, and no new findings on CNS imaging. Steroid use for management of CNS metastases must be at a stable dose for two weeks preceding study entry. 2.1.2.7 Patients with greater than or equal to Grade 2 neuropathy. 2.1.2.8 Treatment with proton pump inhibitors within 3 days prior to study entry. If continued use of gastrointestinal (GI) prophylaxis is required, the patient will be switched to an appropriate Histamine H2-receptor antagonists (H2) with appropriate counsel and caution. 2.1.2.9 Currently receiving any prohibited medications including vitamins and herbal Supplements. 2.1.2.10 Major surgery within 4 weeks prior to initiating treatment, excluding the placement of vascular access. 2.1.2.11 The subject has not recovered to baseline, Common Terminology Criteria for Adverse Events (CTCAE) less than or equal to Grade 1 from toxicity due to all prior therapies for RCC or to a level permitted under other sections of the eligibility criteria except alopecia and other non-clinically significant adverse events (AEs). 2.1.2.12 Any other condition that would, in the Investigators judgment, contraindicate participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc. 2.1.2.13 Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test (> 30 mIU/mL). Laboratory values >5 mIU/mL, but <30 mIU/mL should be repeated in 48 hours. 2.1.2.14 Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 months days after stopping study drug. Highly effective contraception methods include: Total abstinence or Male or female sterilization or Combination of any two of the following (a+b or a+c or b+c): Use of oral, injected or implanted hormonal methods of contraception Placement of an intrauterine device (IUD) or intrauterine system (IUS) Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 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. 2.1.2.15 Sexually active males must use a condom during intercourse while taking the drug and for 3 months after stopping study drug and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. 2.1.2.16 Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Capmatinib (INC280). 2.1.2.17 Prior invasive malignancy of other histology currently requiring treatment.

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).