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INC280 400 mg twice every day by mouth, continuously

Supplied by Novartis as film-coated tablet for oral use.

INC280

Ramaprasad Srinivasan, M.D.

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.

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

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

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.

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.

National Cancer Institute (NCI)

Principal Investigator

Participants received a starting dose of 600mg twice a day (BID) of capmatinib initially; following a change in formulation during the study, the starting dose was changed to 400mg BID, based on pharmacokinetic (PK) studies that demonstrated that this corresponded to the starting dose of 600mg BID of the old formulation.

Capmatinib (INC280)

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Ramaprasad Srinivasan

Complete Response

Partial Response

Stable Disease

Progressive Disease

Not evaluable for response

Percentage of Participants With Response

Progression Free Survival (PFS)

Overall Survival

Disease Control Rate (Partial and Complete Response Plus Stable Disease > 6 Months)

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Number of Grades 1-5 Adverse Events Related to Treatment

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

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Phase 2 Study of the MET Kinase Inhibitor INC280 in Papillary Renal Cell Cancer	NCT02019693	Kidney Cancer	INC280	18 Years -	National Institutes of Health Clinical Center (CC)
A Phase 2 Study of the MET Kinase Inhibitor INC280 in Papillary Renal Cell Cancer	NCT02019693	Kidney Cancer	INC280	18 Years -	National Institutes of Health Clinical Center (CC)

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