A Phase 2 Study of the MET Kinase Inhibitor INC280 in Papillary Renal Cell Cancer
Condition: Kidney Cancer
MeSH terms: Carcinoma, Renal Cell; Kidney Neoplasms
Intervention: INC280
Intervention description: Supplied by Novartis as film-coated tablet for oral use.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Hereditary Papillary Renal Cell Carcinoma; VEGF Pathway; mTOR Inhibitor; Kidney Cancer

Summary:

      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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA

        2.1.1.1 Patients must have histologically or cytologically confirmed papillary Renal Cell
        Cancer (RCC).

          1. Patients with bilateral multifocal disease can have tumors localized to the kidney or
             have metastatic disease

          2. 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):

               1. Use of oral, injected or implanted hormonal methods of contraception

               2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

               3. 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.