Tivantinib With or Without Erlotinib Hydrochloride in Treating Patients With Metastatic or Locally Advanced Kidney Cancer That Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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This randomized phase II trial studies how well tivantinib with or without erlotinib hydrochloride works in treating patients with metastatic or locally advanced kidney cancer that cannot be removed by surgery. Tivantinib and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the response rate (confirmed complete and partial response) of patients with locally advanced or metastatic papillary renal cell carcinoma treated with either ARQ 197 (tivantinib) or ARQ 197 combined with erlotinib (erlotinib hydrochloride). SECONDARY OBJECTIVES: I. To assess the progression free survival (PFS) of patients with locally advanced or metastatic papillary renal cell carcinoma treated with either ARQ 197 or ARQ 197 combined with erlotinib. II. To assess the safety and tolerability of ARQ 197 therapy and ARQ 197 combined with erlotinib. III. To descriptively assess the role of prior treatment on outcome. TERTIARY OBJECTIVES: I. To bank tissue specimens for future use and once funding is obtained to evaluate the expression of tissue correlative biomarkers such as hepatocyte growth factor receptor (c-MET) and epidermal growth factor receptor (EGFR), and to perform exploratory correlation with clinical outcomes. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive tivantinib orally (PO) twice daily (BID) on days 1-28. ARM II: Patients receive tivantinib PO BID and erlotinib hydrochloride PO once daily (QD) on days 1-28. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for up to 2 years.

Official Title
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Parallel (Randomized) Phase II Evaluation of ARQ 197 and ARQ 197 in Combination With Erlotinib in Papillary Renal Cell Carcinoma

Conditions
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Recurrent Renal Cell Carcinoma, Stage III Renal Cell Cancer, Stage IV Renal Cell Cancer, Type 1 Papillary Renal Cell Carcinoma, Type 2 Papillary Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Erlotinib Hydrochloride
* Other: Laboratory Biomarker Analysis
* Drug: Tivantinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed papillary histology renal cell carcinoma which is metastatic, or locally advanced and unresectable; mixed histologies will be allowed provided that they contain >= 50% of the papillary component Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension; x-rays, scans or physical examinations used for tumor measurement must have been completed within 28 days prior to registration; x-rays, scans or physical examinations for non-measurable disease must have been completed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment form Patients with metastatic disease who have a resectable primary tumor and are deemed a surgical candidate may have undergone resection; at least 28 days must have elapsed since surgery and patient must have recovered from any adverse effects of surgery Patients with a history of brain metastases who are asymptomatic and have not received steroid therapy in the 14 days prior to registration are eligible; anti-seizure medications are allowed provided they are non-enzyme inducing (e.g. topiramate, levetiracetam, gabapentin) Patients may have received up to one prior systemic therapy for advanced or metastatic renal cell carcinoma; patients must not have received a MET inhibitor or erlotinib as prior therapy; at least 21 days must have elapsed since completion of prior systemic therapy, 42 days for nitrosoureas or mitomycin C; patients must have recovered from all associated toxicities at the time of registration Patients may have received prior radiation therapy, but must have measurable disease outside the radiation port; at least 21 days must have elapsed since completion of prior radiation therapy; patients must have recovered from all associated toxicities at the time of registration Patients must not be receiving or planning to receive any other investigational agents Patients must have a complete physical examination and medical history within 28 days prior to registration Patients must have a Zubrod performance status of 0-2 White blood cell (WBC) >= 2,000/mcL Absolute neutrophil count (ANC) >= 1,000/mcL Platelet count >= 75,000/mcL Serum bilirubin =< 1.5 x institutional upper limits of normal (ULN) Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) and serum glutamic pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) must be =< 1.5 x the institutional ULN unless the liver is involved with the tumor, in which case serum transaminase (SGOT/SGPT) must be =< 5 x the institutional ULN Serum creatinine must be =< 2 x the institutional ULN Sodium, potassium and calcium must be obtained within 14 days prior to registration Patients with a known history of the following corneal diseases are not eligible: dry eye syndrome, Sjogren's syndrome, keratoconjunctivitis sicca, exposure keratopathy, Fuchs' dystrophy or other active disorders of cornea Patients known to be human immunodeficiency virus (HIV)-positive and receiving combination anti-retroviral therapy are not eligible Patients must be able to take oral medications; patients must not have gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease; patients with intractable nausea or vomiting are not eligible Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of reproductive potential if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, effective contraception also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years Patients must be offered the opportunity to participate in specimen banking for future translational medicine studies All patients must be informed of the investigational nature of this study and must sign and give written informed consent As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (tivantinib)<br>Patients receive tivantinib PO BID on days 1-28. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Tivantinib<br>* 360 mg (3 tablets) by mouth, Twice daily (720 mg total daily dose) on days 1-28, until disease progression<br>|
| Experimental: Arm II (tivantinib and erlotinib hydrochloride)<br>Patients receive tivantinib PO BID and erlotinib hydrochloride PO QD on days 1-28. | Drug: Erlotinib Hydrochloride<br>* 150 mg (1 tablet) by mouth on days 1-28, once daily, until disease progression<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Tivantinib<br>* 360 mg (3 tablets) by mouth, Twice daily (720 mg total daily dose) on days 1-28, until disease progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (Confirmed Complete Response or Partial Response), Determined According to Response Evaluation Criteria in Solid Tumors | Best Response is calculated from the sequence of objective statuses. CR: Two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. PR: Two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration, but not qualifying as CR. Stable/no response: At least one objective status of stable/no response documented at least 6 weeks after registration and before progression or symptomatic deterioration, but not qualifying as anything else above. Increasing disease: Objective status of progression within 12 weeks of registration, not qualifying as anything else above. Symptomatic deterioration: Objective status of symptomatic deterioration within 12 weeks of registration, not qualifying as anything else above. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and Severity of Toxicities, Graded by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | This study utilized the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0 for toxicity and Serious Adverse Event reporting. Patients were evaluated every two weeks for the first eight weeks and then once every four weeks. If all protocol treatment is delayed more than three weeks, patients were removed from protocol treatment | Up to 3 years | 
| Progression-free Survival (PFS) | From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive without report of progression are censored at date of last contact. | 30 months |