A Randomized, Phase II Efficacy Assessment of Multiple MET Kinase Inhibitors (Cabozantinib [NSC #761968], Crizotinib [NSC #749005], Savolitinib [NSC #785348], and Sunitinib [NSC #736511]) in Metastatic Papillary Renal Carcinoma (PAPMET)
Overview
- Phase
- Phase 2
- Intervention
- Biospecimen Collection
- Conditions
- Locally Advanced Papillary Renal Cell Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 152
- Locations
- 595
- Primary Endpoint
- Progression Free Survival (PFS)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This phase II trial studies how well cabozantinib s-malate, crizotinib, savolitinib, or sunitinib malate work in treating patients with kidney cancer that has spread from where it started to nearby tissue or lymph nodes or to other places in the body. Cabozantinib s-malate, crizotinib, savolitinib, and sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving cabozantinib s-malate, crizotinib, or savolitinib will work better in treating patients with kidney cancer compared to sunitinib malate.
Detailed Description
PRIMARY OBJECTIVE: I. To compare progression-free survival (PFS) in patients with metastatic papillary renal cell carcinoma (mPRCC) treated with sunitinib malate (sunitinib) to PFS in patients with mPRCC treated with MET kinase inhibitors. SECONDARY OBJECTIVES: I. To compare Response Evaluation Criteria in Solid Tumors (RECIST) response rate (RR; defined as the combined rate of confirmed and unconfirmed partial response \[PR\] and confirmed and unconfirmed complete response \[CR\]) in patients with mPRCC treated with sunitinib to RR in patients treated with putative MET inhibitors. II. To compare overall survival (OS) in patients with mPRCC treated with sunitinib to OS in patients with mPRCC treated with putative MET inhibitors. III. To compare the safety profile of sunitinib and putative MET inhibitors in patients with mPRCC. TRANSLATIONAL OBJECTIVES: I. To evaluate the prognostic and predictive value of MET mutations, MET copy number or other markers of MET signaling in patients with mPRCC treated with putative MET inhibitors. II. To estimate the frequency of high oncometabolite levels in formalin-fixed, paraffin-embedded (FFPE) tissues of patients with advanced papillary renal cell carcinoma by liquid chromatography-mass spectrometry (LC-MS/MS) and estimate progression free survival for those with and without high oncometabolite levels being treated. III. To correlate the mutational signature suggestive of a homologous recombination defect with high oncometabolite levels in patients with papillary renal cell carcinoma pRCC. OUTLINE: Patients are randomized to 1 of 4 treatment arms. As of 12/5/18, patients will only be randomized to Arm I or Arm II. ARM I: Patients receive sunitinib malate orally (PO) once daily (QD) on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up. ARM II: Patients receive cabozantinib s-malate PO QD on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up. ARM III (CLOSED TO ACCRUAL 12/5/18): Patients receive crizotinib PO twice daily (BID) on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up. ARM IV (CLOSED TO ACCRUAL 12/5/18): Patients receive savolitinib PO QD on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up. After completion of study treatment, patients are followed up for 3 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically or cytologically confirmed papillary histology renal cell carcinoma which is metastatic or locally advanced disease not amenable to surgical resection; (NOTE: a designation of type I or type II should be made by the local pathologist if possible); mixed histologies containing type I or type II will be allowed provided that they contain \>= 50% of the papillary component
- •Patients must also have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension; disease X-rays, scans or physical examinations used for tumor measurement must have been completed within 28 days prior to registration; if there is clinical suspicion for bone metastases at the time of enrollment (at the discretion of the investigator), bone scan should be performed at baseline (within 42 days prior to registration); all disease must be assessed and documented on the Baseline Tumor Assessment form
- •Patients with a history of treated 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 must not have cavitating pulmonary lesions; patients must not have tumor invading the gastrointestinal (GI) tract or evidence of endotracheal or endobronchial tumor within 28 days prior to registration
- •Patients may have received prior surgery; at least 28 days must have elapsed since surgery and patient must have recovered from any adverse effects of surgery
- •Patients may have received up to one prior systemic therapy for advanced or metastatic renal cell carcinoma with the exception of another VEGF inhibitor Food and Drug Administration (FDA)-approved for advanced renal cell carcinoma (RCC) (i.e., pazopanib, bevacizumab, sorafenib or axitinib); if a patient develops metastatic disease within six months of discontinuation of adjuvant therapy, this will constitute one prior systemic therapy for advanced or metastatic RCC; if a patient develops metastatic disease and more than six months has elapsed since discontinuation of adjuvant therapy, this will not constitute prior systemic therapy for advanced or metastatic RCC; patients may have also received prior immunotherapy; patients must not have received a MET/hepatocyte growth factor (HGF) inhibitor or sunitinib as prior therapy; at least 14 days must have elapsed since completion of prior systemic therapy; 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 14 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 taking, nor plan to take while on protocol treatment, strong CYP3A4 inhibitors (e.g. boceprevir, cobicistat, danoprevir, elvitegravir/RIT, fluvoxamine, indinavir, itraconazole, ketoconazole, lopinavir/RIT, nefazodone, nelfinavir, posaconazole, ritonavir, telaprevir, telithromycin, tipravavir/RIT, or voriconazole); strong CYP3A4 inducers (e.g. avasimibe, phenytoin, rifampin, rifabutin); potent inhibitors of CYP1A2 (e.g. ciprofloxacin); and/or drugs known to be CYP3A4 substrates with a narrow therapeutic range (e.g., diergotamine, ergotamine) within 14 days prior to randomization; moderate inhibitors or inducers of isoenzyme CYP3A4 should be avoided, but if necessary can be used with caution
- •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
Exclusion Criteria
- Not provided
Arms & Interventions
Arm I (sunitinib malate)
Patients receive sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Biospecimen Collection
Arm I (sunitinib malate)
Patients receive sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Bone Scan
Arm I (sunitinib malate)
Patients receive sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Computed Tomography
Arm I (sunitinib malate)
Patients receive sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Sunitinib Malate
Arm II (cabozantinib s-malate)
Patients receive cabozantinib s-malate PO QD on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Biospecimen Collection
Arm II (cabozantinib s-malate)
Patients receive cabozantinib s-malate PO QD on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Bone Scan
Arm II (cabozantinib s-malate)
Patients receive cabozantinib s-malate PO QD on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Cabozantinib S-malate
Arm II (cabozantinib s-malate)
Patients receive cabozantinib s-malate PO QD on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Computed Tomography
Arm III (crizotinib closed to accrual 12/5/18)
Patients receive crizotinib PO BID on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Biospecimen Collection
Arm III (crizotinib closed to accrual 12/5/18)
Patients receive crizotinib PO BID on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Bone Scan
Arm III (crizotinib closed to accrual 12/5/18)
Patients receive crizotinib PO BID on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Computed Tomography
Arm III (crizotinib closed to accrual 12/5/18)
Patients receive crizotinib PO BID on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Crizotinib
Arm IV (savolitinib closed to accrual 12/5/18)
Patients receive savolitinib PO QD on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Biospecimen Collection
Arm IV (savolitinib closed to accrual 12/5/18)
Patients receive savolitinib PO QD on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Bone Scan
Arm IV (savolitinib closed to accrual 12/5/18)
Patients receive savolitinib PO QD on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Computed Tomography
Arm IV (savolitinib closed to accrual 12/5/18)
Patients receive savolitinib PO QD on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Intervention: Savolitinib
Outcomes
Primary Outcomes
Progression Free Survival (PFS)
Time Frame: From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause; assessed up to 3 years
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of appropriate diameters of target lesions over smallest sum observed, or a measurable increase in a non-target lesion, or the appearance of new lesions
Secondary Outcomes
- Response Rate (RR)(Up to 3 years)
- Overall Survival (OS)(Up to 3 years)
- Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs(Duration of treatment and follow up until death or 3 years post registration)