Testing Cabozantinib, Crizotinib, Savolitinib and Sunitinib in Kidney Cancer Which Has Progressed
Testing Cabozantinib, Crizotinib, Savolitinib and Sunitinib in Kidney Cancer Which Has Progressed
This randomized 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.
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 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.

 ARM II: Patients receive cabozantinib s-malate PO QD on days 1-42.

 ARM III (CLOSED TO ACCRUAL 12/5/18): Patients receive crizotinib PO twice daily (BID) on days
 1-42.

 ARM IV (CLOSED TO ACCRUAL 12/5/18): Patients receive savolitinib PO QD on days 1-42.

 In all arms, cycles repeat every 42 days in the absence of disease progression or
 unacceptable toxicity.

 After completion of study treatment, patients are followed up for 3 years.
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 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 renal cell carcinoma (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

 -  Patients must have a Zubrod performance status of 0 - 1

 -  White blood cell count (WBC) >= 2,000/mcL (must be obtained within 28 days prior to
 registration)

 -  Absolute neutrophil count (ANC) >= 1,000/mcL (must be obtained within 28 days prior to
 registration)

 -  Platelet count >= 75,000/mcL (must be obtained within 28 days prior to registration)

 -  Serum bilirubin =< 1.5 x institutional upper limits of normal (ULN) (must be obtained
 within 28 days prior to registration)

 -  Serum transaminase (serum glutamic oxaloacetic transaminase [SGOT]/aspartate
 aminotransferase [AST] and serum glutamate pyruvate transaminase [SGPT]/alanine
 aminotransferase [ALT]) must be =< 2.5 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 (must be obtained within 28 days prior to registration)

 -  Serum creatinine must be =< 2 x the institutional ULN OR creatinine clearance (either
 measured or calculated) must be > 30 mL/min (must be obtained within 28 days prior to
 registration)

 -  Patients must not have any clinical evidence of congestive heart failure (CHF)
 (specifically, New York Heart Association [NYHA] class III [moderate] or class IV
 [severe]) at the time of registration; baseline echocardiogram within 28 days of
 registration must demonstrate an ejection fraction (EF) >= 50%; due to the potential
 cardiac toxicity of the agents utilized in this protocol, patients must have corrected
 QT (QTc) interval < 500 msec on prestudy electrocardiogram (EKG) and no known history
 of congenital long QT syndrome; patients must not have experienced unstable angina
 pectoris, clinically significant cardiac arrhythmias, or stroke (transient ischemic
 attack [TIA] or other ischemic event) within 3 months prior to registration and not
 have experienced myocardial infarction or thromboembolic event requiring
 anticoagulation within 6 months of registration; prestudy EKG must be obtained within
 28 days prior to registration

 -  Baseline urinalysis should show urine protein < 3+ and must be obtained within 28 days
 prior to registration; if urine protein is 3+ or greater, then urine protein by 24
 hour collection must show less than 3 grams of protein

 -  Patients must not have inadequately controlled hypertension; patients must have
 documented blood pressures of systolic blood pressure (SBP) < 150 and diastolic blood
 pressure (DBP) < 90 within 14 days of starting randomization; blood pressure
 medications (any number) are permitted

 -  Patients must be able to take oral medications (i.e., swallow pills whole); 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 that could in the opinion of the treating investigator affect absorption,
 or active peptic ulcer disease; patients with intractable nausea or vomiting are not
 eligible

 -  Patients must not have had any clinically-significant GI bleeding within 6 months
 prior to registration and patients must not have a GI disorder which (at the
 discretion of the investigator) bears a high risk of perforation or fistula; examples
 of this include (but are not limited to) Crohn's disease or tumor with transmural
 extension through the gastrointestinal lining

 -  Patients must not have had hemoptysis of >= 0.5 teaspoon (2.5 ml) of red blood within
 3 months prior registration

 -  Patients must not demonstrate any other signs indicative of pulmonary hemorrhage
 within 3 months prior to registration

 -  Patient's baseline imaging must not indicate the presence of tumor invading or
 encasing any major blood vessels

 -  Patients must not have any unresolved wounds from previous surgery

 -  Albumin, alkaline phosphatase, bicarbonate, blood urea (BUN), chloride, glucose,
 phosphorus, and total protein must be assessed within 28 days of registration

 -  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 3 years; men receiving
 active surveillance for prostate cancer may also be enrolled

 -  Due to the unknown effects of the study drugs, patients must not be pregnant or
 nursing; women/men of reproductive potential must have agreed to use an effective
 contraceptive method while receiving study drug and for three months after last dose
 of study drug; 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

 -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
 therapy are ineligible because of the potential for pharmacokinetic interactions with
 cabozantinib, crizotinib, savolitinib or sunitinib; in addition these patients are at
 increased risk of lethal infections when treated with marrow suppressive therapy;
 appropriate studies will be undertaken in patients receiving combination
 antiretroviral therapy when indicated

 -  Patients must have tissue available and be willing to submit for independent
 pathologic review in order to classify type I versus type II papillary disease

 -  Patients must be offered the opportunity to participate in specimen banking for future
 translational medicine studies

 -  Patients must be informed of the investigational nature of this study and must sign
 and give written informed consent in accordance with institutional and federal
 guidelines

 -  As a part of the 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