Testing Cabozantinib, Crizotinib, Savolitinib and Sunitinib in Kidney Cancer Which Has Progressed
Condition: Locally Advanced Papillary Renal Cell Carcinoma; Metastatic Papillary Renal Cell Carcinoma; Stage III Renal Cell Cancer AJCC v7; Stage IV Renal Cell Cancer AJCC v7; Type 1 Papillary Renal Cell Carcinoma; Type 2 Papillary Renal Cell Carcinoma; Unresectable Renal Cell Carcinoma
MeSH terms: Carcinoma; Carcinoma, Renal Cell
Intervention: Cabozantinib S-malate; Crizotinib; Savolitinib; Sunitinib Malate
Intervention description: Given PO; Given PO; Given PO; Given PO
Intervention MeSH terms: Sunitinib; Crizotinib; Tyrosine Protein Kinase Inhibitors
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 152.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

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 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