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
Documented evidence of advanced RCC
More than 1 prior VEGF-targeted treatment for advanced RCC
During dose escalation only, an additional population with unresectable advanced and/or metastatic 2nd line RCC patients is allowed
Patients must have histologically or cytologically confirmed papillary RCC\r\n* Patients with bilateral multifocal disease can have tumors localized to the kidney or have metastatic disease\r\n* Patients with sporadic papillary RCC (but without multifocal disease) should have advanced disease that is considered unresectable
Diagnosis of advanced RCC associated with HLRCC (cohort 1) or sporadic/non-HLRCC papillary RCC (cohort 2)
Cohort C: advanced or metastatic (stage 4) RCC
Prior systemic treatment of any kind or radiotherapy for RCC
Has at least 1 measurable solid RCC tumor and no RCC tumor that requires immediate surgical intervention. The diagnosis of RCC can be radiologic (histologic diagnosis not required). Patients may have VHL disease-associated tumors in other organ systems
Has received no prior systemic therapy for advanced RCC.
Has received prior radiotherapy for RCC.
Advanced or metastatic RCC
No more than three total prior systemic treatment regimens in the advanced or metastatic RCC setting
Prior systemic therapy for advanced RCC; however, treatment with immunotherapy (i.e., high-dose bolus IL-2, ipilimumab + nivolumab, etc.) is allowed
Metastatic RCC
Prior use of systemic checkpoint inhibitors for the management of metastatic RCC is excluded; prior IFN-alpha or IL-2 is allowed
Radiotherapy for RCC within 14 days of first study treatment with the exception of a single fraction of radiation administered for palliation of symptoms
Patient has received prior treatment for RCC including surgery, radiation, thermoablation or systemic therapy
Prior systemic therapy directed at advanced or metastatic RCC
Must not have had prior systemic therapy for stage IV RCC (except for nivolumab as part of part A of this protocol)
PHASE I: Histologically confirmed advanced RCC of any subtype
PHASE II: Advanced RCC associated with 1) HLRCC or SDH (Cohort 1); OR 2) advanced non HLRCC-related papillary RCC (Cohort 2)
RENAL CELL CARCINOMA (RCC) COHORT INCLUSION CRITERIA: History of histologically-proven locally advanced or metastatic (cT2a-T4NanyMany) chromophobe RCC
(Dose levels 1 and 2) - may have received one or more systemic treatments or regimens for metastatic RCC; (dose level 3) - cannot have received prior systemic treatment for RCC
Metastatic RCC
Recurrent, unresectable, or metastatic RCC or STS (any histologic type) for which pazopanib is an appropriate therapy
Advanced or metastatic RCC
Histologically confirmed, previously untreated (treatment-naive) RCC
No prior systemic therapy for RCC except for one prior adjuvant or neoadjuvant therapy for completely resectable RCC
Phase 2 expansion: RCC
Patient must not have received any prior or concurrent systemic therapy for RCC; adjuvant placebo administration is permitted
For RCC:
Has received no prior systemic therapy for advanced RCC. Prior neoadjuvant/adjuvant therapy for RCC is acceptable if completed >12 months prior to allocation.
Has received no prior systemic therapy for advanced RCC.
Subjects with metastatic RCC who have failed 2 or 3 prior systemic regimens, one of which includes a VEGFR TKI other than sorafenib or tivozanib.
More than 3 prior regimens for metastatic RCC.
RCC subjects must have received ?1 prior line of therapy for metastatic disease (Part 1A)
Prior systemic therapy directed at advanced RCC.
No prior systemic therapy for RCC with the following exception:
Prior treatment with systemic therapy for advanced RCC
For subjects with metastatic RCC who have had no prior systemic treatment for RCC and are considered a poor risk according to Motzer criteria, defined by having >= 3 of the following 5 risk factors for short survival: Karnofsky performance score < 80%, lactate dehydrogenase (LDH) > 1.5 X of ULN, hemoglobin < lower limit of normal (LLN), corrected serum calcium > 10 mg/dL (2.5mM), a time from initial diagnosis of RCC to initiation of systemic therapy of < 1 year
Advanced/metastatic RCC
Subjects enrolled in the I-1, I-3 expansion arms and IN-3 addition arms must not have received any prior systemic therapy for RCC with the following exceptions:
Subjects must have a pathologic diagnosis of advanced renal cell carcinoma (RCC), with histological or cytological confirmation of RCC and must have failed at least 1 prior line of anti-VEGF therapy (including but not limited to sunitinib, and/or sorafenib, and/or bevacizumab and/or pazopanib, and/or axitinib) and must not have received prior therapy with a TORC1 inhibitor (such as temsirolimus or everolimus); or
Subjects must have a pathologic diagnosis of advanced renal cell carcinoma (RCC) and must have progressed on treatment with a TORC1 inhibitor (such as temsirolimus or everolimus).
Have localized non-metastatic renal cell carcinoma (RCC) (< pT2, NO, MO), as per the American Joint Committee on Cancer (AJCC) seventh (7th) edition criteria; patients who have not had a biopsy must have a solid renal mass suggestive of RCC with confirmation of RCC at screening biopsy
Have metastatic RCC with primary tumor in place
1-2 lines of prior therapy for advanced or metastatic RCC including at least one antiangiogenic therapy or nivolumab + ipilimumab
Phase 2: Subjects with advanced or metastatic urothelial carcinoma or RCC.
Patients must not have received systemic therapy for RCC within four weeks prior to registration
Renal Cell Carcinoma (RCC): --Histologic diagnosis of either clear-cell or papillary RCC (metastatic and unresectable, or bilateral, multifocal, unresectable RCC localized to kidneys).
Metastatic or locally advanced unresectable RCC. NOTE: Prior nephrectomy is not mandatory.
Radiotherapy for RCC within 14 days of first study treatment with the exception of a single fraction of radiation administered for palliation of symptoms
LOCALIZED RCC TREATED WITH PARTIAL NEPHRECTOMY:\r\nHave primary or suspected diagnosis of RCC, with presence of cT1-2 renal mass by diagnostic computed tomography (CT) assessment
LOCALIZED RCC TREATED WITH PARTIAL NEPHRECTOMY:\r\nScheduled for partial nephrectomy of renal mass
LOCALIZED RCC TREATED WITH PARTIAL NEPHRECTOMY:\r\nExpected survival of at least 3 months
LOCALIZED RCC TREATED WITH PARTIAL NEPHRECTOMY:\r\nWritten informed consent available
LOCALIZED RCC TREATED WITH PARTIAL NEPHRECTOMY:\r\nEastern Cooperative Oncology Group (ECOG) =< 1
LOCALIZED RCC TREATED WITH PARTIAL NEPHRECTOMY:\r\nNegative serum or urine pregnancy test within 24 hours for females of child bearing age
LOCALIZED RCC TREATED WITH PARTIAL NEPHRECTOMY:\r\nRecovered from toxicity of any prior therapy to >= grade 1
ADVANCED RCC TREATED WITH RADICAL NEPHRECTOMY:\r\nHave pathologic or suspected diagnosis of RCC with presence of cT1-4 renal mass and evidence of nodal or metastatic involvement by diagnostic CT assessment
ADVANCED RCC TREATED WITH RADICAL NEPHRECTOMY:\r\nScheduled for radical nephrectomy and lymph node dissection
ADVANCED RCC TREATED WITH RADICAL NEPHRECTOMY:\r\nExpected survival of at least 3 months
ADVANCED RCC TREATED WITH RADICAL NEPHRECTOMY:\r\nECOG =< 2
ADVANCED RCC TREATED WITH RADICAL NEPHRECTOMY:\r\nNegative serum or urine pregnancy test within 24 hours for females of child bearing age
ADVANCED RCC TREATED WITH RADICAL NEPHRECTOMY:\r\nRecovered from toxicity of any prior therapy to >= grade 1
ADVANCED RCC TREATED WITH RADICAL NEPHRECTOMY:\r\nWritten informed consent available
Previously received cryotherapy of RCC
Advanced or Metastatic renal cell carcinoma (RCC)