Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Carcinoma, Renal Cell

Kidney Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Papillary Renal Cell Carcinoma

Chromophil Renal Cell Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Sunitinib

Crizotinib

Tyrosine Kinase Inhibitors

Angiogenesis Inhibitors

Growth Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

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.

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.

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.

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.

Undergo collection of plasma and serum samples

Biospecimen Collection

Bone Scan

Cabozantinib S-malate

Computed Tomography

Savolitinib

Sunitinib Malate

Sumanta K Pal

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.

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.

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

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)

The hazard ratio between the MET inhibitor versus (vs.) sunitinib in those with versus without the mutation (i.e., the interaction) will be compared. Response Evaluation Criteria in Solid Tumors (RECIST) response rate (confirmed and unconfirmed partial response and complete response) based on MET mutation/expression level will be compared using the chi-square test.

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

The response rate (RR) is defined as the combined rate of confirmed and unconfirmed partial response and confirmed and unconfirmed complete response. Complete response (CR) is defined as the complete disappearance of all target and non-target lesions, along with no new lesions. Partial response (PR) is defined as \>=30% decrease of the sum of appropriate diameters of all target measurable lesions, along with no new lesions.

Duration from date of randomization to date of death from any cause.

Only adverse events that are possibly, probably or definitely related to study drug are reported.

Canadian Cancer Trials Group

National Cancer Institute (NCI)

143 participants who received protocol treatment were evaluable for AEs: 45 on sunitinib arm, 43 on cabozantinib arm, 27 on crizotinib arm, and 28 on savolitinib arm. Adverse Events (AEs) are reported by CTCAE Version 4.0 and Serious Adverse Events (SAEs) are reported by CTCAE Version 5.0. All started participants were monitored/assessed for All-Cause Mortality".

Experimental: Arm I (sunitinib malate) Patients receive sunitinib malate PO on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

Drug: Sunitinib Malate Given PO

Other Names:

SU011248 SU11248 sunitinib Sunitinib Malate Sutent

Experimental: Arm II (cabozantinib s-malate) Patients receive cabozantinib s-malate PO on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

Drug: Cabozantinib S-malate Given PO

Other Names:

BMS-907351 Cabometyx CABOZANTINIB S-MALATE Cometriq XL-184 XL184

Cabozantinib

Experimental: 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.

Drug: Crizotinib Given PO

Other Names:

CRIZOTINIB MET Tyrosine Kinase Inhibitor PF-02341066 PF-02341066 PF-2341066 Xalkori

Experimental: Arm IV (savolitinib closed to accrual 12/5/18) Patients receive savolitinib PO on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

Drug: Savolitinib Given PO

Other Names:

AZD 6094 AZD6094 HMPL-504 SAVOLITINIB Volitinib

Patients receive sunitinib malate PO on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

Sunitinib Malate: Given PO

Arm I (Sunitinib Malate)

Patients receive cabozantinib s-malate PO on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

Cabozantinib S-malate: Given PO

Arm II (Cabozantinib S-malate)

Patients receive crizotinib PO BID on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

Crizotinib: Given PO

Arm III (Crizotinib Closed to Accrual 12/5/18)

Patients receive savolitinib PO on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

Savolitinib: Given PO

Arm IV (Savolitinib Closed to Accrual 12/5/18)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Previous Systemic Therapy

Papillary renal cell carcinoma (pRCC) histological subtype as determined by a local pathologist. Type 1 is characterized by small cells in a a single layer with scant basophilic cytoplasm and oval nuclei. Type 2 is characterized by large cells with eosinophilic cytoplasm and spherical nuclei with prominent nucleoli and pseudostratification. Type 1 is more common and grows slowly and type 2 is more aggressive and grows more quickly. In general, type 2 pRCC has a poorer prognosis than type 1.

Histological Subtype (Local Assessment)

Papillary renal cell carcinoma (pRCC) histological subtype as determined by a central pathologic assessment. Type 1 is characterized by small cells in a a single layer with scant basophilic cytoplasm and oval nuclei. Type 2 is characterized by large cells with eosinophilic cytoplasm and spherical nuclei with prominent nucleoli and pseudostratification. Type 1 is more common and grows slowly and type 2 is more aggressive and grows more quickly. In general, type 2 pRCC has a poorer prognosis than type 1.

Histological Subtype (Central Assessment)

The International Metastatic Renal Cell Carcinoma Database Consortium's (IMDC) prognostic model to predict survival of metastatic kidney cancer patients has become the standard model used in clinical trials to categorize patients into favorable, intermediate, and poor risk based on treatment time, performance status, and hemoglobin, calcium, neutrophil, and platelet counts.

IMDC Risk Group

Zubrod performance status scores range from 0 to 4, with higher scores reflecting greater disability. This study only includes participants with a score of 0-1.

0: Fully active, able to carry on all pre-disease performance without restriction.

1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work.

Zubrod Performance Score

Previous Nephrectomy

Bone

Metastatic Sites of Interest

Analysis population included only eligible participants.

Genitourinary Committee Statistician

A proportional hazards model was used to compare the Hazard Ratio (HR) for PFS.

Experimental: Arm I (sunitinib malate) Patients receive sunitinib malate PO on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity

Drug: Sunitinib Malate Given PO

Other Names:

SU011248 SU11248 sunitinib Sunitinib Malate Sutent

Experimental: 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.

Drug: Crizotinib Given PO

Other Names:

CRIZOTINIB MET Tyrosine Kinase Inhibitor PF-02341066XXPF-02341066 PF-2341066 Xalkori

Analysis population included eligible participants.

Progression Free Survival (PFS)

The Chi-Square test will be used to compare RR between sunitinib and cabozantinib.

Response Rate (RR)

The log-rank test will be used to compare OS.

Overall Survival (OS)

Abdominal pain

Acute kidney injury

Alanine aminotransferase increased

Allergic reaction

Anemia

Anorexia

Aspartate aminotransferase increased

Back pain

Confusion

Dehydration

Diarrhea

Duodenal ulcer

Dyspnea

Edema limbs

Epistaxis

Facial pain

Fall

Fatigue

Febrile neutropenia

Gastrointestinal disorders - Other, specify

Generalized muscle weakness

Genital edema

Hearing impaired

Hematoma

Hypercalcemia

Hyperkalemia

Hypermagnesemia

Hypertension

Hypoalbuminemia

Hypocalcemia

Hypomagnesemia

Hyponatremia

Hypophosphatemia

Hypoxia

Infections and infestations - Other, specify

Lung infection

Lymphedema

Lymphocyte count decreased

Lymphocyte count increased

Mucositis oral

Muscle weakness lower limb

Nausea

Nervous system disorders - Other, specify

Neutrophil count decreased

Pain

Pain in extremity

Palmar-plantar erythrodysesthesia syndrome

Pancreatitis

Paronychia

Platelet count decreased

Pleural effusion

Pneumonitis

Proteinuria

Rash maculo-papular

Renal calculi

Reproductive system and breast disorders - Other

Sinus bradycardia

Sinus tachycardia

Skin ulceration

Somnolence

Syncope

Thromboembolic event

Thrombotic thrombocytopenic purpura

Vascular disorders - Other, specify

Vomiting

White blood cell decreased

Eligible participants who received at least one dose of protocol treatment.

Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs

MET Mutation Rate

Overall Study

Spots Global Cancer Trial Database for locally advanced papillary renal cell carcinoma