Cabozantinib S-malate and Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Genitourinary Tumors

NCT02496208 | Active Not Recruiting Phase 1

• 9 other identifiers: NCI-2014-0237915-C-0160150160P1417069681UM1CA186712UM1CA186716UM1CA186717ZIABC011078
• Study Type: interventional
• Target: 152
• Locations: 1 country
• Sites: 8

Brief Summary

This phase I trial studies the side effects and best doses of cabozantinib s-malate and nivolumab with or without ipilimumab in treating patients with genitourinary (genital and urinary organ) tumors that have spread from where it first started (primary site) to other places in the body (metastatic). Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving cabozantinib s-malate and nivolumab alone or with ipilimumab works better in treating patients with genitourinary tumors.

Conditions

Clear Cell Renal Cell Carcinoma; Kidney Medullary Carcinoma; Malignant Genitourinary System Neoplasm; Malignant Solid Neoplasm; Penile Carcinoma; Renal Cell Carcinoma; Stage III Bladder Cancer AJCC v8; Stage III Penile Cancer AJCC v8; Stage III Renal Cell Cancer AJCC v8; Stage III Urethral Cancer AJCC v8; Stage IV Bladder Cancer AJCC v8; Stage IV Renal Pelvis and Ureter Cancer AJCC v8; Stage IV Renal Cell Cancer AJCC v8; Bladder Small Cell Neuroendocrine Carcinoma; Invasive Bladder Plasmacytoid Urothelial Carcinoma; Invasive Bladder Sarcomatoid Urothelial Carcinoma; Invasive Sarcomatoid Urothelial Carcinoma; Penile Squamous Cell Carcinoma; Renal Pelvis Urothelial Carcinoma; Sarcomatoid Renal Cell Carcinoma; Stage III Renal Pelvis and Ureter Cancer AJCC v8; Stage III Renal Pelvis Cancer AJCC v8; Stage III Ureter Cancer AJCC v8; Stage IV Penile Cancer AJCC v8; Stage IV Ureter Cancer AJCC v8; Stage IV Urethral Cancer AJCC v8; Ureter Urothelial Carcinoma; Urethral Urothelial Carcinoma; Bladder Squamous Cell Carcinoma; Bladder Urothelial Carcinoma

Outcome Measures

Primary Outcomes (2)

• Recommended phase II dose (Phase I)

  Will be defined as the highest dose for which no more than 1/6 patients experience a dose limiting toxicity evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The safe dose level of cabozantinib and nivolumab, as well as of cabozantinib, nivolumab, and ipilimumab will be established.

  Up to 4-6 weeks

• Incidence of adverse events (Phase I)

  Will be evaluated according National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The safety and tolerability of a novel dose of cabozantinib, nivolumab and ipilimumab in patients with genitourinary cancer will be assessed.

  Up to 30 days post treatment

Secondary Outcomes (3)

• Clinical response rate

  Up to 3 years

• Fraction of patients who have been identified as being alive and progression free at two months

  At 2 months

• PDL-1 and MET expression

  Up to day 1 of final cycle

Other Outcomes (2)

• Overall response rate in patients receiving ipilimumab challenge/re-challenge

  Up to 3 years

• Progression free survival in bone-only urothelial carcinoma

  Up to 3 years

Study Arms (2)

Part I (cabozantinib s-malate, nivolumab)

EXPERIMENTAL

Patients receive cabozantinib s-malate PO QD on days 1-28 and nivolumab IV over 30 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After 21 cycles, patients receive nivolumab IV over 30 minutes every 4 weeks in the absence of disease progression or unacceptable toxicity. After progression, patients may receive cabozantinib s-malate PO, nivolumab IV, and ipilimumab IV at the part II RP2D for 4 cycles followed by cabozantinib s-malate PO QD and nivolumab IV every 2 weeks or 4 weeks if post-cycle 21 in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography or magnetic resonance imaging and collection of blood samples throughout the trial. Patients may also undergo echocardiography at baseline and biopsies throughout the trial.

Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Drug: Cabozantinib S-malate; Procedure: Computed Tomography; Procedure: Echocardiography Test; Procedure: Magnetic Resonance Imaging; Biological: Nivolumab

Part II (cabozantinib s-malate, nivolumab, ipilimumab)

EXPERIMENTAL

See detailed description.

Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Drug: Cabozantinib S-malate; Procedure: Computed Tomography; Procedure: Echocardiography Test; Biological: Ipilimumab; Procedure: Magnetic Resonance Imaging; Biological: Nivolumab

Interventions

Computed Tomography PROCEDURE

Undergo CT scan

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Part I (cabozantinib s-malate, nivolumab); Part II (cabozantinib s-malate, nivolumab, ipilimumab)

Echocardiography Test PROCEDURE

Undergo echocardiography

Also known as: EC, Echocardiography

Part I (cabozantinib s-malate, nivolumab); Part II (cabozantinib s-malate, nivolumab, ipilimumab)

Biopsy Procedure PROCEDURE

Undergo biopsies

Also known as: Biopsy, BIOPSY_TYPE, Bx

Part I (cabozantinib s-malate, nivolumab); Part II (cabozantinib s-malate, nivolumab, ipilimumab)

Biospecimen Collection PROCEDURE

Undergo collection of blood

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Part I (cabozantinib s-malate, nivolumab); Part II (cabozantinib s-malate, nivolumab, ipilimumab)

Cabozantinib S-malate DRUG

Given PO

Also known as: BMS-907351, Cabometyx, Cometriq, XL 184, XL-184, XL184

Part I (cabozantinib s-malate, nivolumab); Part II (cabozantinib s-malate, nivolumab, ipilimumab)

Ipilimumab BIOLOGICAL

Given IV

Also known as: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS 734016, BMS-734016, BMS734016, Ipilimumab Biosimilar CS1002, MDX 010, MDX-010, MDX-CTLA4, MDX010, Yervoy

Part II (cabozantinib s-malate, nivolumab, ipilimumab)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Part I (cabozantinib s-malate, nivolumab); Part II (cabozantinib s-malate, nivolumab, ipilimumab)

Nivolumab BIOLOGICAL

Given IV

Also known as: ABP 206, BCD-263, BMS 936558, BMS-936558, BMS936558, CMAB819, MDX 1106, MDX-1106, MDX1106, NIVO, Nivolumab Biosimilar ABP 206, Nivolumab Biosimilar BCD-263, Nivolumab Biosimilar CMAB819, ONO 4538, ONO-4538, ONO4538, Opdivo

Part I (cabozantinib s-malate, nivolumab); Part II (cabozantinib s-malate, nivolumab, ipilimumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients in the phase I portion must have:
• Histologically confirmed diagnosis of metastatic, genitourinary solid tumor
• Metastatic disease defined as new or progressive lesions on cross-sectional imaging; patients must have at least:
• One evaluable site of disease
• Or, appearance of one new bone lesion
• Patients in the expansion portion must have:
• Histologically confirmed diagnosis of metastatic:
• Urothelial carcinoma of the bladder, urethra, ureter, renal pelvis, OR
• Clear cell renal cell carcinoma OR
• Adenocarcinoma of the bladder OR
• Non-resectable squamous cell carcinoma of the penis OR
• Squamous or small cell carcinoma of the bladder, renal medullary carcinoma (RMC), sarcomatoid bladder and renal cell carcinomas, plasmacytoid carcinoma of the bladder or other rare bladder/kidney cancer histology AND
• Patients with urothelial cancer or renal cell carcinoma must have progressive metastatic disease defined as new or progressive lesions on cross-sectional imaging; patients must have at least:
• One measurable site of disease (according to RECIST criteria) or bone disease by NaF PET/CT
• Patients must have either progressed on at least one standard therapy or there must be no standard treatment that has been shown to prolong survival for the patient's disease (patients with urothelial carcinoma who are cisplatin-ineligible may receive protocol therapy as a first line therapy); patients may have received any number of prior cytotoxic agents

You may not qualify if:

• The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment
• Patients who have been previously treated with MET or VEGFR inhibitors (except for patients on renal cell cancer \[RCC\] cohort) are not eligible for the expansion cohorts but can enroll in the phase I portion
• Prior treatment with any therapy on the PD-1/PD-L1 axis or CTLA-4 inhibitors unless enrolling the urothelial carcinoma with previous checkpoint inhibition therapy expansion cohort
• The subject has received radiation therapy:
• To the thoracic cavity or abdomen within 3 months before the first dose of study treatment, or has ongoing complications, or is without complete recovery and healing from prior radiation therapy
• To bone or brain metastasis within 3 weeks before the first dose of study treatment
• To any other site(s) within 28 days before the first dose of study treatment
• The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment
• The subject has received prior treatment with a small molecule kinase inhibitor within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment
• The subject has received prior treatment with hormonal therapy within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment; subjects receiving gonadotropin-releasing hormone (GnRH) agonists and antagonists are allowed to participate
• The subject has received any other type of investigational agent within 28 days before the first dose of study treatment
• The subject has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =\< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs) defined as lab elevation with no associated symptoms or sequelae
• The subject has active brain metastases or epidural disease; subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain imaging with contrast-enhanced CT or magnetic resonance imaging (MRI) scans for subjects with known brain metastases is required to confirm eligibility
• The subject has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test \>= 1.5 x the laboratory ULN within 7 days before the first dose of study treatment
• No concomitant treatment with warfarin is permitted. Aspirin (up to 325 mg/day), thrombin or factor Xa inhibitors, low-dose warfarin (=\<1 mg/day), prophylactic and therapeutic low molecular weight heparin (LMWH) are permitted

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (8)

City of Hope Comprehensive Cancer Center

Duarte, California, 91010, United States

Location

Los Angeles General Medical Center

Los Angeles, California, 90033, United States

Location

USC / Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

University of California Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

NCI - Center for Cancer Research

Bethesda, Maryland, 20892, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08903, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Related Publications (3)

• Apolo AB, Girardi DM, Niglio SA, Nadal R, Kydd AR, Simon N, Ley L, Cordes LM, Chandran E, Steinberg SM, Lee S, Lee MJ, Rastogi S, Sato N, Cao L, Banday AR, Boudjadi S, Merino MJ, Toubaji A, Akbulut D, Redd B, Bagheri H, Costello R, Gurram S, Agarwal PK, Chalfin HJ, Valera V, Streicher H, Wright JJ, Sharon E, Figg WD, Parnes HL, Gulley JL, Saraiya B, Pal SK, Quinn D, Stein MN, Lara PN, Bottaro DP, Mortazavi A. Final Results From a Phase I Trial and Expansion Cohorts of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced/Metastatic Genitourinary Tumors. J Clin Oncol. 2024 Sep 1;42(25):3033-3046. doi: 10.1200/JCO.23.02233. Epub 2024 Jul 2.

  PMID: 38954785 DERIVED

• Girardi DM, Niglio SA, Mortazavi A, Nadal R, Lara P, Pal SK, Saraiya B, Cordes L, Ley L, Ortiz OS, Cadena J, Diaz C, Bagheri H, Redd B, Steinberg SM, Costello R, Chan KS, Lee MJ, Lee S, Yu Y, Gurram S, Chalfin HJ, Valera V, Figg WD, Merino M, Toubaji A, Streicher H, Wright JJ, Sharon E, Parnes HL, Ning YM, Bottaro DP, Cao L, Trepel JB, Apolo AB. Cabozantinib plus Nivolumab Phase I Expansion Study in Patients with Metastatic Urothelial Carcinoma Refractory to Immune Checkpoint Inhibitor Therapy. Clin Cancer Res. 2022 Apr 1;28(7):1353-1362. doi: 10.1158/1078-0432.CCR-21-3726.

  PMID: 35031545 DERIVED

• Apolo AB, Nadal R, Girardi DM, Niglio SA, Ley L, Cordes LM, Steinberg SM, Sierra Ortiz O, Cadena J, Diaz C, Mallek M, Davarpanah NN, Costello R, Trepel JB, Lee MJ, Merino MJ, Bagheri MH, Monk P, Figg WD, Gulley JL, Agarwal PK, Valera V, Chalfin HJ, Jones J, Streicher H, Wright JJ, Ning YM, Parnes HL, Dahut WL, Bottaro DP, Lara PN Jr, Saraiya B, Pal SK, Stein MN, Mortazavi A. Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors. J Clin Oncol. 2020 Nov 1;38(31):3672-3684. doi: 10.1200/JCO.20.01652. Epub 2020 Sep 11.

  PMID: 32915679 DERIVED

MeSH Terms

Conditions

Carcinoma, Renal Cell; Urogenital Neoplasms; Penile Neoplasms; Urinary Bladder Neoplasms; Ureteral Neoplasms; Urethral Neoplasms

Interventions

Biopsy; Specimen Handling; cabozantinib; Ipilimumab; CTLA-4 Antigen; Magnetic Resonance Spectroscopy; Nivolumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Genital Neoplasms, Male; Genital Diseases, Male; Genital Diseases; Penile Diseases; Urinary Bladder Diseases; Ureteral Diseases; Urethral Diseases

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immune Checkpoint Proteins; Costimulatory and Inhibitory T-Cell Receptors; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Antigens, Differentiation, T-Lymphocyte; Antigens, Differentiation; Antigens, Surface; Antigens; Biological Factors; Biomarkers; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Andrea B Apolo

  National Cancer Institute LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 8, 2015
• First Posted: July 14, 2015
• Study Start: July 22, 2015
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2026
• Last Updated: April 13, 2026

Record last verified: 2026-03

Locations

US (8)