Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Carcinoma, Squamous Cell

Urinary Bladder Neoplasms

Carcinoma, Renal Cell

Carcinoma, Transitional Cell

Carcinoma, Neuroendocrine

Carcinoma, Small Cell

Carcinoma, Medullary

Urethral Neoplasms

Penile Neoplasms

Ureteral Neoplasms

Pelvic Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Adenocarcinoma

Kidney Neoplasms

Kidney Diseases

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Urethral Diseases

Genital Neoplasms, Male

Genital Diseases

Genital Diseases, Male

Penile Diseases

Ureteral Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Transitional Cell Carcinoma

Penile Cancer

Thyroid Cancer, Medullary

Renal Medullary Carcinoma

Urethral Cancer

Neuroendocrine Tumor

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Nivolumab

Ipilimumab

Immunoglobulins

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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.

Biopsy

Biospecimen Collection

Cabozantinib S-malate

Computed Tomography

Echocardiography

Magnetic Resonance Imaging

Andrea B Apolo

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.

PRIMARY OBJECTIVES:

I. Determine the dose limiting toxicity (DLT) and recommended phase II dose (RP2D) of the combination of cabozantinib s-malate (cabozantinib) and nivolumab (cabo-nivo) and separately the combination of cabozantinib, nivolumab and ipilimumab (cabo-nivo-ipi) in patients with genitourinary tumors. (Phase I) II. Assess safety and tolerability of cabozantinib, nivolumab and ipilimumab (cabo-nivo-ipi) in patients with genitourinary tumors at this novel dose. (Dose Level 8 Cohort)

SECONDARY OBJECTIVES:

I. Preliminarily evaluate the activity, as determined by objective response rate using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the modified Immune-Related Response Criteria (irRC), derived from RECIST 1.1, of:

Ia. Cabo-nivo and cabo-nivo-ipi in patients with advanced/refractory metastatic urothelial carcinoma (checkpoint inhibition therapy naive) and with renal cell carcinoma in the second-line and beyond setting.

Ib. Cabo-nivo in patients with adenocarcinoma and with rare histologies (including squamous or small cell carcinomas of the bladder, renal medullary carcinoma, sarcomatoid bladder and renal cell carcinomas, plasmacytoid carcinoma of the bladder and others) in the first line or beyond setting.

Ic. Cabo-nivo in patients with urothelial carcinoma previously treated with checkpoint inhibition therapy in the second line or beyond setting.

Id. Cabo-nivo-ipi in patients with squamous cell carcinoma of the penis.

II. To evaluate the activity as determined by progression free survival (PFS) and overall survival (OS) of:

IIa. Cabo-nivo and cabo-nivo-ipi in patients with advanced/refractory metastatic urothelial carcinoma (checkpoint inhibition therapy naive) or with renal cell carcinoma in the second-line and beyond setting.

IIb. Cabo-nivo in patients with adenocarcinoma and with rare histologies (including squamous, small cell carcinomas of the bladder, renal medullary carcinoma, sarcomatoid bladder and renal cell carcinomas, plasmacytoid carcinoma of the bladder and others) in the first line or beyond setting.

IIc. Cabo-nivo in patients with urothelial carcinoma previously treated with checkpoint inhibition therapy in the second line or beyond setting.

IId. Cabo-nivo-ipi in patients with squamous cell carcinoma of the penis. III. To obtain additional data to evaluate the safety of both combinations in patients with clear cell renal cell carcinoma (ccRCC).

IV. To assess the number of malignant soft tissue and bone lesions on fludeoxyglucose F-18 (18F-FDG) positron emission tomography (PET)/computed tomography (CT) (scan 1) versus combined fluorine F 18 sodium fluoride (18F-NaF) and 18F-FDG PET/CT (scan 2).

V. To assess response assessment by RECIST 1.1 using CT of the chest, abdomen, and pelvis with intravenous (IV) contrast versus assessment by combined 18F-NaF and 18F-FDG PET/CT (scan 2) using number of malignant and change (modified PET RECIST \[PERCIST\]) of soft tissue and bone lesions.

VI. To test the feasibility of automated density and volume application (ADaVA) as a means of assessing tumor response.

VII. To assess PDL-1 and MET expression data and in exploratory fashion analyze their association to response or clinical benefit.

EXPLORATORY OBJECTIVES:

I. To assess overall response rates (ORR) on patients who have been challenged or re-challenged with ipilimumab therapy post disease progression.

II. To assess effects of treatment in patients with bone-only disease.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 treatment arms.

PART I: Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28 and nivolumab intravenously (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.

PART II: Patients receive cabozantinib s-malate PO QD on days 1-21, nivolumab IV over 30 minutes on day 1, and ipilimumab IV over 90 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of 4 cycles with ipilimumab, patients continue receiving 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.

After completion of study treatment, patients are followed up at 16 weeks, and then every 3 months thereafter.

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

A Phase 1 Study of Cabozantinib Plus Nivolumab (CaboNivo) Alone or in Combination With Ipilimumab (CaboNivoIpi) in Patients With Advanced/Metastatic Urothelial Carcinoma and Other Genitourinary Tumors

The overall response rates determined at this time point will be combined and reported along with 95% confidence intervals.

Patients with bone-only disease will be enrolled and evaluated using progression free survival for a descriptive analysis of the effect of treatment. In addition, if PDL-1 or MET data are obtained in this small cohort, exploratory and descriptive analyses may be done as appropriate.

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.

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.

Will be assessed by Response Evaluation Criteria in Solid Tumors 1.1 and Immune-Related Response Criteria. The response rate may be used to guide the further development of the combinations.

May be determined as well and reported on both arms. This fraction will be considered as a secondary endpoint for the expansion cohorts as well, and this information may be used to guide the further development of the combinations. A Kaplan-Meier curve for progression free survival will also be presented as a secondary endpoint, in addition to reporting the fraction without progression at two months.

PDL-1 and MET expression data will be obtained in patients with urothelial carcinoma checkpoint inhibition naive, clear cell renal cell carcinoma, adenocarcinoma of the bladder, squamous cell carcinoma of the bladder, urothelial carcinoma with prior checkpoint inhibition therapy, and penile cancer. Data will be obtained in pre- and post-treatment biopsies and analyze, in at least an exploratory fashion, their association to response or clinical benefit.

National Cancer Institute (NCI)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Cabozantinib S-malate and Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Genitourinary Tumors	NCT02496208	Bladder Small C... Bladder Squamou... Bladder Urothel... Clear Cell Rena... Invasive Bladde... Invasive Bladde... Invasive Sarcom... Kidney Medullar... Malignant Genit... Malignant Solid... Penile Carcinom... Penile Squamous... Renal Cell Carc... Renal Pelvis Ur... Sarcomatoid Ren... Stage III Bladd... Stage III Penil... Stage III Renal... Stage III Renal... Stage III Renal... Stage III Urete... Stage III Ureth... Stage IV Bladde... Stage IV Penile... Stage IV Renal ... Stage IV Renal ... Stage IV Ureter... Stage IV Urethr... Ureter Urotheli... Urethral Urothe...	Biopsy Biospecimen Col... Cabozantinib S-... Computed Tomogr... Echocardiograph... Ipilimumab Magnetic Resona... Nivolumab	18 Years -	National Cancer Institute (NCI)
Cabozantinib S-malate and Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Genitourinary Tumors	NCT02496208	Bladder Small C... Bladder Squamou... Bladder Urothel... Clear Cell Rena... Invasive Bladde... Invasive Bladde... Invasive Sarcom... Kidney Medullar... Malignant Genit... Malignant Solid... Penile Carcinom... Penile Squamous... Renal Cell Carc... Renal Pelvis Ur... Sarcomatoid Ren... Stage III Bladd... Stage III Penil... Stage III Renal... Stage III Renal... Stage III Renal... Stage III Urete... Stage III Ureth... Stage IV Bladde... Stage IV Penile... Stage IV Renal ... Stage IV Renal ... Stage IV Ureter... Stage IV Urethr... Ureter Urotheli... Urethral Urothe...	Biopsy Biospecimen Col... Cabozantinib S-... Computed Tomogr... Echocardiograph... Ipilimumab Magnetic Resona... Nivolumab	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for invasive sarcomatoid urothelial carcinoma