Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Carcinoma, Squamous Cell

Adenocarcinoma

Urinary Bladder Neoplasms

Ureteral Neoplasms

Pelvic Neoplasms

Urethral Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

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

Urethral Diseases

Ureteral Diseases

Urachal Adenocarcinoma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Pembrolizumab

Immunoglobulins

Immunoconjugates

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Immunologic Factors

Patients receive enfortumab vedotin IV and pembrolizumab IV on study. Patients also undergo CT scan or MRI, and collection of blood throughout the trial.

Biospecimen Collection

Computed Tomography

Enfortumab Vedotin

Magnetic Resonance Imaging

Questionnaire Administration

Bassel Nazha, MD, MPH

Wilena Session

This phase II trial tests how well enfortumab vedotin (EV) and pembrolizumab works in treating patients with bladder cancer of variant histology (a group of less common types of bladder cancer) that have spread to nearby tissue or lymph nodes (locally advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to an anticancer drug called vedotin. Enfortumab attaches to a protein called nectin-4 on cancer cells in a targeted way and delivers vedotin to kill them. It is a type of antibody-drug conjugate. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving enfortumab vedotin and pembrolizumab may kill more tumor cells in patients with locally advanced or metastatic bladder cancer of variant histology.

PRIMARY OBJECTIVE:

I. To evaluate the anti-tumor activity of the combination of enfortumab vedotin (EV) plus pembrolizumab by assessing the overall response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

SECONDARY OBJECTIVES:

I. To evaluate the efficacy of the combination as measured by progression free survival, overall survival, and duration of response.

II. To evaluate the safety as measured by incidence of adverse events assessed up to 2 years.

EXPLORATORY OBJECTIVE:

I. To assess tissue-based assays in archival tissue and correlative changes in peripheral T-cell subsets, myeloid derived suppressor cells (MDSC), blood inflammatory markers and cytokines.

OUTLINE:

Patients receive enfortumab vedotin intravenously (IV) and pembrolizumab IV on study. Patients also undergo computed tomography (CT) scan or magnetic resonance imaging (MRI), and collection of blood throughout the trial.

Enfortumab Vedotin Plus Pembrolizumab for the Treatment of Locally Advanced or Metastatic Bladder Cancer of Variant Histology

Phase II Single-Arm Study of Enfortumab Vedotin (EV) Plus Pembrolizumab in the Treatment of Locally Advanced or Metastatic Bladder Cancer of Variant Histology

Will be measured by Response Evaluation Criteria in Solid Tumors version 1.1, and estimated by the Clopper-Pearson method with 95% confidence intervals.

Kalan-Meier method will be used to estimate median event time and 2-year survival rate with 95% confidence interval.

Determined by occurrence of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.

Graded according to the Common Terminology Criteria for Adverse Events version 5.0, and will be tabulated using descriptive statistics (mean, median, minimum, maximum, standard deviation).

National Cancer Institute (NCI)

Seagen Inc.

Astellas Pharma Inc

Merck Sharp & Dohme LLC

Emory University

Principal Investigator

Gland and Hormone Related Diseases

Prostatic Neoplasms

Carcinoma, Renal Cell

Carcinoma, Ductal

Carcinoma, Transitional Cell

Carcinoma, Neuroendocrine

Adenocarcinoma, Clear Cell

Carcinoma, Small Cell

Carcinoma, Medullary

Leydig Cell Tumor

Sertoli Cell Tumor

Penile Neoplasms

Thyroid Neoplasms

Thyroid Diseases

Genital Neoplasms, Male

Genital Diseases

Genital Diseases, Male

Neoplasms, Squamous Cell

Kidney Neoplasms

Kidney Diseases

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Penile Diseases

Endocrine Gland Neoplasms

Head and Neck Neoplasms

Endocrine System Diseases

Sertoli-Leydig Cell Tumor

Sex Cord-Gonadal Stromal Tumors

Testicular Neoplasms

Testicular Diseases

Gonadal Disorders

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Transitional Cell Carcinoma

Penile Cancer

Papillary Renal Cell Carcinoma

Chromophil Renal Cell Carcinoma

Chromophobe Renal Cell Carcinoma

Thyroid Cancer, Medullary

Collecting Duct Carcinoma

Renal Medullary Carcinoma

Urethral Cancer

Neuroendocrine Tumor

Neuroepithelioma

Sertoli-leydig Cell Tumors

Immunomodulating Agents

Nivolumab

Ipilimumab

Patients receive cabozantinib PO, nivolumab IV and ipilimumab IV while on study. Patients undergo CT scan, MRI, PET and bone scans throughout the study.

Bone Scan

Cabozantinib S-malate

Positron Emission Tomography

Site Public Contact

Arnab Basu

Lance C. Pagliaro

Uzair B. Chaudhary

Anishka D'Souza

Nancy A. Dawson

Tareq Al Baghdadi

Hatem Hassanein

Mehmet A. Bilen

John M. Schallenkamp

Jeffrey A. Sosman

Thomas C. Westbrook

Walter M. Stadler

Vamsi K. Vasireddy

Bryan A. Faller

Ami Badami

Andrea B Apolo

This phase II trial studies how well cabozantinib works in combination with nivolumab and ipilimumab in treating patients with rare genitourinary (GU) tumors that that has spread from where it first started (primary site) to other places in the body. Cabozantinib 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. Giving cabozantinib, nivolumab, and ipilimumab may work better in treating patients with genitourinary tumors that have no treatment options compared to giving cabozantinib, nivolumab, or ipilimumab alone.

PRIMARY OBJECTIVE:

I. To evaluate the efficacy of cabozantinib s-malate (cabozantinib) combined with nivolumab and ipilimumab in the first or second-line (and beyond) setting for patients within each of the rare genitourinary (GU) variant histology group of interest, as measured by objective response rate (ORR).

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival (PFS) for patients treated with cabozantinib combined with nivolumab and ipilimumab within each rare variant histology.

II. To estimate the overall survival (OS) for patients treated with cabozantinib combined with nivolumab and ipilimumab within each rare variant histology.

III. To estimate the clinical benefit rate (defined as complete response \[CR\] or partial response \[PR\] or stable disease \[SD\]) for patients treated with cabozantinib combined with nivolumab and ipilimumab within each rare variant histology.

IV. To assess the safety of treating patients with rare variant histologies with cabozantinib combined with nivolumab and ipilimumab.

V. To support tissue banking and collection of clinical follow-up data for GU tract rare histological variants.

EXPLORATORY OBJECTIVES:

I. To assess effects of treatment in patients with bone-only disease by bone scan.

OUTLINE:

Patients receive cabozantinib orally (PO), nivolumab intravenously (IV) and ipilimumab IV while on study. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), positron emission tomography (PET) and bone scans throughout the study.

Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare Genitourinary Tumors

A Phase II Study of Ipilimumab, Cabozantinib, and Nivolumab in Rare Genitourinary Cancers (ICONIC)

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

The bone-only tumor patients will be evaluated in an exploratory fashion (if no RECIST measurements are available). A maximum of 15 patients with bone-only disease will be enrolled and evaluated using PFS for a descriptive analysis of the effect of treatment.

An objective response is defined as a confirmed complete response (CR) or partial response (PR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A confirmed tumor response is defined to be either a CR or PR noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. Will be estimated by the number of confirmed objective responses divided by the total number of evaluable patients. Confidence intervals for the true ORR will be calculated.

Defined for all evaluable patients who have achieved an objective response as the date at which the patient's earliest best objective status is first noted to be either a CR or PR to the earliest date progression is documented.

The median its 95% confidence interval will be determined and will be summarized using the Kaplan-Meier estimator.

A confirmed clinical benefit is defined to be either a CR or PR noted as the objective status on 2 consecutive evaluations at least 4 weeks apart or a confirmed stable disease at two consecutive tumor assessments at least 3 months apart. The CBR will be estimated by the number of patients with confirmed clinical benefit divided by the total number of evaluable patients. Confidence intervals for the true CBR will be calculated using exact binomial confidence intervals.

Will be assessed using Common Terminology Criteria for Adverse Events version 5.0. The maximum of a particular AE will be determined for each patient. Tables will summarize the number and relative frequency of patients observing an AE as well as the number and relative frequency of patients experiencing any AE of grade 3 or greater.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Enfortumab Vedotin Plus Pembrolizumab for the Treatment of Locally Advanced or Metastatic Bladder Cancer of Variant Histology	NCT05756569	Bladder Squamou... Locally Advance... Malignant Renal... Malignant Urete... Malignant Ureth... Metastatic Blad... Stage III Bladd... Stage IV Bladde... Unresectable Bl... Urachal Adenoca... Bladder Adenoca...	Biospecimen Col... Computed Tomogr... Enfortumab Vedo... Magnetic Resona... Pembrolizumab Questionnaire A...	18 Years -	Emory University
Enfortumab Vedotin Plus Pembrolizumab for the Treatment of Locally Advanced or Metastatic Bladder Cancer of Variant Histology	NCT05756569	Bladder Squamou... Locally Advance... Malignant Renal... Malignant Urete... Malignant Ureth... Metastatic Blad... Stage III Bladd... Stage IV Bladde... Unresectable Bl... Urachal Adenoca... Bladder Adenoca...	Biospecimen Col... Computed Tomogr... Enfortumab Vedo... Magnetic Resona... Pembrolizumab Questionnaire A...	18 Years -	Emory University
Testing the Effectiveness of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) With One Anti-cancer Targeted Drug (Cabozantinib) for Rare Genitourinary Tumors	NCT03866382	Bladder Adenoca... Bladder Clear C... Bladder Mixed A... Bladder Neuroen... Bladder Small C... Bladder Squamou... Chromophobe Ren... Collecting Duct... Invasive Bladde... Invasive Bladde... Invasive Bladde... Invasive Bladde... Invasive Bladde... Invasive Bladde... Kidney Medullar... Large Cell Neur... Malignant Testi... Malignant Testi... Metastatic Blad... Metastatic Blad... Metastatic Blad... Metastatic Blad... Metastatic Blad... Metastatic Blad... Metastatic Blad... Metastatic Blad... Metastatic Blad... Metastatic Blad... Metastatic Chro... Metastatic Kidn... Metastatic Mali... Metastatic Papi... Metastatic Peni... Metastatic Pros... Metastatic Sarc... Metastatic Uret... Papillary Renal... Sarcomatoid Ren... Stage IV Bladde... Stage IV Penile... Stage IV Renal ... Stage IV Urethr... Stage IVB Prost... Urachal Adenoca... Urethral Clear ...	Bone Scan Cabozantinib S-... Computed Tomogr... Ipilimumab Magnetic Resona... Nivolumab Positron Emissi...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for urachal adenocarcinoma