E-Newsletter - July 2019
Spotlight on Alliance Trials

 

Alliance Trial Examines Effectiveness of THE COMBINATION OF Two Immunotherapy Drugs with An Anti-cancer Targeted Drug for Rare Genitourinary Tumors

Alliance A031702 - A phase II study of ipilimumab, cabozantinib, and nivolumab in rare genitourinary cancers (ICONIC)

The Alliance trial looks at how well cabozantinib s-malate, nivolumab, and ipilimumab work together in treating patients with rare genitourinary (GU) cancers that have spread to other places in the body. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, specifically checkpoint inhibitors, 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 s-malate, nivolumab, and ipilimumab may work better in treating patients with rare GU cancers that have no treatment options compared to giving cabozantinib s-malate, nivolumab, or ipilimumab alone.

Study Rationale
Rare GU cancers are cancers of aberrant histology occurring in the GU tract including kidney, bladder, ureters, and penis. These tumors occur so infrequently that large randomized clinical trials to develop optimal effective therapies are logistically difficult. Therefore, treatment information is obtained from case reports, retrospective studies and small-size (often incomplete) clinical trials. In this phase II trial (Alliance A031702 ICONIC), Alliance investigators aim to study the role of combination nivolumab, ipilimumab, and  cabozantinib in the rare histological variants of the GU tract, including rare bladder tumors including  adenocarcinoma, squamous cell carcinoma, and small cell carcinoma; variants of urothelial  carcinoma including plasmacytoid, sarcomatoid, and others; rare renal tumors including sarcomatoid renal cell carcinoma and renal medullary carcinoma; and penile cancers. Investigators have seen preliminary responses to this triple combination in rare GU tumors.  

Peripheral blood mononuclear cells from patients in a phase II study of monotherapy cabozantinib for advanced urothelial carcinoma and a separate cohort of rare bladder cancers demonstrated an increase in T-regulatory cells, showing that cabozantinib has immunomodulatory properties. This provides a strong rationale for combining cabozantinib with immune checkpoint inhibitors, such as nivolumab alone or in combination with ipilimumab. A phase I study of the doublet and triplet combination in patients with GU malignancies was conducted and the recommended phase II dose for the triplet is being used in this study. There were no dose-limiting toxicities seen at any level. 

Study Outcomes
The primary, secondary, and exploratory objectives are described below.

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

Secondary objectives:
1. To estimate the progression-free survival (PFS) for patients treated with cabozantinib combined with nivolumab and ipilimumab within each rare variant histology.
2. To estimate the overall survival (OS) for patients treated with cabozantinib combined with nivolumab and ipilimumab within each rare variant histology.
3. To estimate the clinical benefit rate (defined as CR or PR or SD) for patients treated with cabozantinib combined with nivolumab and ipilimumab within each rare variant histology.
4. To assess the safety of treating patients with rare variant histologies with cabozantinib combined with nivolumab and ipilimumab.
5. To support tissue banking and collection of clinical follow-up data for GU tract rare histological variants.

Exploratory objective:
To assess effects of treatment in patients with bone-only disease by bone scan.

Key Eligibility Criteria
Patients may have received any number of prior anti-cancer treatments with the exception of patients with small cell carcinoma of the bladder.

Some of the eligibility criteria include:

Inclusion Criteria:

-- Metastatic disease defined as new or progressive lesions on cross-sectional imaging
-- Histologically confirmed diagnosis of metastatic: small cell carcinoma of the bladder; adenocarcinoma of the bladder; squamous cell carcinoma of the bladder; plasmacytoid urothelial carcinoma; any penile cancer; sarcomatoid renal cell carcinoma; sarcomatoid urothelial carcinoma; renal medullary carcinoma or other miscellaneous histologic variants of the urothelial carcinoma, such as, but not limited to micropapillary, giant cell, lipid-rich, clear cell and nested variants, large cell neuroendocrine carcinoma, lymphoepithelioma-like carcinoma and mixed patterns will be considered, as well as small cell neuroendocrine prostate cancer, testicular Sertoli or Leydig cell tumors, and papillary and chromophobe RCC
-- Hematoxylin and eosin (H&E) slides from diagnostic tumor tissue for retrospective central pathology review
-- Patients may have received any number of prior anti-cancer treatments or be treatment-naive (with exception of patients with small cell carcinoma of the bladder, who should have received a platinum-based combination regimen
-- Age > 18 years on day of consent
-- Patients must be able to swallow oral formulation of the tablets
-- Karnofsky performance status > 70%
-- Required laboratory values as detailed in the protocol/schema page of protocol
-- Prior treatment with MET or VEGFR inhibitors is allowed. However, prior cabozantinib is not allowed.
-- Prior treatment with any therapy on the PD-1/PD-L1 axis or anti-CTLA4/CTLA-4 inhibitors is allowed, either in the perioperative or metastatic setting.
-- Patients that have received both prior MET or VEGF and prior PD-1/PD-L1/CTLA-4 (sequentially or in combination) are not eligible for this trial.
-- HIV-positive patients are eligible if on stable dose of HAART, no clinically significant drug-drug interactions are anticipated with the current HAART regimen, CD4 counts are greater than 350 and viral load is undetectable

Description of Treatment
For the first 12 weeks, patients will receive cabozantinib orally once a day, every day, along with nivolumab and ipilimumab intravenously once every three weeks. After 12 weeks, patients will then receive cabozantinib orally once a day, every day, along with nivolumab intravenously once every four weeks for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 5 years.

Refer to the study protocol, which can be found on the Alliance website at www.AllianceNCTN.org, for complete information on the trial design, treatment plan and patient eligibility. 

Study Chair: Andrea Apolo, MD - NCI Center for Cancer Research
E-mail: andrea.apolo@nih.gov
Activated: 4/12/19
Status: Now accepting patients
ClinicalTrials.gov Identifier: NCT03927027

 

 

For other articles in this issue of the Alliance E-News newsletter, see below.