Exelixis, Inc., a biopharmaceutical company committed to developing small molecule therapies for the treatment of cancer, has started a phase 1 trial of cabozantinib in combination with nivolumab alone or in combination with nivolumab plus ipilimumab in patients with advanced/metastatic urothelial (bladder) and other genitourinary tumours.

The primary endpoint of the trial is the determination of dose-limiting toxicities (DLT) and a recommended phase 2 dose (RP2D) for the combination of cabozantinib and nivolumab, and separately, for the combination of cabozantinib, nivolumab and ipilimumab, in patients with genitourinary solid tumours. Secondary endpoints include evaluating the activity of the two combinations by objective response rate, as well as progression-free survival (PFS) and overall survival (OS), in cohorts of patients with urothelial carcinoma of the bladder, urethra, ureter or renal pelvis.

The trial is sponsored by the US National Cancer Institute (NCI) through Cooperative Research and Development Agreements between the NCI’s Cancer Therapy Evaluation Programme (CTEP), Division of Cancer Treatment and Diagnosis, and both Bristol-Myers Squibb and Exelixis. Andrea Apolo, M.D., of the NCI’s Genitourinary Malignancies Branch, is the principal investigator. The trial will be conducted by the NCI and includes centres from its Experimental Therapeutics Clinical Trials Network.

“In the United States, bladder cancer is one of the ten most common malignancies for men and women alike, and there are no drugs approved for use in the second-line setting,” said Dr. Apolo. “In a previous study, single-agent cabozantinib demonstrated intriguing clinical activity in bladder cancer. Now, with this trial, we’ll explore the safety and tolerability, and the antitumor activity of the combination of cabozantinib with the immune checkpoint inhibitor nivolumab, alone or together with ipilimumab, in this and other important genitourinary cancer settings.”

This open label, non-randomized phase 1 trial will enroll a maximum of 66 patients. The trial is divided into two parts: a dose-escalation phase and an expansion cohort phase. The dose-escalation phase will enroll patients with metastatic genitourinary solid tumors including renal cell carcinoma, urothelial cancer and castration-resistant prostate cancer who have progressed following treatment with at least one standard therapy. Up to 24 patients will be treated with the combination of cabozantinib plus nivolumab (CaboNivo), and up to 18 patients will receive the combination of cabozantinib, nivolumab, and ipilimumab (CaboNivoIpi). The starting dose of cabozantinib will be 40 mg daily for each combination and can increase up to 60 mg daily. Depending upon the cohort, dose levels for nivolumab will range from 1 to 3 mg/kg administered on an every two or every three week schedule, and ipilimumab will be administered at a dose level of 1 mg/kg every three weeks for a maximum of 4 doses.

Once the RP2Ds are determined for the combinations of CaboNivo and CaboNivoIpi, the trial will enroll expansion cohorts of up to 12 eligible patients for each combination, for up to 24 patients total in the expansion cohort. To be eligible for the expansion cohort, patients must have histologically confirmed metastatic, progressive urothelial cancer of the bladder, urethra, ureter, or renal pelvis. Patients in the expansion cohort will be evaluated for objective response rate, PFS and OS: all secondary endpoints of the trial.

“There is a strong rationale for combining cabozantinib with immunoncology agents, including clinical evidence of the compound’s ability to create a more immune-permissive environment, as well as preclinical data that suggest cabozantinib increases T-cell infiltration into tumors,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis.

“In addition to bladder cancer, we believe that data on the tolerability and activity of the therapy combinations studied in this trial could have relevance in other disease settings, including non-small cell lung cancer and kidney cancer.”

Dr. Morrissey continued “Our collaboration with NCI-CTEP allows researchers to evaluate cabozantinib’s potential in diverse cancers while Exelixis focuses its internal resources on late-stage development, including the METEOR phase 3 pivotal trial in metastatic renal cell cancer expected to read out early this quarter. We look forward to following the progress of Dr. Apolo’s trial, which is one of more than 45 studies of cabozantinib either planned or ongoing under the CTEP collaboration and our investigator-sponsored trial programme.”

Cabozantinib inhibits the activity of tyrosine kinases including MET, VEGFRs and RET. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumour microenvironment.

Cometriq (cabozantinib) is currently approved by the US Food and Drug Administration for the treatment of progressive, metastatic medullary thyroid cancer (MTC).

The European Commission granted Cometriq conditional approval for the treatment of adult patients with progressive, unresectable locally advanced or metastatic MTC. Similar to another drug approved in this setting, the approved indication states that for patients in whom Rearranged during Transfection (RET) mutation status is not known or is negative, a possible lower benefit should be taken into account before individual treatment decisions.

The most commonly reported adverse drug reactions (=25 per cent) are diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (=25 per cent) are increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.