Date: 2017-02-17
Type of information: Presentation of results at a congress
phase: 1
Announcement: presentation of results at the 2017 Genitourinary Cancers Symposium
Company: National Cancer Institute (NCI) (USA)
Product: cabozantinib, nivolumab and ipilimumab
Action
mechanism: monoclonal antibody/immune checkpoint inhibitor/tyrosine kinase inhibitor. Cabozantinib (Cometriq®) is a kinase inhibitor that blocks abnormal kinase proteins involved in the development and growth of medullary cancer cells. Patients should not eat for at least 2 hours before and 1 hour after taking Cometriq®. Nivolumab is an investigational, fully-human PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 (programmed death-1) expressed on activated T-cells. PD-1, a receptor expressed on the surface of lymphocytes, plays a role in a regulatory pathway that suppresses activated lymphocytes in the body. Available evidence suggests that cancer cells exploit this pathway to escape from immune responses. Opdivo® is thought to provide benefit by blocking PD-1-mediated negative regulation of lymphocytes (i.e., the interaction of PD-1 with its ligands PD-L1 and PD-L2), thereby enhancing the ability of the immune system to recognize cancer cells as foreign and eliminate them. Opdivo® is the world’s first approved drug targeting PD-1. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses.
The active substance of Cometriq® is cabozantinib, an antineoplastic agent, protein kinase inhibitor. 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 tumor microenvironment.
Disease: urothelial cancer, bladder cancer, genitourinary cancer, urogenital neoplasms, urogenital cancer
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: Urothelial carcinoma (UC) of the bladder is a common cancer in U.S. men and women. There is no approved second-line drug for people with metastatic UC. Researchers want to see if new drug combinations are safe for people with UC. The trial will test if cabozantinib given with nivolumab or with nivolumab and ipilimumab is safe in people with advanced UC. Participants will be split into 4 groups: - Group 1: - Cabozantinib by mouth once daily. - Nivolumab in a vein once every 2 weeks for up to 84 weeks. - Group 2: - Cabozantinib by mouth once daily. - Nivolumab and ipilimumab in a vein once every 3 weeks for up to 12 weeks, then nivolumab alone in a vein every 3 weeks. - Group 3 will take the highest safe dose of study drugs from Group 1. - Group 4 will take the highest safe dose of study drugs from Group 2. - Participants may continue to take cabozantinib. - After participants finish taking the study drugs, their doctor will follow up for 100 days. Then they will be contacted every 2 months to update their survival status. (NCT02496208)
Latest
news: * On February 17, 2017, Exelixis announced results from a phase 1 trial of cabozantinib in combination with either nivolumab or nivolumab plus ipilimumab in patients with refractory genitourinary tumors. The primary endpoint of the trial is to determine the dose limiting toxicity (DLT) and recommended phase 2 doses of the doublet and triplet combinations. The findings were presented during a poster session (Abstract #293) on February 17 at the 2017 Genitourinary Cancers Symposium. Between July 22, 2015 and December 31, 2016, 48 patients were accrued with previously treated metastatic urothelial carcinoma (mUC, n=19), urachal adenocarcinoma (n=4), squamous cell carcinoma of the bladder or urethra (n=2), germ cell tumor (n=4), castration-resistant prostate cancer (n=9), renal cell carcinoma (n=4), trophoblastic tumor (n=1), sertoli cell tumor (n=1) or penile squamous cell carcinoma (n=4) and treated in two parts. In Part I, 30 patients were treated with the doublet combination of cabozantinib and nivolumab at four dose levels. In Part II, 18 patients were treated with the triplet combination of cabozantinib, nivolumab and ipilimumab at three dose levels. Among the 43 patients who were evaluable for response, the objective response rate (ORR) for all tumor types was 30 percent (38 percent for the doublet dosing schedule and 18 percent for the triplet dosing schedule), with a 7 percent complete response (CR) rate and a 23 percent partial response (PR) rate. Stable disease (SD) was reported in 56 percent of patients. The ORR for patients with mUC was 38 percent, and 2 of 16 patients achieved a CR, while 2 patients with squamous cell carcinoma of the bladder had objective responses (1 CR and 1 PR). In the mUC cohort, 15 of 16 patients had a CR, PR or SD as their best response. Grade 3 adverse events (>5 percent of patients) observed in the doublet combination included neutropenia (17 percent), hypophosphatemia (13 percent), hypertension (10 percent), lipase increase (7 percent), fatigue (7 percent), diarrhea (7 percent) and dehydration (7 percent). Grade 3 adverse events (>5 percent of patients) observed in the triplet combination included hypertension (17 percent), hypophosphatemia (17 percent), fatigue (13 percent), hyponatremia (13 percent), lipase increase (13 percent), nausea (13 percent) and rash (6 percent). There were limited numbers of grade 4 adverse events (10 percent including thrombocytopenia and lipase increase in the doublet combination, and 6 percent (lipase increase) in the triplet combination), and no grade 5 adverse events observed in either part of the trial. The recommended doses for the ongoing expansion cohorts were determined to be cabozantinib 40 mg daily plus nivolumab 3 mg/kg once every 2 weeks for the doublet and cabozantinib 40 mg daily, nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses, then nivolumab 3 mg/kg every 2 weeks for the triplet. Exelixis will now further examine the potential of cabozantinib in combination with immunotherapies to treat a broad range of genitourinary and other cancers. * On July 13, 2015, Exelixis announced the initiation of 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 tumors. 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 tumors. 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 U.S. National Cancer Institute (NCI) through Cooperative Research and Development Agreements between the NCI’s Cancer Therapy Evaluation Program (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 centers 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.
