Exelixis announced the initiation of the dose-escalation stage of a phase Ib trial of cabozantinib in combination with atezolizumab (TECENTRIQ) in patients with locally advanced or metastatic urothelial carcinoma (UC) or renal cell carcinoma (RCC). The primary objective is to determine the optimal dose and schedule of daily oral administration of cabozantinib when given in combination with atezolizumab to inform the trial’s subsequent expansion stage.

“Patients with locally advanced or metastatic urothelial or renal cell carcinoma are in need of additional therapies that can slow disease progression,” said Sumanta Kumar Pal, M.D., co-director, Kidney Cancer Program at City of Hope, and Principal Investigator of the study. “As new investigational and approved therapies become available, research into their use in combination with other treatments may be a productive avenue for improving clinical outcomes in patients with these tumor types. Identifying the appropriate dose for cabozantinib when paired with the immunotherapy atezolizumab is the first step in examining this potential combination therapy.”

This multicenter phase Ib, open-label study is divided in two parts: a dose-escalation phase and an expansion cohort phase. The dose-escalation phase will enroll nine to 36 patients with inoperable, locally advanced, metastatic or recurrent UC (including renal, pelvis, ureter, urinary bladder and urethra) after prior platinum-based therapy or RCC with or without prior systemic therapy. The starting dose of cabozantinib will be 40mg daily and may be increased to 60mg daily or decreased to 20mg daily. All patients will receive the standard atezolizumab dosing regimen (1200mg infusion once every three weeks).

The secondary objectives of the dose-escalation stage are to evaluate the plasma pharmacokinetics of daily oral administration of cabozantinib when given in combination with atezolizumab and to assess safety of the combination therapy through the evaluation of incidence and severity of adverse events, including immune-related adverse events. Exploratory endpoints include the correlation of clinical outcome with immune cell, tumor cell and blood biomarker analyses.

Once the recommended dose and schedule are determined, the trial will enroll four expansion cohorts, each with up to 30 patients, for a total of up to 120 patients with advanced or metastatic UC or RCC. The primary objective in the expansion stage of the trial is to determine the objective response rate in each cohort. The three UC expansion cohorts will enroll: 1) patients who have progressed on or after platinum-containing chemotherapy; 2) patients who are ineligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy for inoperable, locally advanced or metastatic disease; and 3) patients who are eligible for cisplatin-based chemotherapy and have not received prior systemic chemotherapy for inoperable, locally advanced or metastatic disease. The RCC expansion cohort will enroll patients with clear cell histology who have not had prior systemic anticancer therapy.

“There is a strong rationale for combining cabozantinib with immunotherapies, including clinical and preclinical observations consistent with the ability of cabozantinib to promote an immuno-permissive environment, which might present an opportunity for synergistic effects from combination treatment with immune checkpoint inhibitors and other immuno-oncology agents,” said Gisela Schwab, M.D., president, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. “We are excited to evaluate the combination of cabozantinib plus atezolizumab and look forward to the determination of a recommended phase II dose and to further examining this combination regimen to treat advanced cancers.”