Phase 1/1b multicenter trial of the adenosine A2a receptor antagonist (A2aR) CPI-444 as single agent and in combination with atezolizumab (ATZ) in patients(Pts) with advanced cancers

Abstract

Background: Adenosine is an extracellular signaling molecule that increases in response to acute tissue injury/inflammation to restore tissue homeostasis. Elevated levels of adenosine are produced in the tumor microenvironment and signaling through A2aR on immune cells leads to immunosuppression, promoting tumor growth. CPI-444 is an oral A2aR antagonist that has been evaluated in phase 1 and 2 clinical trials outside the oncology setting. CPI-444 binds to A2aR with a Ki of 3.5 nM and > 50 fold selectivity over other adenosine receptor subtypes. Preclinical studies with various mouse tumor models demonstrate efficacy of CPI-444 as a single agent (SA) and in combination with anti-PD1/PDL1 antibodies. Trial design:We have initiated a phase 1/1b multicenter, open label trial to evaluate CPI-444 as a SA and in combination with ATZ(anti-PDL1), in pts with advanced cancers. The objectives are 1)evaluate the safety and tolerability of multiple doses of CPI-444 2) identify a recommended dose and schedule for further study and 3) evaluate efficacy. Eligibility criteria: 1)histology: non-small cell lung cancer, melanoma, renal cell cancer, triple-negative breast cancer, bladder cancer, head and neck cancer and MSI colorectal cancer and 2) 1 but not more than 5 prior therapies. This phase 1/ 1b adaptive design is composed of 2 steps with multiple expansion cohorts within Step 2 based on a 3-stage expansion design. Step 1 is a dose selection step with 4 cohorts (3 SA cohorts with CPI-444 at various dosing schedules and 1 cohort combined with ATZ). After Step 1, the optimal dose SA cohort of CPI-444 determined by safety and other biomarkers and the optimal dose from the combination cohort will proceed to Step 2. Step 2 has 10 multiple expansion cohorts: 5 cohorts (stratified by disease)will receive CPI-444 as a SA and 5 cohorts will receive the combination. The total sample size is up to 534 pts. This trial is accruing in N America and will expand to Australia and Europe.