On January 8, 2019 Corvus Pharmaceuticals, Inc. (Nasdaq: CRVS), a clinical-stage biopharmaceutical company focused on the development and commercialization of precisely targeted oncology therapies, reported that it has initiated patient enrollment in the second arm of its ongoing Phase 1/1b dose-escalation study (Press release, Corvus Pharmaceuticals, JAN 8, 2019, View Source [SID1234532576]). This arm is evaluating CPI-006, a humanized monoclonal antibody directed against CD73, in combination with CPI-444, a selective and potent inhibitor of the adenosine A2A receptor.
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The Phase 1/1b study is currently enrolling patients with non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) and other cancers who have failed standard therapies. The first arm of the study is evaluating CPI-006 as a single agent and has dosed patients in several cohorts of escalating doses. A third arm is planned to evaluate CPI-006 in combination with pembrolizumab, an anti-PD-1 antibody.
"Enrollment in our CPI-006 Phase 1/1b trial is progressing well," said Richard A. Miller, M.D., an oncologist and co-founder, president and chief executive officer of Corvus. "With this combination of drugs from our two lead programs, we believe we have initiated the first trial targeting two points in the adenosine pathway: blocking CD73 to reduce adenosine production with CPI-006, and inhibiting the binding of adenosine to its receptor with CPI-444. We believe this approach represents a unique mechanism of action that may result in a more complete adenosine blockade and immune cell activation."
Corvus previously reported initial data from the single-agent arm of the Phase 1/1b study demonstrating that CPI-006 blocked production of adenosine by inhibiting the enzymatic active site of CD73, activated peripheral blood B cells, and affected B lymphocyte trafficking. To date, CPI-006 has been well tolerated at the doses evaluated, with no dose-limiting toxicities. Dr. Miller added, "We have reported encouraging results from our ongoing Phase 1/1b and 1b/2 studies of CPI-444, including the recently described adenosine biomarker signature. We plan to initiate clinical studies for our third pipeline program, a covalent inhibitor of ITK, CPI-818, in the first quarter of 2019, demonstrating the depth of our pipeline and strong overall momentum for our precisely-targeted development programs."
About the Phase 1/1b Trial Design
The Phase 1/1b trial is designed to select the dose and evaluate the safety, pharmacokinetics, immune biomarkers and efficacy of CPI-006 as a single agent, in combination with CPI-444, and in combination with pembrolizumab. Patients with non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and other cancers who have failed standard therapies are eligible. The efficacy endpoints are complete response (CR), partial response (PR), disease control rate, duration of response, progression-free survival and overall survival.
In the dose-selection part of the trial, doses of CPI-006 will be escalated in the single-agent arm and in the two combination arms to determine the maximally tolerated dose or the dose that saturates the CD73 enzyme. Fixed doses of CPI-444 will be used. Once an optimum dose of CPI-006 is determined, the second part of the trial is planned to enroll patients in nine cohorts: three will receive CPI-006 alone, three will receive CPI-006 in combination with CPI-444, and three will receive CPI-006 with pembrolizumab. Patients with NSCLC, RCC and the group of other cancers will be enrolled into each of the three disease-specific arms. Each of the nine cohorts may initially enroll up to 11 patients. However, if there are one or more objective responses (CR or PR) in the 11 patients, the cohort may be expanded to 28 patients. The trial may enroll up to 350 patients in total.
About CD73 and Adenosine
CD73 is a cell surface enzyme whose function is to convert adenosine monophosphate (AMP) to adenosine by removing phosphate from AMP. CD73 is expressed on cells of the immune system, including T-cells and B-cells. CD73 is also present on many tumors, including lung, renal, melanoma, colon, prostate, breast and others. In the tumor microenvironment, CD73 produces adenosine, which binds to the adenosine A2A receptor on immune cells and inhibits various immune responses including those directed against the tumor. Tumors utilize this immunosuppressive mechanism to escape attack by the immune system.
About CPI-006
CPI-006 is a potent humanized monoclonal antibody that reacts with the active site of CD73, blocking the conversion of AMP to adenosine. In vitro studies of CPI-006 have shown it is capable of substantially inhibiting the production of adenosine by blocking the CD73 enzyme and leads to activation of peripheral blood B cells.
About CPI-444
CPI-444 is a small molecule, oral, checkpoint inhibitor designed to disable a tumor’s ability to subvert attack by the immune system by blocking the binding of adenosine in the tumor microenvironment to the A2A receptor. Adenosine, a metabolite of ATP (adenosine tri-phosphate), is produced within the tumor microenvironment where it may bind to the adenosine A2A receptor present on immune cells and block their activity. CD39 and CD73 are enzymes on the surface of tumor cells and immune cells. These enzymes work in concert to convert ATP to adenosine. In vitro and preclinical studies have shown that dual blockade of CD73 and the A2A receptor may be synergistic.