Date: 2017-01-10
Type of information: update on patient enrollment
phase: 1-1b
Announcement: update on patient enrollment
Company: Corvus Pharmaceuticals (USA - CA)
Product: CPI-444
Action
mechanism: adenosine A2A receptor antagonist/immune checkpoint inhibitor. CPI-444 is an adenosine A2A receptor antagonist. It is designed to disable a tumor’s ability to subvert attack by the immune system by inhibiting adenosine in the tumor microenvironment. CPI-444 is a small molecule that is taken orally.
Disease: solid tumors
Therapeutic area: Cancer - Oncology
Country: Australia, Canada,USA
Trial
details: The Phase 1/1b trial is designed to examine the activity of CPI-444 as a single agent and in combination with Genentech’s Tecentriq® (atezolizumab), an anti-PD-L1 antibody. The first part of the study (dose-selection) includes four cohorts of 12 patients each – three cohorts treated with single agent CPI-444 (100 mg twice daily for 14 days; 100 mg twice daily for 28 days; 200 mg once daily for 14 days) and one cohort treated with the combination (CPI-444 50 mg or 100 mg twice daily for 14 days combined with Tecentriq®). A treatment cycle is 28 days. Patients with non-small cell lung cancer, melanoma, renal cell cancer, triple-negative breast cancer, colorectal cancer, head and neck cancer, bladder cancer and prostate cancer who have failed all standard therapies are eligible. Based on safety and biomarker analyses, an optimum single agent and combination dose will be selected. The second part of the study will evaluate CPI-444 as a single agent in five disease-specific cohorts, and CPI-444 in combination with Tecentriq® in five additional matched disease-specific cohorts. Corvus expects that each of these 10 cohorts will initially enroll 14 patients, but each cohort may be expanded based on efficacy.
Latest
news: * On January 10, 2017, Corvus Pharmaceuticals announced that the protocol-predefined criteria for expansion has been reached for the cohort of patients with renal cell carcinoma treated with single-agent CPI-444 in the Company’s ongoing Phase 1/1b study. The size of that cohort will be increased from 14 to 26 patients. The Phase 1/1b study is evaluating CPI-444, a selective and potent inhibitor of the adenosine A2A receptor, as a single agent and in combination with Genentech’s Tecentriq® (atezolizumab),? a humanized monoclonal antibody targeting protein programmed cell death ligand 1 (PD-L1). The study has been enrolling patients ahead of schedule. The first part of the trial (dose-selection) was completed in October 2016, and enrollment of patients in disease-specific cohorts in the second part of the trial is currently underway. The protocol-predefined criteria for expansion is the finding of a response (defined as a complete response, partial response or stable disease) in at least one patient in the disease-specific cohort of 14 patients with renal cell cancer. In the initial four patients treated with single agent CPI-444 (in either the dose-selection or disease-specific cohorts), one patient, refractory to prior treatment with anti-PD1, achieved a partial response, two have stable disease, and one has shown tumor progression. A fifth patient (in the dose-selection cohort), refractory to prior treatment with anti-PD1, received CPI-444 in combination with Tecentriq (atezolizumab),? and has stable disease. Four of the five patients remain on treatment, with two receiving treatment for more than 30 weeks. All patients had previously failed approved therapies. To date, CPI-444 has been well tolerated when given orally twice daily. * On November 11, 2016, Corvus Pharmaceuticals announced preliminary clinical safety and efficacy data from the dose-selection phase of its ongoing Phase 1/1b study of CPI-444 as a single agent and in combination with Genentech’s Tecentriq® (atezolizumab),? a fully humanized monoclonal antibody targeting protein programmed cell death ligand 1 (PD-L1). The data were presented in a poster session by John Powderly II, M.D., founder and president of the Carolina BioOncology Institute, at the Society for Immunotherapy of Cancer’s (SITC) 31ST Annual Meeting & Associated Programs in National Harbor, Maryland. The poster can be accessed online here. Initial safety and efficacy data from the first 46 patients enrolled in the dose-selection phase of the Phase 1/1b trial with a median follow up of two months were presented at the conference. All patients had failed all approved therapies for their disease, with a median of four prior treatment regimens (range: 1-5). Fifty-two percent of patients were refractory to prior treatment with anti-PD-1/PD-L1 antibodies. Enrolled patients had the following cancers: non-small cell lung (NSCLC), N=10; triple negative breast (TNBC), N=10; bladder, N=6; renal, N=5; melanoma, N=7; colorectal, N=3; prostate, N=2; and head and neck, N=3. The primary endpoints of the study are response rate and duration of clinical benefit (defined as complete response, partial response or stable disease). Patients are treated until disease progression or evidence of grade 3 or 4 toxicity. Results presented showed: Of the 32 patients who reached the first efficacy assessment at two months, 12 have shown stable disease and 20 have shown disease progression. Fourteen patients have not yet reached the two-month assessment. Six of the patients with disease progression remain on treatment based on investigator judgement that there is clinical benefit. Overall, 32 patients continue to receive treatment in the study and 14 have discontinued therapy. In a separate poster presentation, Corvus reported on the effects of treatment with CPI-444 on circulating blood immune cells and T-cell clonality. These results indicate: Single agent treatment with CPI-444 leads to activation of T-cells in peripheral blood as well as increases in memory T-cells, key mediators of T-cell mediated immune responses. * On September 25, 2016, Corvus Pharmaceuticals announced preclinical data as well as preliminary biomarker data from its ongoing Phase 1/1b study of CPI-444 as a single agent and in combination with Genentech’s Tecentriq® (atezolizumab).The data were presented in both oral and poster presentations by Stephen Willingham, Ph.D., Corvus senior scientist, at the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival, which is taking place in New York at the Sheraton New York Times Square Hotel and the New York Hilton Midtown. According to preclinical study results presented at the Conference: CPI-444 has been shown to be active, both as a single agent and in combination with anti-PD-1 and anti-PD-L1 antibodies, in stimulating various immune cells, generating anti-tumor immunity, suppressing tumor growth, delaying tumor progression and generating complete tumor rejection in multiple animal models of cancer. Results from mechanism of action studies indicate that CD8+ cytotoxic T-lymphocytes are necessary for CPI-444’s activity in animal models. Long-term immunity was demonstrated upon tumor re-challenge in animals previously treated with CPI-444. Preliminary biomarker data from ongoing analyses of patients with various solid tumors treated to date in the ongoing Phase 1/1b study presented at the Conference demonstrated: In the first 11 patients analyzed, 40-100 percent blockade of peripheral blood lymphocyte A2A receptors was achieved in a dose-dependent manner with CPI-444 treatment. All three patients receiving CPI-444 100 mg twice daily for 28 days achieved 90-100 percent continuous, sustained blockade of peripheral blood lymphocyte A2A receptors. Pharmacodynamic markers on peripheral blood lymphocytes showed evidence of activation of T-cell mediated immunity in all three patients treated with CPI-444 100 mg twice daily for 28 days. In these patients, increases in cytotoxic T-lymphocytes that were both PD-1-positive and CD8-positive (double positive) were seen in the blood following 28 days of treatment compared to baseline pretreatment. Previous research from others has shown that PD-1, CD8 double positive T-cells are associated with anti-tumor immune responses. CPI-444 has been well tolerated to date, with no drug-related dose limiting toxicities or serious adverse events observed. The trial is currently enrolling patients at 25 sites in the United States, Canada and Australia with 39 patients enrolled to date. The Adenosine A2A Receptor Antagonist, CPI-444, Blocks Adenosine-Mediated T-Cell Suppression and Exhibits Anti-Tumor Activity Alone and in Combination with Anti-PD-1 and Anti-PD-L1 (abstract #2337) Inhibition of Adenosine A2A Receptor (A2AR) by CPI-444 Enhances CD8+ T-Cell Killing of a HER-2/neu Expressing Murine Tumor (abstract #320) Adenosine A2A Receptor (A2AR) Antagonist as a Means of Enhancing the Efficacy of Checkpoint Blockade and Adoptive T-Cell Therapy (abstract #4364)
Of the 12 patients with stable disease, several have shown ongoing tumor regression (1-20 percent reduction of the volume of indicator tumor lesions) by CT scan but have not yet reached the criteria for partial response (>30 percent reduction in tumor size per RECIST criteria). Seven of the 12 patients with stable disease received CPI-444 as a single agent.
Of the 10 patients with NSCLC, seven received single agent CPI-444. Five of seven evaluable patients have stable disease at two or more months (three of whom received single agent therapy). Nine patients remain on treatment and one patient has discontinued.
Of the five patients with RENAL CANCER, four received single agent CPI-444. Four patients remain on treatment and three of four evaluable patients have stable disease.
Two of four evaluable patients with BLADDER CANCER showed stable disease at first assessment, both of whom received single agent CPI-444.
Of the ten patients with TNBC, one of seven evaluable patients showed stable disease. Eight patients remain on treatment.
One of four evaluable patients with MELANOMA has stable disease with regression of cutaneous tumor lesions; this patient received single agent CPI-444.
One of two evaluable patients with PROSTATE CANCER treated with combination therapy has stable disease and showed a decrease in prostate-specific antigen (PSA) at 29 weeks; this patient has gained weight and requires significantly less narcotics for pain management.
CPI-444 has been well tolerated to date, with one patient treated with combination therapy experiencing a possibly drug-related serious adverse event. This patient developed autoimmune hemolytic anemia that resolved upon discontinuation of therapy.
Patients receiving CPI-444 100 mg twice daily had sustained, complete blockade of A2A receptor activity in peripheral blood immune cells.
Consistent with this observation, single agent CPI-444 leads to changes in the repertoire of T-cell clones in peripheral blood, consistent with induction of T-cell mediated immune responses. Limited changes in T-cell repertoires were seen in patients who progressed on treatment with either CPI-444 alone or in combination with atezolizumab.
Changes in T-cell repertoires were observed in anti-PD-1/PD-L1 treatment-naïve patients and in patients that were refractory to prior treatment with anti-PD-1/PD-L1 antibodies.
* On April 19, 2016, Corvus Pharmaceuticals announced results of three preclinical studies of CPI-444, the Company’s lead oral checkpoint inhibitor. The studies demonstrated that CPI-444 was effective in stimulating various immune cells, generating anti-tumor immunity, suppressing tumor growth and delaying tumor progression in animal models of cancer. The data were presented in oral and poster sessions at the American Association for Cancer Research (AACR) Annual Meeting 2016 in New Orleans.
Data from this preclinical study were presented in a poster session by Stephen Willingham, Ph.D., senior scientist at Corvus Pharmaceuticals. Results showed that CPI-444 restored T-cell activation in vitro in T-cells that were treated with immuno-suppressive levels of adenosine. CPI-444 demonstrated single-agent anti-tumor activity and synergized with either anti-PD-1 or anti-PD-L1 in multiple animal tumor models, resulting in a significant number of cured animals. CPI-444 combined with anti-PD-L1 treatment resulted in increased CD8+ T-cell infiltrates in tumors, indicating a heightened anti-tumor immune response. In tumor-bearing mice cured by treatment with CPI-444, long-term anti-tumor immunity was demonstrated by showing that all these mice were protected from tumor re-challenge.
Data from this preclinical study were presented by Blake Scott, a member of the lab of Elizabeth Jaffee, M.D., in The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine. Jaffee also is associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins. Results showed that CPI-444 enhanced the activity of adoptively transferred, cancer-specific CD8+ T-cells when administered with a T-cell-inducing tumor vaccine.
Data from this preclinical study were presented in an oral session by Robert D. Leone, M.D., Ph.D., of The Sidney Kimmel Comprehensive Cancer Research Center at Johns Hopkins University School of Medicine. Treatment of animals with CPI-444 enhanced tumor immunity by lowering the expression of other inhibitory checkpoint receptors on tumor infiltrating immune cells (e.g., Lag 3, Tim 3 and PD-1). CPI-444 also enhanced the efficacy of adoptively transferred T-cells, leading to suppressed tumor growth and increased survival compared with controls. CPI-444 increased the expansion of antigen-specific T-cells in vitro and synergized with anti-PD-1 antibody treatment and glutamine metabolism inhibitors in animal models of colon tumors. A co-author of the study is Jonathan Powell, M.D., Ph.D., professor of oncology at the Johns Hopkins Kimmel Cancer Center and associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins.
