Date: 2014-06-23
Type of information: Treatment of the first patient
phase: 1-2
Announcement: treatment of the first patient
Company: Clovis Oncology (USA - CO)
Product: CO-1686 - rociletinib
Action
mechanism: CO-1686 is a novel, oral, targeted covalent (irreversible) inhibitor of mutant forms of the epidermal growth factor receptor (EGFR) for the treatment of non-small cell lung cancer (NSCLC) in patients with initial activating EGFR mutations as well as the dominant resistance mutation T790M.
Disease: non-small cell lung cancer
Therapeutic area: Cancer- Oncology
Country: USA, France, Australia, Poland
Trial
details: This phase 1/2 trial is an open-label, safety, pharmacokinetic and preliminary efficacy study of oral CO-1686 in patients with previously treated mutant EGFR non-small cell lung cancer (NSCLC) (NCT01526928). Clovis Oncology is currently enrolling two Phase 2 expansion cohorts of its Phase 1/2 study in EGFR mutant patients with the T790M mutation; the first includes approximately 150 to 200 T790M positive patients directly after progression on their first and only TKI therapy, comparable to the population the Company will seek to enroll in its TIGER2 registration study. The second cohort includes approximately 150 to 200 later-line T790M positive patients after progression on their second or later TKI therapy or subsequent chemotherapy. Both cohorts are exploring doses of 500mg, 625mg and 750mg BID. Data from the expansion cohorts, combined with data from TIGER2, are expected to serve as the basis of an NDA submission for CO-1686 by mid-2015. Clovis expects to initiate three registration studies in the TIGER program during 2014. The TIGER2 study is the first of three registration studies in the TIGER (Third-generation inhibitor of mutant EGFR in lung cancer) program expected to initiate during 2014. The TIGER2 study is being conducted in T790M positive patients directly after progression on their first and only TKI therapy. Study sites are now enrolling in the U.S., Europe and Australia. The TIGER2 study is currently enrolling 125 patients with EGFR-mutant NSCLC with a centrally-confirmed T790M mutation who will receive CO-1686 at the recommended Phase 2 dose (RP2D) of 625mg BID. The primary study endpoint is overall response rate; secondary endpoints include duration of response, progression-free survival, overall survival, and safety. In addition to TIGER2, Clovis is currently enrolling two Phase 2 expansion cohorts of its Phase 1/2 study in EGFR mutant patients with the T790M mutation; the first includes approximately 150 to 200 T790M positive patients directly after progression on their first and only TKI therapy, comparable to the population in its TIGER2 registration study. The second cohort includes approximately 150 to 200 later-line T790M positive patients after progression on their second or later TKI therapy or subsequent chemotherapy. Both cohorts are exploring doses of 500mg, 625mg and 750mg BID. Data from the expansion cohorts, combined with data from TIGER2, are expected to serve as the basis of an NDA submission for CO-1686 by mid-2015. Clovis expects to initiate the Phase 2 portion of the TIGER1 study, a randomized Phase 2/3 registration study of CO-1686 vs. erlotinib in newly-diagnosed EGFR mutant patients, in mid-2014. The TIGER3 study, a randomized, comparative study versus chemotherapy in T790M positive patients directly after progression on their first and only TKI therapy, is expected to initiate during the second half of 2014. The Company initiated its Phase 1 study of CO-1686 in Japan during the first quarter of 2014
Latest
news: * On June 23, 2014, Clovis Oncology announced that the TIGER2 study has commenced with the dosing of the first patient at a U.S. study site. Data recently presented at the 2014 American Society of Clinical Oncology annual meeting included activity and safety results in 40 evaluable centrally-confirmed T790M positive patients across efficacious dose levels in the Phase 1 dose-expansion study and the early Phase 2 expansion cohorts. These include 23 partial responses (PRs) observed as of early May, for a 58 percent objective response rate (ORR). Thirty-six of the 40 evaluable T790M positive patients, or 90 percent, have experienced stable disease or a PR. Central nervous system (CNS) responses have also been observed in heavily pre-treated T790M positive patients. The median duration of response cannot yet be determined in the T790M positive patients. Similarly, median PFS has not been reached. However, follow-up for some patients exceeds one year, and the current estimate for median PFS is greater than 12 months. CO-1686 is well-tolerated, with no evidence of systemic wild-type EGFR inhibition. In the Phase 1 study, the most common adverse events were nausea, hyperglycemia, diarrhea, vomiting and decreased appetite, and these were mostly grade 1 or 2 in severity. The most common grade 3 adverse event was hyperglycemia, which was observed in 22 percent of patients. Hyperglycemia, when observed and requiring treatment, is typically managed with a commonly-prescribed single oral agent. Breakthrough therapy designation was granted by the FDA last month for CO-1686 as monotherapy for the treatment of mutant EGFR NSCLC in patients with the T790M mutation after progression on EGFR-directed therapy. * On May 31, 2014, Clovis Oncology announced updated findings from the Phase 1 and early Phase 2 portions of its ongoing Phase 1/2 clinical study of CO-1686, an oral, targeted covalent (irreversible) inhibitor of mutant forms of the epidermal growth factor receptor (EGFR) for the treatment of non-small cell lung cancer in patients with initial activating EGFR mutations as well as the dominant resistance mutation T790M. These data have been presented in an oral presentation by Dr. Lecia Sequist at the 2014 American Society of Clinical Oncology (ASCO) annual meeting in Chicago (First-in-human evaluation of CO-1686: An irreversible, highly-selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M)” ). The Phase 1 dose escalation portion of the study is being conducted in the United States, France and Australia in patients with metastatic or unresectable recurrent NSCLC and a documented EGFR mutation. Patients were not required to be T790M positive for the Phase 1 portion of the study but had to have progressed on prior EGFR-directed tyrosine kinase inhibitor (TKI) therapy (prior chemotherapy was also allowed).
The two Phase 2 expansion cohorts are currently enrolling in the United States, Europe, and Australia in EGFR mutant patients with the T790M mutation. The first cohort includes approximately 150 to 200 T790M positive patients directly after progression on their first and only TKI therapy, comparable to the population planned for the TIGER2 registration study. The second cohort includes approximately 150 to 200 later-line T790M positive patients after progression on their second or later TKI therapy or subsequent chemotherapy. Both cohorts are exploring doses of 500mg, 625mg and 750mg BID.
Approximately 160 patients have been treated with CO-1686 to date across all dosing cohorts in the trial. Data from 81 evaluable patients treated with CO-1686 at efficacious doses (comprising patients treated with 900mg BID of freebase or any dose of the hydrobromide salt (HBr) formulation) were presented today, including 72 from the Phase 1 study and nine from the early part of the Phase 2 portion of the study. Of these 81 patients, 40 are centrally-confirmed T790M positive. Patients enrolled in the Phase 1 study were heavily pretreated prior to receiving CO-1686; 75 percent of patients across all doses had immediately progressed on TKI therapy prior to CO-1686 treatment. The median number of previous lines of therapy across patients at all doses was three; the median number of previous TKI lines was two.
In the 40 evaluable centrally-confirmed T790M positive patients across efficacious dose levels in the Phase 1 dose-expansion study and the early Phase 2 expansion cohorts, 23 partial responses (PRs) have been observed to date, for a 58 percent objective response rate (ORR). Thirty-six of the 40 evaluable T790M positive patients, or 90 percent, have experienced stable disease or a PR. Central nervous system (CNS) responses have also been observed in heavily pre-treated T790M positive patients.
The median duration of response cannot yet be determined in the T790M positive patients. Similarly, median PFS has not been reached. However, follow-up for some patients exceeds one year, and the current estimate for median PFS is greater than 12 months.
Safety and Tolerability
CO-1686 is well-tolerated, with no evidence of systemic wild-type EGFR inhibition. In the Phase 1 study, the most common adverse events were nausea, hyperglycemia, diarrhea, vomiting and decreased appetite, and these were mostly grade 1 or 2 in severity. The most common grade 3 adverse event was hyperglycemia, which was observed in 22 percent of patients. Hyperglycemia, when observed and requiring treatment, is typically managed with a commonly-prescribed single oral agent.
