【醒目】Rociletinib （CO1686）一期临床结果（ASCO2013全文）

老马 · 发表于 2014-11-16 09:57:39

http://www.tigertrials.com/

The TIGER-1 study is the second of three registration studies in the program expected to initiate during 2014. The TIGER-1 study is a randomized Phase 2/3 registration study of rociletinib vs. erlotinib in newly-diagnosed EGFR-mutant patients. The Phase 2 portion of the study will enroll 200 patients. Upon completion of enrollment of the Phase 2 portion of the study, the Phase 3 portion of the study will initiate. The Phase 3 portion is a blinded study and the sizing will be determined in part by the initial data from the Phase 2 portion of the study. Study sites are currently enrolling in the U.S. and will enroll soon in Europe, Australia and Asia. For more information about the study, please visit www.tigertrials.com.

In addition to TIGER-1, Clovis is currently enrolling several studies in EGFR-mutant NSCLC:

The TIGER-2 study is currently enrolling 125 patients with EGFR-mutant NSCLC with a centrally-confirmed T790M mutation directly after progression on their first and only TKI therapy. Patients receive rociletinib 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.
Two TIGER-X Phase 2 expansion cohorts of its Phase 1/2 study in EGFR-mutant patients with the T790M mutation are currently enrolling; 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 TIGER-2 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.
A Phase 1 study of rociletinib is underway in Japan.
Data from the TIGER-X expansion cohorts, combined with data from TIGER-2, are expected to serve as the basis of U.S. and E.U. regulatory submissions for rociletinib in mid-2015.

The TIGER-3 study, a randomized, comparative study of rociletinib versus chemotherapy in T790M-positive and T790M-negative patients with EGFR-mutant NSCLC and acquired TKI resistance, is expected to initiate in the next few months.

老马 · 发表于 2014-11-19 20:26:34

本帖最后由老马于 2014-11-19 21:08 编辑

Interim Data from Rociletinib (CO-1686) Phase 1/2 Study Shows Compelling and Durable Clinical Activity and Progression-free Survival (PFS) in Patients with EGFR-Mutant Non-small Cell Lung Cancer (NSCLC)
67% objective response rate (ORR) observed in evaluable heavily-pretreated T790M+ patients treated with 625mg or 500mg BID (clinical dose group)
Median PFS of 10.4 months in clinical dose group; data continue to mature
Well-tolerated – majority of treatment-related adverse events are grade 1-2
In T790M-negative patients treated with 625mg or 500mg BID, 36% ORR and median PFS of 7.5 months observed
Only TKI shown to spare wild-type EGFR signaling
U.S. and E.U. regulatory submissions planned in mid-2015
http://finance.yahoo.com/news/in ... 1686-233600842.html
BARCELONA, Spain--(BUSINESS WIRE)--

Clovis Oncology (CLVS) announced today updated findings from its ongoing Phase 2 clinical study of rociletinib (CO-1686), the Company’s novel, oral, targeted covalent (irreversible) mutant-selective inhibitor of the epidermal growth factor receptor (EGFR) for the treatment of NSCLC in patients with initial activating EGFR mutations as well as the primary resistance mutation T790M. These data are being presented Friday, November 21 in an oral presentation (Abstract No. LBA 10) by Professor Jean-Charles Soria at the 26th EORTC-NCI-AACR (ENA) Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, Spain.

“I have been involved in the clinical development of rociletinib since the first patient was dosed, and it is gratifying to see the progress made and the data presented at the ENA Symposium today,” said Dr. Jonathan Goldman, Assistant Professor, UCLA Hematology & Oncology, Associate Director of Drug Development and Director of Clinical Trials in Thoracic Oncology. “In particular, the data presented are consistent with my own experience that the 625mg BID dose provides very encouraging efficacy with excellent tolerability. In addition, the early evidence of activity in the T790M negative patients is surprising and may address a remaining unmet medical need for this additional group of patients who have also progressed on initial TKI therapy.”

“These data demonstrate the very encouraging activity and tolerability observed with rociletinib at our go-forward dose of 625mg BID, and our step-down dose of 500mg BID,” said Patrick J. Mahaffy, President and CEO of Clovis Oncology. “We are now expanding beyond our initial focus on T790M-positive patients and are very enthusiastic about our expansion into front-line patients with TIGER-1, and soon, into an all-comer population of patients with acquired TKI resistance, including both T790M-positive and T790M-negative patients with TIGER-3. We are actively preparing for the first of our planned regulatory filings, which include the U.S. NDA and E.U. MAA in mid-2015.”

Two Phase 2 expansion cohorts (known as TIGER-X) are currently enrolling in the United States, Europe, and Australia in EGFR mutant patients with the T790M mutation. Patients in these cohorts are receiving 625mg BID of the intended commercial tablet formulation of rociletinib, and data from these cohorts will form part of the NDA/MAA submission packages. The two cohorts include patients with T790M+ disease either after progression on their first and only TKI therapy, or after progression on their second or later TKI therapy or chemotherapy.

Data from 56 T790M-positive patients treated with rociletinib in the clinical dose group – which includes the recommended Phase 2 dose of 625mg BID (n=30) and the step-down dose of 500mg BID (n=26) – are being presented today, together with data from 11 T790M-negative patients treated at the same doses.

Patients in the clinical dose group were heavily pre-treated prior to receiving rociletinib; 79 percent of patients had immediately progressed on TKI therapy prior to rociletinib treatment. The median number of previous lines of therapy across patients was three.

Evidence of Activity

The objective response rate (ORR) in 27 evaluable T790M-positive patients receiving either 625 or 500mg BID was 67%. The ORR was comparable in the 625mg BID and 500mg BID dose groups. The disease control rate was 89% for the clinical dose group, and again, was consistent across doses. The median PFS for the clinical dose group was 10.4 months, with follow-up for some patients exceeding one year.

In 11 evaluable T790M-negative patients treated at 625 or 500mg BID, a 36% ORR and median PFS of 7.5 months were observed. This activity in the non-target T790M-negative patient group is surprising and may, in part, relate to the inhibition of IGF1-R (insulin growth factor receptor 1) by a metabolite of rociletinib. In addition to Clovis’ other clinical trials focused on newly-diagnosed EGFR-mutant NSCLC patients in TIGER-1 and T790M-positive patients in TIGER-X and TIGER-2, the Company is now exploring treatment of the T790M-negative population in its TIGER-3 comparative study versus chemotherapy, which includes both T790M-positive and –negative patients. Forty percent of patients who progress on TKI therapy do so for reasons other than the T790M mutation, and this represents a serious unmet medical need.

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Safety and Tolerability

Data presented at ENA demonstrate that rociletinib is well-tolerated, with no evidence of systemic wild-type EGFR inhibition. The most common treatment-related adverse events (AEs) reported in ≥15 percent of all patients included: hyperglycemia, diarrhea, nausea, and reduced appetite. Most adverse events were grade 1 or 2 in severity. The only grade 3/4 treatment-related adverse event observed in more than one patient was hyperglycemia (14 percent). Hyperglycemia, when observed and requiring treatment, is typically managed with a commonly-prescribed single oral agent.

CO-1686 Clinical Development

Clovis is currently enrolling several studies in EGFR-mutant NSCLC in addition to the TIGER-X expansion cohorts noted above:

The TIGER-2 study is currently enrolling patients with EGFR-mutant NSCLC with a centrally-confirmed T790M mutation directly after progression on their first and only TKI therapy. Patients receive rociletinib 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. This global study includes, for the first time, patients from Asian countries including South Korea, Taiwan and Hong Kong.
The TIGER-1 study is a randomized Phase 2/3 registration study of rociletinib vs. erlotinib in newly-diagnosed EGFR-mutant patients. The Phase 2 portion of the study will enroll 200 patients. Upon completion of enrollment of the Phase 2 portion of the study, the Phase 3 portion of the study will immediately follow. The Phase 3 portion is a blinded study and the sizing will be determined in part by the initial data from the Phase 2 portion of the study. Study sites are currently enrolling in the U.S. and will enroll soon in Europe, Australia and Asia.
The TIGER-3 study is an international, randomized, comparative study of rociletinib versus chemotherapy in T790M-positive and T790M-negative patients with EGFR-mutant NSCLC and acquired TKI resistance, which is expected to initiate in the next few months. As well as measuring efficacy in T790M-positive patients, this study will explore whether rociletinib activity in all-comers, including T790M-negative patients, is superior to single-agent chemotherapy, the current standard of care.
For more information, please visit www.tigertrials.com.
In addition, a Phase 1 study of rociletinib is underway in Japan and an expansion cohort is currently enrolling at 625mg BID to confirm a global recommended Phase 2 dose (RP2D).
Data from the TIGER-X expansion cohorts, combined with data from TIGER-2, are expected to serve as the basis of a U.S. NDA and E.U. MAA for rociletinib in mid-2015.

Presentation Details

The presentation, titled “Interim phase 2 results with the irreversible, mutant selective, EGFR inhibitor rociletinib (CO-1686)” is being presented on Friday, November 21, during Plenary Session 8, from 11:00 to 13:00 CET.

Event Webcast Details

Clovis will host an investor/analyst webcast conference call following the rociletinib data presentation at ENA Friday, November 21 from 14:00 to 15:00 CET. Dial in information for the U.S. is 877 280 4960 and International is 857 244 7317. The passcode is 78436017. The event will be simultaneously webcast on the Company’s web site at www.clovisoncology.com, and archived for future review.