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ArQule, Inc.

Partner : Daiichi Sankyo

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PLEASE SCROLL DOWN TO THE RESULTS SECTION (below) TO SEE THE OUTCOME OF THIS EVENT.

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Paolo Pucci, Chief Executive Officer, maintained guidance for data from the phase II colorectal cancer trial. He stated, "Let me now move on to colorectal. We are looking forward to data from the phase II randomized trial in colorectal cancer that was conducted by our partner, Daiichi Sankyo, and the endpoint of this trial with the endpoint being PFS and with data expected late this year, early next."
Source: Q3 2012 earnings conference call, 11/01/12.

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Paolo Pucci, Chief Executive Officer, gave guidance for the data read from the Trivantinib phase II trial for CRC. He stated, "We are predicting at this point that we should have top-line data from this phase II, double blind, randomized, trial, either late this year or very early next year."
Source: Q1 2012 earnings conference call, 5/03/12.

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A Randomized, Placebo-Controlled, Phase 1/2 Study Of ARQ 197 in Combination With Irinotecan and Cetuximab in Subjects With Metastatic Colorectal Cancer With Wild-type KRAS Who Have Received Front-Line Systemic Therapy
Estimated Enrollment: 150
Study Start Date: January 2010
Estimated Study Completion Date: February 2013
Estimated Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Source: clinical trials.gov. http://clinicaltrials.gov/ct2/show/NCT01075048?term=ARQ+197&cond=colorec...

Compound/DeviceSpecialtyIndicationCompound ClassTarget
Tivantinib (ARQ 197) (1) CRCOncologyColorectal Cancer (2nd line treatment) (K-ras wildtype)c-Met inhibitorc-Met protein

Mechanism of action: Tivantinib is an orally bioavailable small molecule inhibitor of c-Met with potential antineoplastic activity. Tivantinib binds to the c-Met protein and disrupts c-Met signal transduction pathways, which may induce cell death in tumor cells overexpressing c-Met protein or expressing consitutively activated c-Met protein. c-Met protein, the product of the proto-oncogene c-Met, is a receptor tyrosine kinase also known as hepatocyte growth factor receptor (HGFR); this protein is overexpressed or mutated in many tumor cell types and plays key roles in tumor cell proliferation, survival, invasion, and metastasis, and tumor angiogenesis.

Phase of Development: II

Event Type: Data: Phase II trial results

Dates: 2012-12-01 - 2013-01-31

Results:

June 1, 2013
Phase 2 Study Results for Tivantinib in Combination with Cetuximab and Irinotecan for Colorectal Cancer Presented at ASCO 2013

Signals of clinical benefit observed in consistent trends toward improved progression-free survival, overall response rate and overall survival
Patients pre-treated with oxaliplatin show particular benefit

WOBURN, Mass.--(BUSINESS WIRE)-- ArQule, Inc. (Nasdaq: ARQL) today announced final data from a randomized, placebo-controlled, double-blind, Phase 2 clinical trial with tivantinib in combination with cetuximab and irinotecan in patients with relapsed or refractory KRAS wild-type metastatic colorectal cancer (CRC). These data were presented today at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO) (abstract number 3508) by Dr. Cathy Eng, M.D., F.A.C.P., M.D. Anderson Cancer Center, Associate Director, Colorectal Center.

"The multiple encouraging signals of clinical benefit observed in this trial include consistent trends in improved progression free survival (PFS), overall response rate (ORR) and overall survival (OS) in patients who received tivantinib in combination with cetuximab and irinotecan," said Dr. Eng. "Trends toward improvements in all of these outcomes were also seen in a small MET high sub-group, but a larger sample size is required to validate conclusively the treatment impact in this population. The results also underscore the need to ensure standardized pretreatment regimens among enrolled patients and uniform tissue collection procedures at enrollment to allow for more robust correlative outcome assessments related to the MET pathway."
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Source: press release, 6/02/13. http://investors.arqule.com/releasedetail.cfm?ReleaseID=768483

ASCO ABstract:

A randomized, placebo-controlled, phase I/II study of tivantinib (ARQ 197) in combination with cetuximab and irinotecan in patients (pts) with KRAS wild-type (WT) metastatic colorectal cancer (CRC) who had received previous front-line systemic therapy.

Sub-category: Colorectal Cancer

Category: Gastrointestinal (Colorectal) Cancer

Meeting: 2013 ASCO Annual Meeting

Abstract No: 3508

Citation: J Clin Oncol 31, 2013 (suppl; abstr 3508)

Author(s): Cathy Eng, Lowell L. Hart, Aleksey Severtsev, Oleg Gladkov, Lothar Mueller, Mikhail V. Kopp, Vladimir Ivanovich Vladimirov, Robert M. Langdon, Bogdan Kotiv, Sandro Barni, Ching Hsu, Ellen Bolotin, Reinhard Von Roemeling, Brian E. Schwartz, Johanna C. Bendell; The University of Texas MD Anderson Cancer Center, Houston, TX; Florida Cancer Specialists/SCRI, Fort Myers, FL; The Central Clinical Hospital #1 of the OAO, Moscow, Russia; Chelyabinsk Regional Clinical Oncology Center, Chelyabinsk, Russia; Oncological Practice, Leer, Germany; Samara Regional Clinical Oncology Dispensary, Samara, Russia; State Medical Institution Pyatigorsk, Pyatigorsk, Russia; Nebraska Methodist Hospital, Omaha, NE; State Educational Institution High Professional Education Military Medical Academy named after S.M.Kirov, St Petersburg, Russia; Division of Oncology, Treviglio, Italy; Daiichi Sankyo Co., Ltd., Edison, NJ; ArQule, Inc., Woburn, MA; Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN

Abstract Disclosures

Abstract:

Background: Tivantinib (ARQ 197) selectively inhibits the MET receptor tyrosine kinase, which is implicated in tumor cell migration, invasion, and metastasis. Resistance to EGFR inhibitors has been associated with activation of alternative pathways including MET. Methods: Pts with advanced KRAS WT CRC that progressed on or after 1 prior line of chemotherapy and no previous treatment with an EGFR inhibitor were eligible. Pts were randomized 1:1 to receive cetuximab (500 mg/m2) and irinotecan (180 mg/m2) on days 1 and 15 every 28 days, plus oral tivantinib (360 mg twice daily [BID]) or placebo. The primary endpoint was progression-free survival (PFS); additional endpoints include safety, objective response rate, overall survival (OS) and exploratory biomarker analyses. Results: Between Jul 2010 and Feb 2012, 122 pts were randomized; 117 pts were eligible for analysis (60 tivantinib, 57 placebo). Mean age was 57 years (range, 27-79 years); ECOG PS 0/1 55%/45%; and 81% received prior oxaliplatin. Median PFS was 8.3 months in the tivantinib arm vs 7.3 months in the placebo arm (hazard ratio [HR] = 0.85; 95% CI, 0.55-1.33; P = 0.38). Objective response rate (95% CI) was 45% (33%-58%) in the tivantinib arm and 33% (23%-46%) in the placebo arm. Median OS has not yet been reached but is trending in favor of tivantinib vs placebo (HR = 0.67). Among pts with prior oxaliplatin therapy, median PFS was 8.4 months for tivantinib and 7.2 months for placebo (HR = 0.67; 95% CI, 0.44-1.00; P= 0.1). The most common grade 3/4 adverse events (≥ 10%) were neutropenia, diarrhea, and nausea. Correlation of clinical outcomes with additional factors including mutation status and immunohistochemical analysis of tumor MET expression will be presented. Conclusions: Outcomes in this trial trended towards improvement with tivantinib (360 mg BID) plus cetuximab and irinotecan, particularly in the subgroup who had previous oxaliplatin. Further studies are needed to identify the CRC population most likely to benefit from addition of tivantinib to standard therapy. Clinical trial information: NCT01075048.
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Source: ASCO Abstract. http://abstracts2.asco.org/AbstView_132_113021.html

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January 11, 2013
Daiichi Sankyo and ArQule Announce Top-Line Results of Phase 2 Trial with Tivantinib in Colorectal Cancer

Tivantinib in combination with irinotecan and cetuximab shows a trend of prolonged progression free survival and improved objective response rate in signal generation trial

ArQule conference call scheduled today at 9:00 a.m. eastern time

TOKYO & WOBURN, Mass.--(BUSINESS WIRE)-- Daiichi Sankyo Company, Limited (TSE 4568) and ArQule, Inc. (Nasdaq: ARQL) today announced the top-line results of a randomized Phase 2 signal generation trial of tivantinib (ARQ 197) used in combination with irinotecan and cetuximab in patients with refractory or relapsed colorectal cancer (CRC). Although the trial did not meet its primary endpoint of Progression-Free Survival (PFS), the analysis of the patients enrolled (n=122) showed that median PFS was 8.3 months in the experimental arm (patients treated with irinotecan and cetuximab plus tivantinib), compared with 7.3 months in the control arm (patients treated with irinotecan and cetuximab plus placebo) (hazard ratio = 0.85, 95% CI: 0.55, 1.33). Objective Response Rate (ORR), a secondary endpoint, was 45 percent in the experimental arm versus 33 percent in the control arm but was not statistically significant. The PFS results obtained in both the control arm and the experimental arm were longer than expected compared to previously published historical norms.

Additional data and analyses from this trial are planned for presentation at a future medical meeting and will include mature OS data as well as analyses of patient sub-groups, biomarker status and regional variability, including pre- and post study treatments.

"We are encouraged by these findings that expand the body of data for tivantinib in CRC and offer the potential for further exploration," said Reinhard von Roemeling, M.S., Vice President, Clinical Development-Oncology, Daiichi Sankyo. "We plan to continue discussions with key opinion leaders in the field of CRC to determine how best to proceed with further clinical development of tivantinib in this tumor type."

Adverse events were reported at similar rates in the experimental and control arms, except for increased neutropenia observed in the experimental arm, with no discontinuations of treatment for this reason. No treatment-emergent adverse events leading to death were assessed as related to study treatment. Tivantinib was generally well tolerated in combination with the doses of cetuximab and irinotecan studied in this trial.
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Source: press release, 1/11/13. http://investors.arqule.com/releasedetail.cfm?ReleaseID=732833