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Partner : Daiichi Sankyo

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Daiichi Sankyo and ArQule Announce Continuation of METIV-HCC Phase 3
Study of Tivantinib in Second-Line Hepatocellular Carcinoma

Independent Data Monitoring Committee (DMC) Conducts Interim Assessment Burlington, MA and Parsippany, NJ – March 22, 2016 – ArQule, Inc. (Nasdaq: ARQL) and Daiichi Sankyo today announced that the independent data monitoring committee (DMC) of the METIV-HCC study conducted the planned interim assessment and it was determined the trial will continue to its final analysis.

METIV-HCC is a biomarker-selected, double-blind, placebo-controlled, pivotal phase 3 study evaluating tivantinib (2:1) versus best supportive care in previously systemically-treated patients with MET-high, inoperable HCC, with overall survival as the primary endpoint.

The interim analysis was triggered when at least 60 percent of the target number of events occurred. The final analysis will take place when 100 percent of the target number of events occurs. The METIV-HCC trial completed patient accrual in December 2015 with more than 300 patients with MET-high HCC enrolled.
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Source: press release, 3/22/16. http://files.shareholder.com/downloads/ARQL/1673022183x0x882287/84DDD033...

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Paolo Pucci, Chief Executive Officer, gave guidance for the interim analysis for tivantinib in HCC. He stated, "We are on track to conduct by early in the second quarter of this year, so not so far away in time. The planned interim analysis of the METIV HCC trial in second line hepatocellular carcinoma. The trial evaluates single agent Tivantinib versus placebo in second line HCC and it has enrolled slightly more than 300 patients. The upcoming interim analysis was designed to be triggered when approximately 60% of the events had occurred. As a reminder, the interim analysis includes an efficacy stop and there is no four-month futility stop. We would therefore expect the outcome of this interim analysis to be either stop the trial due to the DMC seeing significant efficacy, or continue the trial until its end which we anticipate to occur towards the very end of this year. Obviously as it is with every trial monitored by a DMC, the possibility exists that the DMC could halt any trial at any time, including this one for safety reasons."
Source: Q4 2015 earnings conference call, 2/29/16.

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Tivantinib pivotal phase 3 trial, METIV-HCC, completed enrollment and preliminary biomarker data analysis reported at ASCO GI: The biomarker-driven phase 3 trial for tivantinib, METIV-HCC, in second line hepatocellular carcinoma (HCC) completed patient enrollment of over 300 patients. The planned interim assessment is expected to occur by early in the second quarter of 2016. Additionally, preliminary biomarker data from the METIV-HCC trial presented at the Gastrointestinal Symposium Conference (ASCO GI) confirmed Phase 2 data demonstrating that MET status, as determined by immunohistochemistry, was more frequently high after first-line therapy.
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Source: press release, 2/29/16. http://investors.arqule.com/releasedetail.cfm?ReleaseID=957657

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Paolo, Pucci, CEO of Arqule, commented on enrollment status of the trial. He stated, "The METIV clinical trial continued to recruit well and is well on track to be fully recruited by year end. As we had anticipated during all the calls we had this year. By year-end METIV will have enrolled just about 300 patients randomized two to one to receive single agent tivantinib against placebo as a second line therapy for HCC patients that are classified as MET-high.
Source: q# 2015 earnings conference call, 11/04/15

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ARQULE AND DAIICHI SANKYO ANNOUNCE COMPLETION OF ACCRUAL IN METIV-HCC PHASE 3 TRIAL OF TIVANTINIB FOR SECOND-LINE HEPATOCELLULAR CARCINOMA

Planned interim analysis expected to occur early in the second quarter of 2016

Burlington, MA and Parsippany, NJ, December 10, 2015 – ArQule, Inc. (Nasdaq: ARQL) and Daiichi Sankyo, Inc. today announced that the phase 3 METIV-HCC trial for tivantinib in second-line hepatocellular carcinoma (HCC) has completed accrual. In addition, the planned interim analysis, which is triggered when 60 percent of events occur, is expected to take place early in the second quarter of 2016.

The METIV-HCC trial is a biomarker-driven, double-blind, placebo-controlled, pivotal phase 3 trial where patients are randomized 2:1 comparing tivantinib to best supportive care. The trial is conducted under a Special Protocol Assessment and has accrued more than 300 HCC patients with MET-high tumors only, as determined by an immunohistochemistry test. The trial is being conducted in western countries by Daiichi Sankyo and ArQule with a primary endpoint of overall survival. The planned interim analysis for Data Monitoring Committee (DMC) review was designed with an early stop for superiority.

“We are pleased to have fully accrued the METIV-HCC trial prior to year-end,” said Brian Schwartz, M.D., Head of Research and Development and Chief Medical Officer at ArQule. “HCC is a disease with high unmet need and with no approved therapy for second-line treatment. It has been very encouraging to see a growing body of evidence supporting the phase 3 clinical evaluation of tivantinib in MET-high populations through a recent presentation at the International Liver Cancer Association conference.”

“We would like to thank all the patients, investigators and clinical sites for partnering with us to achieve this important milestone,” said Mahmoud Ghazzi, M.D., Ph.D, President and Global Head of Development for Daiichi Sankyo. “The completion of planned patient enrollment into METIV-HCC is an important step forward in the development of a potential new targeted treatment for patients with advanced HCC, who currently have limited options.”
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Source: press release, 12/10/15. http://files.shareholder.com/downloads/ARQL/1146962107x0x865961/0D8A6C98...

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ArQule Presents Additional Clinical Biomarker Data From Phase 2 Study of Tivantinib in Hepatocellular Carcinoma at International Liver Cancer Association Conference
Data Supports Tumor MET Status as a Prognostic and Predictive Factor

BURLINGTON, Mass., Sept. 08, 2015 (GLOBE NEWSWIRE) -- ArQule, Inc. (Nasdaq:ARQL) today announced that additional analyses of plasma biomarkers support the prognostic and predictive role of MET status in this previously reported phase 2 trial in hepatocellular carcinoma (HCC). The data was presented at the International Liver Cancer Association (ILCA) 9th Annual Conference on September 6th, 2015.

The phase 2 study, completed in the third quarter of 2011 and published in The Lancet Oncology medical journal in November 2012, enrolled 107 HCC patients who progressed or were intolerant to one prior systemic therapy. Multiple biomarkers were evaluated as part of the study, and MET status as determined by immunohistochemistry emerged as the strongest predictor of tivantinib benefit. In addition, the presentation noted that biopsies were more likely to be categorized as MET-high when taken after sorafenib therapy than before therapy. The presentation can be accessed in the "Investor and Media" section of our website, www.arqule.com, under "Recent Data Presentations."

"The biomarker data from this trial demonstrates that patients with MET-high tumors are more likely to benefit from tivantinib therapy," said Dr. Brian Schwartz, head of research and development at ArQule. "On the basis of the results from the phase 2 trial and in partnership with Daiichi Sankyo, we are conducting the pivotal phase 3 METIV-HCC trial that is enrolling MET-high HCC patients as determined by a required companion diagnostic test."

By the end of 2015 the pivotal phase 3 trial, METIV-HCC, is expected to complete enrollment of approximately 300 patients, randomized 2:1 treatment to best supportive care, with the primary end-point of overall survival.
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Source: press release, 9/08/15. http://investors.arqule.com/releasedetail.cfm?ReleaseID=930442

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Paolo Pucci, Chief Executive Officer, gave guidance for the enrollment completion of the phase-III METIV-HCC trial of Tivantinib in hepatocellular carcinoma. He stated, "What we plan to do is to first update you on the pivotal phase-III METIV-HCC trial of Tivantinib in hepatocellular carcinoma for which we have said and we confirm we expect that by year end this year the last patient will be screened for randomization, starting therefore the clock for interim analysis as well as final analysis. These achievements are made possible thanks to the timely enrollment of patients at now more than 100 clinical sites that are open and actively recruiting worldwide."
Source: Q4 2014 earnings conference call, 3/04/15.

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May 30, 2014
ArQule Announces Data Presentations with Tivantinib to Be Featured at ASCO 2014
Company Also Provides Update on Phase 3 Trial in Hepatocellular Carcinoma

WOBURN, Mass.--(BUSINESS WIRE)-- ArQule, Inc. (Nasdaq: ARQL) today announced that tivantinib will be included in seven presentations during the 2014 Annual Meeting of the American Society of Clinical Oncology (ASCO) to be held from May 30, 2014 to June 3, 2014 in Chicago, Illinois.

The presentations will feature tivantinib in clinical trials across multiple diseases and therapeutic combinations. Data will relate to the safety and combinability of tivantinib with approved anti-cancer agents, supporting the ongoing development of this compound.

The most advanced ongoing clinical trial with tivantinib is a pivotal Phase 3 randomized, double-blind controlled study (the METIV-HCC trial) of the compound as single agent therapy in previously treated patients with MET-diagnostic-high, inoperable hepatocellular carcinoma (HCC).

"Enrollment in the METIV-HCC trial continues to gather momentum, with the Data Monitoring Committee having completed its most recent meeting," said Paolo Pucci, chief executive officer of ArQule. "We believe that recruitment figures reflect our investigators' enthusiasm, which has been further enhanced by recent publications1 that underscore the potential of MET as a target of interest in HCC," said Mr. Pucci.
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Source: press release, 5/30/14. http://investors.arqule.com/releasedetail.cfm?ReleaseID=851539

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January 16, 2014

ArQule Provides Updates on Clinical Trials in Hepatocellular Carcinoma and Non-Small Cell Lung Cancer with Tivantinib
Data Monitoring Committee approves continuation of Phase 3 METIV-HCC liver cancer trial following safety and pharmacokinetic analyses

Asian partner Kyowa Hakko Kirin provides top-line data on ATTENTION trial in non-squamous non-small cell lung cancer

WOBURN, Mass.--(BUSINESS WIRE)-- ArQule, Inc. (Nasdaq: ARQL) today provided clinical updates on the ongoing pivotal Phase 3 METIV-HCC trial in hepatocellular carcinoma (liver cancer) conducted by the Company and its partner, Daiichi Sankyo Co., Ltd., and on the completed amended Phase 3 ATTENTION trial in non-squamous non-small cell lung cancer (NSCLC) conducted in Asian territories by its partner, Kyowa Hakko Kirin Co., Ltd.

METIV-HCC Trial

The Data Monitoring Committee (DMC) of the METIV-HCC trial has recommended continuation of the ongoing pivotal Phase 3 METIV-HCC trial of tivantinib as a single agent in hepatocellular carcinoma with a lower dose of tivantinib, 120 milligrams (mg) tablets administered twice daily (BID). This decision followed the DMC's review of data analyses from a predefined number of patients who received this lower dose.

Recently completed safety analyses among patients treated with 120 mg BID tivantinib tablets showed that the incidence of neutropenia was reduced with this lower dose. In addition, pharmacokinetic analyses from this patient cohort, reviewed by the DMC, demonstrated that the plasma exposure of the 120 mg BID tablets dose was comparable to the exposure achieved with the 240 mg BID capsules dose employed in the Phase 2 trial, with similar medians and overlapping ranges.

A dose reduction from 240 mg BID tablets to 120 mg tablets BID was implemented in September, 2013 following the observation of a higher incidence of neutropenia in the initial phase of the METIV-HCC trial than was observed in the Phase 2 trial in the same patient population where a 240 mg BID capsule dose was administered. Certain enhanced patient monitoring procedures had been temporarily instituted to confirm the safety profile of the lower dose.

The METIV-HCC trial is a pivotal randomized, double-blind study of tivantinib as single agent therapy in previously treated patients with MET diagnostic-high, inoperable HCC. The primary endpoint is overall survival in the intent-to-treat population, and the secondary endpoint is progression free survival in the same population. METIV-HCC is being conducted under a Special Protocol Assessment (SPA).
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Source: press release, 1/16/14. http://investors.arqule.com/releasedetail.cfm?ReleaseID=819847

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ArQule, Inc. (“ArQule” or the “Company”) and its partner, Daiichi Sankyo, Inc. (“Daiichi Sankyo”) are currently sponsoring a Phase 3 trial of tivantinib in the treatment of hepatocellular cancer (“HCC”). This trial is known as the METIV-HCC study. Recently the Company and Daiichi Sankyo received a letter from the trial Data Monitoring Committee (“DMC”) recommending that the study dosage be reduced from 240 mg twice daily (“BID”) to 120 mg BID and that certain enhanced patient monitoring procedures be instituted to confirm the safety profile of the lower dose. This recommendation resulted from the observation of a higher incidence of neutropenia in the METIV-HCC trial than was observed in the Company’s and Daiichi Sankyo’s Phase 2 trial in the same patient population.

The Company and Daiichi Sankyo have accepted the recommendation of the DMC to implement the lower dose and will be filing a protocol amendment with regulatory authorities and related parties. After a prescribed number of patients have been dosed at 120 mg BID, the DMC will review data from that patient cohort to determine the safety profile of the lower dose and whether to recommend any further action. Because the trial is still in the early stages of recruitment, the Company and Daiichi Sankyo are not able to comment at this time on whether the timeline for recruitment of the trial may be delayed compared with original estimates as a result of the proposed amendment and subsequent data review.

The Company and Daiichi Sankyo expect that the dose reduction will reduce the incidence of neutropenia observed to date in the METIV-HCC trial, resulting in greater patient safety and fewer early patient terminations. The Companies also believe they have now selected a dose that will offer the best possibility for a favorable benefit-risk ratio.

The Company and Daiichi Sankyo will continue to review available data from this and other studies to better understand the increased incidence of neutropenia observed in the METIV-HCC trial compared with the Phase 2 HCC trial, including any possible impact from a change in dosage form. The incidence of neutropenia seen in the METIV-HCC trial to date has not been observed in other trials with tivantinib, which continue to employ a dose of 360 mg BID.

The METIV-HCC trial is a randomized, double-blinded study of tivantinib as single agent therapy in previously treated patients with MET diagnostic-high inoperable HCC. It is being conducted under a Special Protocol Assessment with the FDA. The primary endpoint of the study is overall survival in the intent-to-treat population, and the secondary endpoint is progression free survival in the same population.
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Source: FORM 8K, 9/03/13. http://investors.arqule.com/secfiling.cfm?filingid=1188112-13-2621

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Paolo Pucci, Chief Executive Officer, commented on the phase-III program for Tivantinib in HCC. He stated, "Patient recruitment in the METIV trial is in its infancy. We just started in Q1 this year and we are planning by the coming fall to have about half of the 120 sites up and running and recruiting."
Source: Q1 2013 earnings conference call, 5/08/13.

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January 31, 2013
Daiichi Sankyo and ArQule Enroll First Hepatocellular Carcinoma Patient into Global Phase 3 Trial for Tivantinib

TOKYO & WOBURN, Mass.--(BUSINESS WIRE)-- Daiichi Sankyo Company, Limited (TSE 4568) and ArQule, Inc. (Nasdaq: ARQL) today announced that the first patient has been enrolled in the pivotal Phase 3 METIV-HCC (MET-high patients with tivantinib in HCC) trial of tivantinib (ARQ 197). Tivantinib, an investigational selective inhibitor of MET, a receptor tyrosine kinase, is being evaluated for the treatment of patients diagnosed with hepatocellular carcinoma (HCC) who have received one or two prior systemic anti-cancer therapies.

The METIV-HCC trial is a randomized, double-blinded, controlled study of previously treated patients with MET-high inoperable HCC who will receive tivantinib or placebo. The primary endpoint is overall survival (OS), and the secondary endpoint is progression-free survival (PFS). Approximately 300 patients are planned to be enrolled at approximately 120 clinical centers worldwide. Additional details of the trial are available on www.clinicaltrials.gov.

"We are very pleased to begin this Phase 3 trial to advance our understanding of the potential role of tivantinib in the treatment of HCC," said Glenn Gormley, MD, PhD, Global Head of Research and Development and Senior Executive Officer, Daiichi Sankyo. "It is our hope that this late-stage study will confirm the positive results we saw in Phase 2 in time to progression (TTP) and overall survival (OS) observed in patients whose tumors were MET-high."

"Hepatocellular carcinoma is a devastating disease, and patients with advanced HCC are in need of new therapies that can help extend their lives," said Paolo Pucci, chief executive officer of ArQule. "The METIV-HCC trial follows positive Phase 2 results that demonstrated improvements in overall survival and time to progression observed among MET-high patients."

In October 2012, agreement was reached with the U.S. Food and Drug Administration (FDA) on a Special Protocol Assessment (SPA) for this pivotal Phase 3 trial. The SPA process is a procedure by which the FDA provides official evaluation and written guidance on the design and size of proposed protocols that are intended to form the basis for a New Drug Application. Final marketing approval depends on the results of the trial.
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Source: press release, 1/31/13. http://investors.arqule.com/releasedetail.cfm?ReleaseID=737046

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Paolo Pucci, Chief Executive Officer, maintained guidance for the start of the phase III trial of Tivantinib for HCC. He stated, "So, the first visible milestone to be achieved in this process was announced a couple of weeks ago. We with Daiichi Sankyo sought an SPA for our phase III trial and we have recently announced that the SPA had been granted. So that is the first milestone that was achieved. The second visible milestone to be achieved now is the first patient's first visit, and we maintain that, that will occur either late this year or early next year."
Source: Q3 2012 earnings conference call, 11/01/12.

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October 16, 2012
ArQule and Daiichi Sankyo Reach Agreement with FDA on Special Protocol Assessment for Phase 3 Trial of Tivantinib in Hepatocellular Carcinoma

WOBURN, Mass.--(BUSINESS WIRE)-- ArQule, Inc. (Nasdaq: ARQL) today announced a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA) for the design of a pivotal Phase 3 trial of tivantinib in patients with hepatocellular carcinoma (HCC).

The Phase 3 trial will be a randomized, double-blinded study of tivantinib as single agent therapy in previously treated patients with MET diagnostic-high inoperable HCC. The primary endpoint is overall survival in the intent-to-treat population, and the secondary endpoint is progression free survival in the same population. Approximately 300 patients are planned to be enrolled at approximately 120 centers worldwide.

The SPA process is a procedure by which the FDA provides official evaluation and written guidance on the design and size of proposed protocols that are intended to form the basis for a New Drug Application. Final marketing approval depends on the results of the trial.

"We are mindful of the high unmet need among patients suffering from this disease, and we are proceeding with our partner, Daiichi Sankyo, toward the timely initiation of this trial," said Paolo Pucci, chief executive officer of ArQule.
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Source: press release, 10/16/12. http://investors.arqule.com/releasedetail.cfm?ReleaseID=713700

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METIV - A Phase 3, Randomized, Double-Blind Study of Tivantinib (ARQ 197) in Subjects With MET Diagnostic-High Inoperable Hepatocellular Carcinoma Treated With One Prior Systemic Therapy
Estimated Enrollment: 368
Study Start Date: December 2012
Estimated Study Completion Date: June 2017
Estimated Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)
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Source: clinical trials.gov. http://clinicaltrials.gov/ct2/show/NCT01755767?term=METIV+trial&rank=1

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Compound/DeviceSpecialtyIndicationCompound ClassTarget
Tivantinib (ARQ 197) (2) HCCOncologyHepatocelluar carcinomac-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: III

Event Type: Data: Phase III trial results

Dates: 2016-04-01 - 2016-04-30

Results: Pending