ASCO Presentations Highlight Findings from Clinical Trials with ArQule's c-MET Inhibitor, ARQ 197
Preliminary data from ongoing trial in MiT tumors demonstrate clinical benefit as patient enrollment progresses;
Data from other trials include evidence of disease stabilization in non-small cell lung cancer patients and anti-angiogenic effect in patients with metastatic solid tumors
These data were included in a clinical science symposium and three poster discussions, in their order of presentation at ASCO as follows:
1. Final Results of a Pharmacokinetic (PK) and Pharmacodynamic (PD) Phase 1 Trial of ARQ 197 Incorporating Dynamic Contrast-Enhanced (DCE) Magnetic Resonance Imaging (MRI) Studies Investigating the Anti-Angiogenic Activity of Selective c-MET Inhibition: Abstract Number 3523.
2. Phase 1 Dose Escalation Trial (ARQ 197-111) Evaluating Combination of Selective c-MET Inhibitor ARQ 197 and Erlotinib: Abstract Number 3549.
3. Final Results: A Dose Escalation Phase 1 Study of ARQ 197, a Selective c-MET Inhibitor, in Patients with Metastatic Solid Tumors: Abstract Number 3548.
4. Preliminary Results from a Phase 2 Study of ARQ 197 in Patients with Microphthalmia Transcription Factor Family (MiT) Associated Tumors: Abstract Number 10502.
“Key findings from these studies with ARQ 197 include clinical benefit shown in preliminary results from an ongoing Phase 2 trial in patients with MiT-associated tumors, evidence of prolonged stable disease among patients with advanced metastatic non-small cell lung cancer (NSCLC) in a Phase 1 combination with erlotinib, and the observation of an anti-angiogenic effect in a Phase 1 trial among patients with metastatic solid tumors that supports previously presented clinical and pre-clinical data,” said Paolo Pucci, chief executive officer of ArQule.
“These findings provide new signals of activity, strengthen the therapeutic rationale for c-MET inhibition in multiple tumor types and expand the clinical database of ARQ 197,” said Mr. Pucci. “We are building upon these data and making excellent progress with patient enrollment in our lead Phase 2 trials in second and third-line non-small cell lung cancer and microphthalmia transcription factor (MiT)-associated tumors. We expect to complete enrollment in both trials late this year,” said Mr. Pucci, “and we are also accruing patients in our other trials with ARQ 197 in hepatocellular carcinoma and pancreatic cancer.”
Summary of Findings
Final Results of a Pharmacokinetic (PK) and Pharmacodynamic (PD) Phase 1 Trial of ARQ 197 Incorporating Dynamic Contrast-Enhanced (DCE) Magnetic Resonance Imaging (MRI) Studies Investigating the Anti-Angiogenic Activity of Selective c-MET Inhibition: Abstract Number 3523
The primary objective of this trial was to assess the safety, tolerability and recommended Phase 2 dose (RP2D) of ARQ 197. Secondary objectives included evaluation of PK and PD profiles of ARQ 197, and evaluation of the potential anti-angiogenic activity of selective c-MET inhibition by ARQ 197, a pharmacologic effect suggested by previously reported clinical and pre-clinical data.
A total of 46 patients with advanced solid tumors were enrolled in this trial. The most commonly enrolled tumor types included prostate cancer (12 patients), melanoma (11 patients), gastric cancer (6 patients), sarcoma (4 patients), colorectal cancer (3 patients), and breast cancer (2 patients).
The most commonly reported adverse events (AEs) were fatigue (40.9 percent), nausea (25.0 percent), and vomiting (20.5 percent). The most commonly observed AEs considered to be at least possibly related to ARQ 197 were fatigue (15.9 percent), nausea (11.4 percent), diarrhea (6.8 percent) and vomiting (6.8 percent). Three patients experienced five DLT events. The maximum tolerated dose (MTD) and RP2D were established at 360 mg b.i.d.
Tumor regressions up to 12.4 percent were observed in 2 patients. Stable disease lasting up to 23 weeks was observed in 15 of 24 evaluable patients (62.5 percent), while progressive disease was seen in nine of 24 evaluable patients (37.5 percent).
Evidence of anti-angiogenic effect was suggested by declines of circulating endothelial cells (CECs) up to 100 percent in 19 of 31 evaluable patients (61 percent) following administration of ARQ 197. Additionally, preliminary dynamic contrast-enhanced (DCE) and diffusion-weighted magnetic resonance imaging data documented statistically significant day 7 decreases in radiographic markers, further suggesting the anti-angiogenic effect of ARQ 197-mediated c-MET inhibition.
Investigators concluded that ARQ 197 was safe and well tolerated up to the MTD/RP2D of 360 mg b.i.d. Systemic exposure to ARQ 197 increased linearly with dose through the MTD. Inhibition of c-MET phosphorylation in tumor biopsies was observed post-treatment at all doses. Clinical improvement in symptoms was observed, as measured by RECIST (Response Evaluation Criteria in Solid Tumors) stable disease up to 23 weeks and tumor regression.
Phase 1 Dose Escalation Trial (ARQ 197-111) Evaluating Combination of Selective c-MET Inhibitor ARQ 197 and Erlotinib: Abstract Number 3549
The objectives of this trial were to evaluate the safety, tolerability, RP2D, PK, and preliminary signals of anti-tumor activity with escalating doses of ARQ 197 in combination with the approved dose of erlotinib (150 milligrams daily), with particular attention given to NSCLC patients.
A total of 32 patients were enrolled and treated with escalating doses of ARQ 197. Tumor types enrolled included NSCLC (8 patients), colorectal (3 patients), renal cell carcinoma (3 patients) squamous cell carcinoma (3 patients) and pancreatic cancer (2 patients).
Combination therapy AEs were reported for 26 patients, including three patients with therapy-related serious adverse events (SAEs). Dose limiting toxicities (DLTs) were observed in two patients at 360 mg b.i.d. of ARQ 197. PK data revealed linear dose versus exposure of ARQ 197 at doses up to 360 mg b.i.d. and no evidence of ARQ 197-erlotinib interaction.
Seventeen patients had evaluable RECIST responses, with an unconfirmed partial response in head and neck cancer, stable disease in 14 patients (82.4 percent) and progressive disease in 3 patients (17.6 percent). The duration of stable disease ranged from 5.9 to 45.4 weeks, with a median duration of 17.1 weeks. Tumor regressions of between 2.3 percent to 33.3 percent were observed in 5 patients after 8 to 26 weeks on therapy.
Eight patients had NSCLC, 6 of whom had prior treatment with erlotinib. Five of these patients had stable disease lasting more than 17 weeks. The median duration of progression-free survival in NSCLC patients in this trial was 26.3 weeks, or more than 6 months, greater than previously published median progression-free survival of 9.7 weeks in 2nd/3rd line NSCLC patients with erlotinib monotherapy.
In addition to stable disease observed in NSCLC patients, investigators concluded that combination therapy with ARQ 197 and erlotinib was well tolerated and without apparent drug-drug interaction. The recommended Phase 2 combination dose of 360 mg b.i.d. of ARQ 197 plus 150 mg daily of erlotinib is currently being investigated in a randomized Phase 2 clinical trial comparing ARQ 197-erlotinib combination therapy to erlotinib plus placebo in EGFR inhibitor-naïve NSCLC patients in second and third line settings.
Final Results: A Dose Escalation Phase 1 Study of ARQ 197, a Selective c-MET Inhibitor, in Patients with Metastatic Solid Tumors: Abstract Number 3548
The objectives of this trial were to evaluate safety, to determine the MTD and the RP2D, to evaluate the PK profile, and to evaluate preliminary anti-tumor activity of ARQ 197.
A total of 74 patients have been treated in this trial as of May 1, 2009, with 13 cohorts of patients assessed at doses ranging from 10-360 mg b.i.d. Two dosing schedules were explored: (1) Schedule A, oral ARQ 197 twice daily for two weeks followed by one week off drug, and (2) Schedule B (introduced after initial safety was established in Schedule A), continuous twice daily oral dosing of ARQ 197.
AEs considered to be drug-related occurred in 30 (40.5 percent) patients, with the most common being fatigue (16.2 percent), nausea (12.2 percent), vomiting (6.8 percent) and diarrhea (5.4 percent). Drug-related serious AEs occurred in 4 patients. DLTs were reported in 2 patients at 360 mg b.i.d. These DLTs resolved after 6 and 9 days, and treatment continued. No MTD was identified in this trial, although a monotherapy MTD of 360 mg b.i.d. is presented elsewhere (Abstract No. 3523).
Investigators concluded that ARQ 197 has a favorable safety profile up to the dose of 360 mg b.i.d. Although the primary objective of the study was not to determine efficacy, 61 patients were evaluable for anti-tumor activity. Three patients, with neuroendocrine, prostate and testicular cancers, achieved partial responses per RECIST, for an objective response rate of 4.9 percent in the evaluable population. Thirty-eight patients had a best response of stable disease, and 20 had documented progressive disease. The disease control rate (objective responses and stable disease) among evaluable patients was 67.2 percent, suggesting preliminary evidence of anti-cancer activity and supporting further clinical investigation, which is ongoing.
Preliminary Results From a Phase 2 Study of ARQ 197 in Patients with Microphthalmia Transcription Factor Family (MiT) Associated Tumors: Abstract Number 10502
Investigators presented preliminary results from an ongoing, single arm, two-stage Phase 2 clinical trial to evaluate the efficacy of ARQ 197 when used to treat a group of tumors associated with dysregulation of MiT (Microphthalmia Transcription Factor). These tumors include alveolar soft part sarcoma (ASPS), clear cell sarcoma (CCS) and translocation-associated renal cell carcinoma (RCC). These tumors are generally resistant to all conventional therapies.
Patients in this trial had metastatic, advanced-stage disease, with no limitation on the number of prior therapies received. Of 36 patients enrolled in the trial, 28 were evaluable for tumor response, with available pre- and post-baseline tumor assessments.
Findings to date demonstrate a favorable safety profile for ARQ 197 in both adults and pediatric patients receiving the drug at doses up to 360 mg b.i.d. Three drug-related Grade 3 or 4 AEs were observed. Additionally, preliminary evidence of anti-cancer activity was observed, including one patient with clear cell sarcoma experiencing a confirmed partial response per RECIST and an overall disease control rate (objective responses and stable disease) of 81 percent. Patient enrollment in this trial is continuing and expected to be completed in late 2009.
Information regarding trials with ARQ 197
Patients, physicians and other healthcare professionals seeking additional information regarding these trials and others involving ARQ 197 may call 1-800-373-7827.
About ARQ 197 and c-MET
ARQ 197 is a selective inhibitor of c-MET, a receptor tyrosine kinase. When abnormally activated, c-MET plays multiple roles in aspects of human cancer, including cancer cell growth, survival, angiogenesis, invasion and metastasis. Pre-clinical data have demonstrated that ARQ 197 inhibits c-MET activation in a wide range of human tumor cell lines and shows anti-tumor activity against several human tumor xenografts. In clinical studies to date, treatment with ARQ 197 has been well tolerated and has resulted in tumor responses and prolonged stable disease across broad ranges of tumors and doses.
ARQ 197 is currently being evaluated in Phase 2 clinical trials in non-small cell lung cancer, MiT (Microphthalmia Transcription Factor)-associated tumors (which include clear cell sarcoma, alveolar soft parts sarcoma and translocation-associated renal cell carcinoma), and pancreatic cancer, as well as in a Phase 1 / 2 trial in hepatocellular carcinoma.
About ArQule and Daiichi Sankyo Co., Ltd.
On December 19, 2008, ArQule and Daiichi Sankyo signed a license, co-development and co-commercialization agreement to co-develop ARQ 197 in the U.S., Europe, South America and the rest of the world, excluding Japan, China (including Hong Kong), South Korea and Taiwan, where Kyowa Hakko Kirin Co., Ltd. (Kyowa) has exclusive rights for development and commercialization.
About ArQule
ArQule is a biotechnology company engaged in the research and development of next-generation, small-molecule cancer therapeutics. The Company's targeted, broad-spectrum products and research programs are focused on key biological processes that are central to cancer. ArQule's lead product, in Phase 2 clinical development, is ARQ 197, an inhibitor of the c-MET receptor tyrosine kinase. The Company has also initiated Phase 1 clinical testing with ARQ 621, designed to inhibit the Eg5 kinesin motor protein. An additional clinical-stage program includes compounds that activate the cell's DNA damage response mechanism mediated by the E2F-1 transcription factor. The Company's pre-clinical pipeline includes a compound designed to inhibit the BRAF kinase. ArQule's current discovery efforts, which are based on the ArQule Kinase Inhibitor Platform (AKIP™) are focused on the identification of novel kinase inhibitors that are potent, selective and do not compete with ATP (adenosine triphosphate).
This press release contains forward-looking statements regarding the progress of the Company's clinical trials, including Phase 2 trials with ARQ 197. These statements are based on the Company's current beliefs and expectations, and are subject to risks and uncertainties that could cause actual results to differ materially. Positive information about early stage clinical trial results does not ensure that later stage or larger scale clinical trials will be successful. For example, ARQ 197 may not demonstrate promising therapeutic effect; in addition, this compound may not demonstrate an appropriate safety profile in further pre-clinical testing and in current, later stage or larger scale clinical trials as a result of known or as yet unanticipated side effects. The results achieved in later stage trials may not be sufficient to meet applicable regulatory standards. Problems or delays may arise during clinical trials or in the course of developing, testing or manufacturing these compounds that could lead the Company or its partner to discontinue development. Even if later stage clinical trials are successful, the risk exists that unexpected concerns may arise from analysis of data or from additional data or that obstacles may arise or issues be identified in connection with review of clinical data with regulatory authorities or that regulatory authorities may disagree with the Company's view of the data or require additional data, information or studies. In addition, the planned timing of initiation and completion of clinical trials for ARQ 197 is subject to the ability of the Company to enroll patients, enter into agreements with clinical trial sites and investigators, and other technical hurdles and issues that may not be resolved. Drug development involves a high degree of risk. Only a small number of research and development programs result in the commercialization of a product. Furthermore, ArQule may not have the financial or human resources to pursue drug discovery successfully in the future. For more detailed information on the risks and uncertainties associated with the Company's drug development and other activities see the Company's periodic reports filed with the Securities and Exchange Commission. The Company does not undertake any obligation to publicly update any forward-looking statements.
Contact: ArQule, Inc.
William B. Boni, 781-994-0300
VP, Investor Relations/
Corp. Communications
www.ArQule.com
