Kyowa Hakko Kirin   
In June 2010, initiation of a phase II clinical trial with ARG 197 in Asia triggered a $5 million milestone payment to ArQule from Kyowa Hakko Kirin.

In February 2008, Arqule received a $3 million milestone payment from Kyowa Hakko Kogyo, marking the initiation by Kyowa of a dose-escalation phase I clinical trial in Japan with ARQ 197.

In April 2007, ArQule entered into an exclusive license agreement with Kyowa Hakko Kogyo Co. (Kyowa) to develop and commercialize ARQ 197, a small molecule, selective inhibitor of the c-Met receptor tyrosine kinase, in Japan and parts of Asia. The agreement includes $123 million in upfront and potential development milestone payments from Kyowa to ArQule, including a $30 million cash upfront licensing payment. In addition, the agreement includes undisclosed sales milestone payments. Upon commercialization, ArQule will receive double digit royalties from Kyowa on net sales of ARQ 197. Kyowa will be responsible for clinical development costs and commercialization of the compound in certain Asian countries, consisting of Japan, China (including Hong Kong), South Korea and Taiwan. ArQule retains proprietary rights to ARQ 197 in ROW.

Daiichi Sankyo   
In December 2008, ArQule signed a license, co-development and co-commercialization agreement with Daiichi Sankyo Co. to co-develop ARQ 197. The definitive agreement supersedes the binding letter of intent announced in November 2008.

In November 2008, ArQule and Daiichi Sankyo entered into two agreements that form the basis of a strategic relationship for the development and discovery of novel oncology therapeutics. ArQule and Daiichi Sankyo will co-develop ARQ 197 and will also advance the application of ArQule's kinase inhibitor discovery platform (AKIP) to develop a new generation of highly selective, anticancer kinase inhibitors intended to ensure a long term presence in this therapeutic category. On a combined basis, the two deals include $75 million in cash upfront to ArQule from Daiichi Sankyo. ArQule and Daiichi Sankyo entered into a binding letter of intent for an exclusive license, co-development and co-commercialization agreement under which they shall collaborate to conduct research, clinical trials and the market launch of ARQ 197 in human cancer indications in the USA, Europe, South America and the rest of the world, excluding Japan, China (including Hong Kong), South Korea and Taiwan, where Kyowa Hakko Kirin Co. (Kyowa) has exclusive rights for development and commercialization. The binding letter of intent provides for a $60 million cash upfront licensing payment from Daiichi Sankyo to ArQule. In addition, the binding letter of intent includes significant development and sales milestone payments. ArQule and Daiichi Sankyo will share equally the costs of phase II and phase III clinical trials, with ArQule's share of phase III costs payable solely from milestone and royalty payments by Daiichi Sankyo. Upon commercialization, ArQule will receive tiered royalties from Daiichi Sankyo on net sales of ARQ 197. ArQule retains the option to participate in the commercialization of ARQ 197 in the USA. The final contract based on the binding letter of intent, including the terms above, is expected to be signed in December 2008. The upfront payment provided for in the binding letter of intent will be paid upon the later of December 5, 2008 or the expiration or termination of the applicable waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976. ArQule and Daiichi Sankyo have also entered into a research collaboration, exclusive license and co-commercialization agreement under which ArQule will apply its proprietary technology and know-how from its AKIP platform for the discovery of therapeutic compounds that selectively inhibit certain kinases. The agreement defines two such kinase targets, and Daiichi Sankyo will have an option to license compounds directed to these targets following the completion of certain preclinical studies. The agreement provides for a $15 million upfront payment, undisclosed payments in research support for the first and second years of the collaboration, licensing fees for compounds discovered as a result of this research, milestone payments related to clinical development, regulatory review and sales, and royalty payments. ArQule retains the option to co-commercialize licensed products in the USA.

CLINICAL STATUS BY INDICATION

Indication

solid tumors, advanced or metastatic, refractory

Latest Status

Phase I (begin 2/06, closed 1/07, completed 8/09) USA, phase I (begin 4/07, closed 7/09, completed 2/10) Europe (UK), phase I (begin 1/08, ongoing 2/10) Japan, phase I (begin 2/08, closed 9/09) USA (combination), phase I (begin 4/07, ongoing 6/08) Europe (UK), phase I (begin 3/09, ongoing 2/10) USA (combination), phase I (begin 9/09, ongoing 4/10) USA (combination)

Clinical History

In the phase I clinical trial (protocol ID: ARQ 197-103; NCT00612209) of oral ARQ197 BID in patients with advanced solid tumors and with additional dynamic contrast-enhanced (DCE) magnetic resonance imaging studies to evaluate the antiangiogenic activity of the MTD dose, final results in 29 patients (mean age=54.4 years) showed that ARQ197 was administered at doses of 100 mg (n=3), 200 mg (n=6), 300 mg (n=16), and 400 mg (n=4) BID. DLT was observed in 3 patients and consisted of Grade 3 fatigue at 200 mg BID, Grade 3 hand-foot syndrome, Grade 3 mucositis, and Grade 3 febrile neutropenia, all at 400 mg BID. MTD/recommended phase II dose was established at 300 mg BID. Other toxicities were Grade 1/2 and consisted of fatigue (n=5), diarrhea, nausea, and vomiting (n=3 each). Mean AUC(0-12 hours) and Cmax increased linearly through the MTD. Statistically significant post-ARQ197 inhibition of high baseline phosphorylated c-Met and FAK expression in tumor tissue was observed in all dose cohorts confirming target inhibition. Disease stabilized in 11 patients for up to 23 weeks, with tumor regression up to 12.4%. Of 20 patients, 13 had post-ARQ197 CEC declines of up to 100%. In the DCE-MRI cohort to date, preliminary analyses of ktrans histograms from pelvic lesions were consistent with antiangiogenic effects, with ktrans median reduction of 20.1% on day 7 of ARQ197 treatment (intra-patient baseline variability=2.8%). This effect was still present (median ktrans decline=8.3%) on day 56 of ARQ197 treatment. ARQ197 is well tolerated with MTD/recommended phase II dose of 300 mg BID, linear PK and evidence of phosphorylated c-Met and FAK inhibition. CEC and preliminary DCE-MRI data support the antiangiogenic effects of c-Met inhibition with ARQ (Yap TA, etal, ASCO09, Abs. 3523).

To date, 65 patients (median age=61 years) have been treated at 11 dose levels (10 mg BID to 360 mg BID) in the dose-escalation, phase I clinical trial (ARQ 197-101; NCT00302172) of oral ARQ197 BID in metastatic solid tumors. ARQ 197 was initially administered for 2 weeks, followed by 1 week off and then modified to evaluate continuous BID dosing based on favorable safety data. Additional patients were enrolled and treated at the 360 mg bid continuous dose, determined to be the recommended phase II dose in another phase I clinical trial. Tumor types include colorectal cancer (n=9), kidney cancer (n=8), ovarian cancer (n=6), sarcoma (n=6), lung cancer (n=5), and other types. All treated patients achieved plasma drug concentrations significantly above in vitro IC50 values. Most common drug-related AE were fatigue (18.5%) and nausea (12.3%). Drug-related serious AE were reported in 4 patients and consisted of anemia, leukopenia, neutropenia, thrombocytopenia, dehydration, liver failure, abdominal pain, nausea, and vomiting. PR was achieved by 3 patients (neuroendocrine cancer, prostate cancer, and testicular cancer), and disease stabilized in 32 patients and progressed in 13. Patients who achieved PR were initially treated at 10, 40 or 90 mg BID, respectively, and doses were escalated to 50, 70, or 120 mg BID, after 18-33 weeks on treatment. ORR was 6.3% and disease control rate was 72.9% in 48 evaluable patients. ARQ 197 has demonstrated preliminary evidence of anticancer activity and a favorable safety profile up to the dose of 360 mg BID (Mekhail T, etal, ASCO09, Abs. 3548).

In the dose-escalation, phase I clinical trial (protocol ID: ARQ 197-111; NCT00612703) of ARQ197 combined with daily oral erlotinib (150 mg) in patients with advanced solid tumors, 25 patients (mean age=60.5 years) were treated, with a starting ARQ197 dose of 120 mg (n=8), 240 mg (n=4), and 360 mg (n=13) BID. PK data revealed linear kinetics through 360 BID, with no evidence of drug-drug interaction. Possible treatment-related AE (n=13) were sinus bradycardia (n=5), fatigue (n=5), rash (n=4), pruritus (n=3), and diarrhea (n=3). Serious AE were neutropenia in 1 patient at 360 mg BID and sinus bradycardia in another patient at 240 mg BID, and 1 patient died on study, which was later considered non-treatment-related. Of 10 evaluable patients, disease stabilized in 9. Tumor regressed (2.3%-19.4%) in 4/10 patients. Disease stabilized in all 3 evaluable patients with nsclc for durations (14-32 weeks) exceeding the median PFS of 9.7 weeks in the BR21 phase III clinical trial. Continuous therapy with ARQ197 combined with erlotinib appears well tolerated and without drug-drug interaction. While no formal MTD was identified, a phase II combination dose of ARQ197 360 mg BID combined with erlotinib 150 mg daily is recommended (Laux I, etal, ASCO09, Abs. 3549).

A multicenter (n=2), nonrandomized, open label, dose-escalation, phase I clinical trial (protocol ID: ARQ 197-116; NCT00827177) was initiated in September 2009, in the USA, to evaluate the safety of ARQ 197 in combination with sorafenib in treating adult patients with advanced, inoperable or metastatic solid tumors. The trial’s primary objective is to identify the MTD and/or recommended phase II dose of ARQ 197 when administered with sorafenib. Secondary objectives are to determine PK, assess preliminary antitumor activity, and evaluate dynamic changes of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and soluble c-Met in patients' peripheral blood. According to the protocol, patients are treated with PO ARQ 197 (360 mg) and PO sorafenib (200 mg) twice daily. Enrollment of subsequent patient cohort will depend on the safety and tolerability of the combination treatment in the initial cohort. The trial is to enroll about 32 patients.

A 2-center, nonrandomized, open label, phase I clinicalt trial (protocol ID: ARQ 197-117; NCT00874042) was initiated in March 2009, in the USA, to evaluate the safety of ARQ 197 in combination with gemcitabine in patients with locally advanced, inoperable, or metastatic primary solid tumors excluding central nervous system (CNS) metastases. The trial’s primary objectives are to determine the safety, tolerability, and MTD or recommended phase II dose of ARQ 197 when administered with gemcitabine. Secondary objectives are to determine the PK profile, to assess preliminary antitumor activity, and to evaluate dynamic changes of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and soluble c-Met in patients' peripheral blood. According to the protocol, enrollment of the initial cohort of 3 or 6 patients follows the traditional '3 + 3' dose escalation scheme. Patients are treated with ARQ 197 and gemcitabine. PO ARQ 197 is administered continuously twice daily. Gemcitabine is administered IV over 30 minutes once weekly for 3 consecutive weeks followed by a week of rest. Enrollment of subsequent patient cohorts will depend on the safety and tolerability of the combination treatment in the initial cohort. The trial is to enroll about 72 patients.

In June 2008, results of a phase I trial (protocol ID: ARQ 197-103; NCT00612209) with ARQ 197 were presented at the annual meeting of ASCO. This trial was initiated in April 2007, at the Royal Marsden Hospital (Sutton, Surrey, UK), under PI Johann DeBono, MD. Patients with advanced, safely biopsiable, solid tumors were enrolled to determine safety, tolerability, MTD, PK, pharmacodynamics and preliminary antitumor activity. All pre and post therapy tumor biopsies were analyzed for total and phosphorylated c-Met and FAK by IHC, c-Met amplification by FISH, and c-Met mutations by sequencing. Circulating endothelial cell (CEC) enumeration was undertaken. ARQ 197 was administered orally twice a day, beginning with a dose of 100 mg that was escalated incrementally up to 400 mg. Overall, data show that ARQ 197 is safe and well tolerated at oral doses up to 300 mg twice daily, with dose-limiting toxicity (DLT) observed at 400 mg twice a day. ARQ 197 inhibits c-Met and FAK phosphorylation in serial tumor biopsies with minimal toxicity up to 300 mg twice daily. Among the 11 evaluable patients in this trial to date, disease stabilized in 7 patients, and prolonged stable disease by RECIST was observed for up to 32 weeks in 5 patients with multiple tumor types, including melanoma (n=2), Merkel cell carcinoma, chondrosarcoma, and gastric cancer. Tumors regressed after 8 weeks of treatment in one patient with metastatic gastric cancer who remains on the trial. An approximate 60% decline in circulating endothelial cell count was noted post therapy in 6 of 9 patients. The best tumor efficacy response was stable disease in 5 patients for up to 20+ weeks (Yap TA, etal, ASCO08, Abs. 3584). In updated results, 18 patients were treated with ARQ197 at 100, 200, 300 and 400 mg twice daily. According to PK data, the mean Cmax increased linearly from 100 mg to 400 mg bid. The mean AUC0-12 hours also increased linearly to 300 mg twice daily, but the increase to 400 mg twice daily was 2-fold and appeared non-linear. Mean values for t1/2, Cl/F and Vz/F remained relatively constant up to 300 mg twice daily; however at 400 mg bid, a longer mean t1/2 and lower mean Cl/F were observed, suggesting saturation of ARQ197 clearance mechanisms. There were 2 DLT of Grade 3 febrile neutropenia at 400 mg twice daily, one of which was also associated with reversible Grade 3 palmar-plantar erythrodysesthesia and mucositis lasting 2 weeks. This established the MTD of ARQ197 at 300 mg twice daily. Other toxicities included Grade 1/2 fatigue, nausea, vomiting and diarrhea. One patient each at 100, 200 and 300 mg twice daily with high phosphorylated c-Met and FAK expression at baseline, experienced substantial declines post ARQ197, confirming target inhibition. Further evaluation of antiangiogenic activity with dynamic contrast-enhanced magnetic resonance imaging at the MTD dose of ARQ197 is ongoing in 20 patients (Yap TA, etal, EORTC-NCI-AACR08, Abs. 386)

A randomized, open label, phase I clinical trial (protocol ID: ARQ 197-113; NCT00658554), was initiated in April 2008, in the USA, in normal healthy volunteers using a randomized crossover design. Enrollees must be between the ages of 18 and 65, male patients must be surgically sterilized and female patients must be surgically sterilized or postmenopausal and must have a negative serum pregnancy test. The trial’s primary objective is to obtain PK data to assess bioequivalence among three solid states of ARQ 197, i.e. amorphous, crystalline polymorph A, and crystalline polymorph B. A secondary objective is to monitor the safety of the three solid states of ARQ 197. This trial, to enroll about 24 patients, was completed in June 2008.

A nonrandomized, open label, phase I clinical trial (protocol ID: ARQ 197-112; NCT00651638) was initiated in March 2008, in the USA, to assess the PK and safety profile of ARQ 197 in extensive and poor metabolizers, as defined by CYP 2C19 genotype. An additional objective of this trial is to assess the effect of other CYP genotypes on the safety profile and PK profile of ARQ 197. Enrollees must be between the ages of 18 and 65, male patients must be surgically sterilized, and female patients must be surgically sterilized or postmenopausal and must have a negative serum pregnancy test. This trial, to enroll about 17 patients, was completed in June 2008.

In January 2008, Kyowa Hakko Kogyo initiated a nonrandomized, open label, dose-escalation phase I clinical trial (protocol ID: ARQ 197-0701; NCT00609921) with ARQ 197 in Japan, to evaluate the safety of ARQ 197 in treating patients with advanced or recurrent solid tumors. The trial’s primary objectives are to determine safety, tolerability, and recommended phase II dose. Other objectives are to determine the PK profile and to assess the preliminary antitumor activity. The trial is to enroll about 24 patients.

A multicenter (n=3), nonrandomized, open label, phase I clinical trial (protocol ID: ARQ 197-111; NCT00612703), was initiated in the USA, in February 2008, to evaluate the safety and efficacy of ARQ 197 in combination with erlotinib (Tarceva; OSI Pharmaceuticals) in treating patients with advanced solid tumors. The trial’s primary objectives are to determine safety, tolerability, and recommended phase II dose. Secondary objectives are to determine the PK profile and to assess preliminary antitumor activity. The trial, to enroll about 40 patients, was closed in September 2009.

The recommended phase II dose based on PK data from the phase I clinical trial (protocol ID: ARQ 197-101; NCT00302172) is 120 mg twice daily. Doses of up to 180 mg twice daily were administered orally in two different dosing schedules, twice daily for 2 weeks following by 1 week of rest (schedule A) or twice daily continuously (schedule B). Although MTD had not been reached, dose escalation was terminated based on PK data. No DLT was observed among 55 patients (schedule A=37, schedule B=18) treated with ARQ 197, with the safety profile being similar between the two dosing schedules. The most commonly reported drug-related adverse events were fatigue and nausea. Tumor types in the patient population included colon/colorectal cancer (16.4%), renal cancer (7.3%), thyroid cancer (7.3%), ovarian cancer (7.3%), pancreatic cancer (7.3%), prostate cancer (5.5%), non-small cell lung cancer (nsclc; 3.6%), nasopharyngeal cancer (3.6%), neuroendocrine cancer (3.6%), breast cancer (3.6%) and other malignancies (34.5%). Of 47 patients evaluable per the trial protocol, there were 3 (6.4%) PR, and disease stabilized in 28 (59.6%) for more than 2 months; SD lasted for more than 4 months (range=4 to 17 months) in 19 (40.4%) patients. There were also signs of antimetastatic activity. Based on investigators' evaluations, no evidence of new metastatic lesions developed during treatment in 33 of 35 (94.3%) patients treated with ARQ 197 for more than two cycles (6 weeks). New metastatic lesions were observed in 2 (5.7%) patients, one with renal cell carcinoma (RCC) and the other with paraspinal sacral sarcoma, after approximately 10 and 12 months of treatment, respectively. Also, new lesions developed in 7 of 20 (35.0%) patients treated with 2 or fewer cycles of ARQ 197. Tumor types of these 7 patients were colon cancer (n=3) with new lesion(s) developing in the lung, and peritoneum; colorectal (n=1) with new liver lesions; nsclc (n=1) with a new liver lesion; breast (n=1) with a new liver lesion; and spindle cell sarcoma (n=1) with new lung lesions. New lesions occurred only in organs with documented pre-existing metastatic disease, except in one patient with colon cancer with lung and liver metastases at the time of enrollment, who subsequently developed new peritoneal metastases. Patients' original images are being examined by an independent reviewer to assess the antimetastatic activity of ARQ 197 (Rosen L, etal, AACR-NCI-EORTC07, Abs. B91).

In June 2007, data were presented in a phase I clinical trial (protocol ID: ARQ 197-101; NCT00302172) of ARQ 197 in metastatic solid tumors. Of 38 patients enrolled, data are available for 36; 10 dose levels were assessed (range=10-360 mg/day). ARQ 197 was well tolerated, and no DLT was observed. All treated patients achieved plasma drug concentrations significantly above the in vitro IC50. Doses through 70 mg twice a day revealed Cmax and AUC (0-12 hours) increased linearly. There was no further increase in systemic exposure in patients treated with 90-180 mg twice a day. There was notable variability between patients in Cmax and AUC, which is typical of oral dosing. Adverse events (n=29) were generally mild with the most common being fatigue (24%), diarrhea (21%), and constipation (21%). Grade 3+ events included elevated ALP (3%), ALT (3%), and AST (3%). Of the 38 patients enrolled, 36 received at least 1 complete cycle of ARQ 197, with 33 evaluable for efficacy; 2 patients achieved a PR (1 confirmed), and 19 had SD of 10-34+ weeks. Optimal dosage of ARQ 197 is 120 mg twice daily (240 mg); higher oral doses do not result in increased systemic exposure to the drug; a total of 11 patients remain in the trial and continue to be treated (Garcia A, etal, ASCO07, Abs. 3525). In updated results, 57 patients have been enrolled, and a continuous dosing schedule is being explored. Patient compliance with dosing was high (98%), and there were no treatment interruptions because of adverse events. Most adverse events were mild and transient, and no Grade 3/4 drug-related adverse events were reported. No DLT was observed on either dosing regimen (dosing for 2 weeks in 3 week cycles or continuous dosing). Substantial plasma exposure was maintained at levels several times the predicted efficacious concentration. Of 39 patients in the intermittent (dosing 2/3 weeks) cohort, 35 were evaluable; 3 patients had PR and 18 achieved SD, with 11/18 showing some evidence of tumor shrinkage and SD in 10/18 patients lasted 6+ months. The PR was observed in patients with prostate, neuroendocrine, and testicular tumors. Long-term, durable disease control lasting >4+ months was observed in many tumor types, including pancreatic, renal cell, non-small cell lung, and papillary thyroid tumors. Of 18 patients in the continuous dosing cohort, 10 were evaluable; 7 achieved SD at the first assessment, which took place 6 weeks following initiation of treatment. The remaining patients have not yet reached the first tumor evaluation. Data analysis of new lesions among the intermittent dosing cohort showed that only 4 of these patients developed new lesions while on ARQ 197, and 3/4 were treated at low doses. All new lesions developed within the first 6 weeks of therapy. No new lesions developed after 6 weeks of therapy.

An open label, single arm, dose-escalation, phase I clinical trial (protocol ID: ARQ 197-103; NCT00612209) of ARQ 197, administered twice daily continuously, was initiated in April 2007, at the Royal Marsden Hospital (Sutton, Surrey, UK), under PI Johann DeBono, MD, in patients with advanced solid tumors. According to the protocol, patients are treated with ARQ 197 orally twice daily continuously at dose levels specified for their respective dose cohorts. The ARQ 197 starting dose will be a total daily dose of 200 mg (100 mg twice daily). ARQ 197 treatment will be continued until progression of disease, unacceptable toxicity, or another discontinuation criterion is met. In the case of toxicity, dose adjustment is permitted. A treatment cycle is designed as four weeks (28 days) and will be repeated without therapy interruption. The trial’s primary objective is to determine the safety, tolerability and recommended phase II dose with this schedule. Secondary objectives are to evaluate pharmacodynamics of phosphorylated c-Met, total c-Met, apoptosis marker (TUNEL) and phosphorylated FAK in tumor tissue correlated with administration of ARQ 197, and assess its preliminary antitumor activity. Estimated enrollment is 30 patients. This trial was closed in July 2009 and completed in February 2010.

In January 2007, ArQule reported that it completed dose escalation in the phase I clinical trial (protocol ID: ARQ 197-101; NCT00302172) with ARQ 197. Using two weeks of therapy followed by one week off therapy, maximum systemic patient exposure to ARQ 197 was achieved in the absence of DLT. The optimal dose of ARQ 197 when administered orally, two weeks out of three, has been identified as 120 mg twice daily. Based on the excellent safety profile and favorable PK, the company will explore a continuous dosing schedule prior to initiation of phase II testing with ARQ 197 in the second quarter of 2007. In addition to development of a continuous dosing regimen, ArQule is also about to initiate a new trial to investigate biomarkers of activity in both tumor tissue and peripheral blood. This trial will be conducted under PI Dr. Johann de Bono at the Institute of Cancer Research, Royal Marsden Hospital in the UK. Findings from the Marsden study are designed to help correlate antitumor activity with biomarker activity and to establish dosing parameters for phase II clinical testing. Pending these findings, the company expects to employ a continuous dosing regimen for phase II, as compared to dosing two of every three weeks in phase I. The company will also evaluate tumor responses from the phase I trial (Rosen L, etal, EORTC-NCI-AACR06, Abs. 651) in advance of tumor selection for phase II. Tumor regression and prolonged disease stabilization were observed in the phase I trial among patients who had failed prior treatment regimens for a broad range of metastatic solid tumors, including neuroendocrine cancer, non-small cell lung cancer (nsclc), angiomyolipoma, and pancreatic, prostate, renal cell and testicular cancer. All of patients enrolled in this trial had been previously treated with surgery, radiation and/or pharmacotherapy but had failed these treatments or experienced subsequent disease progression. Available patient histories indicate that treatments prior to ARQ 197 date back to 2003 for neuroendocrine cancer, to 1994 for nsclc, to 2004 for pancreatic cancer, and to 1990 for renal cell cancer (RCC).

In November 2006, interim data were reported at the EORTC-NCI-AACR annual meeting in ArQule’s multicenter (n=3) open label, dose-escalation, phase I clinical trial (protocol ID: ARQ 197-101; NCT00302172) of ARQ 197 in patients with multiple metastatic tumor types refractory to available therapy or for which no standard systemic therapy exists. A total of 37 patients with metastatic cancer were enrolled, and PO ARQ 197 was administered twice daily (range=20-360 mg daily) for 14 days in 21 day cycles. Of 31 evaluable patients, 15 achieved a best response of SD or better (range=6-33 weeks); 2 of these patients achieved a PR, according to RECIST. Dose escalation has been well tolerated, with no DLT observed. Adverse events from 27 patients have been mild, with the most common being fatigue. As of August 2006, 30 patients had been enrolled, and data were available from 18 patients in 7 cohorts (range=10-140 mg/day, 140 to 1960 mg/cycle). Adverse events (n=15) included diarrhea (33.3%), constipation (26.7%), dry mouth (26.7%), nausea (20.0%), vomiting (20.0%), fatigue (26.7%), dizziness (20.0%), and urinary tract infection (20.0%). Grade 3 or greater events included abdominal pain (6.7%), elevated ALP (6.7%), elevated ALT (6.7%), elevated AST (6.7%), and hypokalemia (6.7%). Signs of clinical efficacy included a confirmed PR in the liver in a patient with metastatic prostate adenocarcinoma treated at the 80 mg dose level, who remained in the trial after 15 weeks of therapy; 7 patients had shown SD (6-30 weeks), of which 2 had minor tumor regression (10.1 and 19.2%). Prolonged SD (>16 weeks) was observed in neuroendocrine cancer, nsclc, angiomyolipoma, and pancreatic cancer (Rosen L, etal, EORTC-NCI-AACR06, Abs. 651).

In February 2006, ArQule initiated enrollment and successful administration of the first patient in a multicenter (n=3) open label, dose-escalation, phase I clinical trial (protocol ID: ARQ 197-101; NCT00302172) with ARQ 197 in patients with multiple metastatic tumor types refractory to available therapy or for whom no standard systemic therapy exists. Primary objectives are to determine tolerability, safety, and a recommended dose regimen for phase II clinical trials pending successful completion of phase I trials. Additionally, the trial will seek to define the PK profile of ARQ 197 and to collect preliminary data on antitumor activity. The trial is being conducted at Premiere Oncology (Santa Monica, CA) under PI Lee S. Rosen, MD; the Cleveland Clinic, under PI Ronald Bukowski, MD; and the Mary Crowley Medical Research Center (Dallas, TX) under PI Casey Cunningham, MD. This trial was closed in January 2007 and completed in August 2009.

Indication

pancreatic cancer, inoperable, locally advanced or metastatic, first line

Latest Status

Phase II (begin 11/07, closed 10/08, completed 4/09) Europe (Poland, Latvia)

Clinical History

A multicenter (n=20), open label, randomized phase II clinical trial (protocol ID: ARQ 197-205; NCT00558207) of ARQ 197 versus gemcitabine (Gemzar; Lilly) was initiated in Europe (Poland, Latvia), in November 2007, in treatment-naïve (no previous chemotherapy, immunotherapy, vaccines, monoclonal antibodies, major surgery, or irradiation, whether conventional or investigational) patients with inoperable, locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). The trial’s primary objective is PFS in 6 months of treatment. Secondary objectives are to evaluate overall response rate (ORR), 6-month and 1-year overall survival (OS) rates at 6 and 12 months and further characterize the safety profile of ARQ 197. According to the protocol, ARQ 197 (120 mg) capsules are administered twice daily once in the morning and once in the evening one hour prior to or two hours after a meal. Gemcitabine (1000 mg/m2) is administered IV over 30 minutes once weekly for 4 weeks for the first 28 days (cycle 1). Each subsequent cycle consists of gemcitabine (1000 mg/m2) is administered IV over 30 minutes once weekly for 3 weeks with no drug administered in the 4th week. Tumor evaluations will be performed in 8-week intervals. Tumor response will be evaluated using RECIST. Total enrollment is 72 patients. This trial was closed as of October 2008 and completed in April 2009.

Indication

microphthalmia transcription factor associated (MiT) tumors, inoperable, locally advanced or metastatic

Latest Status

Phase II (begin 10/07, closed 2/10) USA

Clinical History

In the multicenter, single arm, phase II clinical trial (protocol ID: ARQ 197-204; NCT00557609) of oral ARQ197 in patients 13 years or older with microphthalmia transcription factor (MIT)-associated tumors, 36 patients (median age=26.5 years, clear cell sarcoma=9, alveolar soft part sarcoma=21, renal cell carcinoma=6) have been treated. A total of 18 patients are on 120 mg BID, 8 patients were escalated from 120 to 260 mg BID, and 10 were on 360 mg BID. Of 28 evaluable patients, PR was confirmed in 1 patient with clear cell sarcoma, disease stabilized in 17 patients (alveolar soft part sarcoma=13, clear cell sarcoma=2, renal cell carcinoma=2), and progressed in 10 patients (alveolar soft part sarcoma=3, clear cell sarcoma=4, renal cell carcinoma=3). Overall disease control rate was 64%. Most common drug-related AE were fatigue (42%), nausea (33%), vomiting (22%), sinus bradycardia (11%), diarrhea (8%), decreased hemoglobin (8%), and cough (11%). To date, the only drug-related Grade 3/AE is anemia (n=2). Drug-related serious AE are Grade 3 febrile neutropenia and Grade 4 thrombocytopenia, both at the 360 mg BID dose. ARQ 197 has demonstrated a favorable safety profile and preliminary evidence of anticancer activity in this patient population. Enrollment at the 360 mg BID dose is ongoing (Goldberg J, etal, ASCO09, Abs. 10502).

In October 2008, ArQule expanded the phase II clinical trial (protocol ID: ARQ 197-204; NCT00557609) with ARQ 197 in microphthalmia transcription factor (MiT)-associated tumors based on the achievement of a PR, as defined by RECIST, in a patient with clear cell sarcoma. The patient continues on treatment. Proceeding to the second phase of this trial stems from the trial’s protocol-defined endpoint of an objective response in the first stage. The trial is being further optimized by the use of a higher dose of ARQ 197 at 360 mg, twice daily. In parallel, the company is preparing to initiate discussions with regulatory authorities to determine the optimal clinical pathway to establish the utility of this compound in the treatment of sarcoma. During the first stage of the trial, 23 patients were enrolled and treated with ARQ 197 (120 mg) twice daily. To date, 14 of these patients are evaluable for efficacy. In addition to the patient with the confirmed PR, disease stabilized in 10 evaluable patients. Preliminary data from the first stage will be presented at the Connective Tissue Oncology Society meeting scheduled in November 2008.

A multicenter (n=10), two-stage, phase II clinical trial (protocol ID: ARQ 197-204; NCT00557609) was initiated in the USA, in October 2007, in adolescent (age 13 or older) and adult patients with inoperable locally advanced or metastatic microphthalmia transcription factor associated (MiT) tumors, including clear cell sarcoma (CCS), alveolar soft parts sarcoma (ASPS), and translocation-associated renal cell carcinoma. The trial’s primary objective is to determine overall response rate (ORR). Secondary outcome measures are to evaluate PFS and 6-month and 1-year overall survival (OS) rates, and further characterize the safety of ARQ 197 in adolescent and young adult patients with MiT tumors. These soft tissue malignancies are characterized by a common transcriptional mechanism that leads to inexorable spread and resistance to all known therapies. They tend to strike adolescents and young adults, and are invariably fatal if not resectable at diagnosis. Several academic laboratories have shown that genetic translocations in these tumors upregulate c-Met, and that such tumors are dependent upon this activity. A total of 45 patients will enroll in this trial. According to the protocol, patients will be treated with ARQ 197 (120 mg ) twice daily. Approximately 23 patients will be treated in the first stage of the trial. If a PR or a CR is observed in more than one patient in this stage, the trial will be continued to the second stage, to enroll an additional 22 patients. Otherwise, the trial will be stopped. Treatment will be continued until progression of disease, unacceptable toxicity, or another discontinuation criterion is met. During the trial, tumor evaluations will be performed at baseline, then in 8-week intervals. Archival tissue specimens and relevant laboratory results on patients' gene translocation/fusion status will be collected. Tumor biopsies may also be collected (optional) with patient's consent. In addition, to explore biologic responses of tumors to ARQ 197 treatment, FDG-PET scanning will be performed at three time points, within 14 days prior to the treatment, on day 8 (± 2 days) of cycle 1 and after two cycles of treatment coinciding with tumor measurement. Participating institutions include Premiere Oncology (Santa Monica, CA), under PI Lee S. Rosen, MD; Dana Farber Cancer Institute, under PI John Goldberg, MD, and Andrew Wagner, MD, PhD; Texas Children's Cancer Center (Houston, TX), under PI Alberto S. Pappo, MD; and Mary Crowley Cancer Research Center (Dallas, X), under PI Neil Senzer, MD. This trial was closed in February 2010.

Indication

gastric cancer, advanced, refractory, second line

Latest Status

Phase II (begin 6/10) Japan, Korea

Clinical History

In June 2010, Kyowa Hakko Kirin initiated a single agent phase II clinical trial (protocol ID: NCT01152645) with ARQ 197 in gastric cancer. The primary objective of this trial is to determine disease control rate, defined as a combination of objective responses and stable disease. Secondary objectives include tumor response, PFS and OS. Approximately 30 patients will be enrolled at clinical trial sites in Japan and Korea.

A multicenter, open label, randomized phase II clinical trial (protocol ID: NCT01070290) that was to enroll 338 patients with gastric cancer was withdrawn in February 2010 prior to enrollment. This trial was designed to evaluate the PFS of ARQ 197 versus investigator's choice of second line chemotherapy in patients with inoperable (locally advanced or metastatic) gastric carcinoma refractory to treatment with a prior regimen consisting of at least two of the drugs 5-FU, cisplatin or docetaxel. Patients were tol be randomized to ARQ 197 arm or investigator's choice arm in a 1:1 ratio. The trial would also evaluate other efficacy and safety parameters including ORR, OS and AE in the two treatment arms.

Indication

non-small cell lung cancer (nsclc), advanced

Latest Status

Phase I/II (begin 3/08, closed 9/09) USA (combination)

Clinical History

In March 2010, ArQule reported that ARQ 197, when used in combination with erlotinib, resulted in a 66% improvement in median PFS in patients with advanced, refractory non-small cell lung cancer (nsclc). In the intent to treat (ITT) population (n=167), median PFS was 16.1 weeks (~4 months) in the ARQ 197 plus erlotinib arm, compared with 9.7 weeks (~2.4 months) in the erlotinib plus placebo arm. This multicenter, randomized, double blind, phase II clinical trial (protocol ID: ARQ 197-209; NCT00777309) evaluated 167 patients who were not previously treated with an epidermal growth factor receptor (EGFr) inhibitor, randomized one-to-one to either the combination of ARQ 197 plus erlotinib or placebo plus erlotinib in second and third line settings. The difference in PFS between the two arms did not achieve statistical significance (HR=0.809) by applying a log-rank test. When adjusting for imbalances in the distribution of key prognostic factors, the difference in PFS was statistically significant (HR=0.675) by applying a Cox regression analysis specified for secondary efficacy analyses. Improvement in median PFS was more pronounced in the predefined subgroup of patients with non-squamous histology (n=117) with a median PFS of 18.9 weeks (~4.7 months) in the treatment arm versus 9.7 weeks (~2.4 months) in the control arm, representing a 94% improvement. Based on an exploratory Cox regression analysis, the endpoint of PFS was met in the subgroup analysis and achieved statistical significance (HR=0.613). There were no clinically relevant differences in AE rates between the treatment and control arms. The majority of AE were mild in intensity and included rash, diarrhea and fatigue. Complete data from this trial, which will include biomarker analysis, will be presented at a future medical meeting during 2010.

A multicenter (n=18), randomized, double blind, phase II clinical trial (protocol ID: ARQ 197-209; NCT00777309) was initiated in September 2008, in the USA, to compare treatment with ARQ 197 plus erlotinib versus erlotinib plus placebo in patients with locally advanced or metastatic non-small cell lung cancer (nsclc). The trial’s primary objective is to evaluate the PFS. Secondary objectives are to evaluate the OS, ORR, and safety of this regimen. According to the protocol, patients are assigned to one of two treatment arms. In arm 1, patients are treated with ARQ 197 (360 mg) twice daily and erlotinib (150 mg) once daily while in arm 2, patients are administered erlotinib (150 mg) once daily plus placebo twice daily until disease progression, unacceptable toxicity or other discontinuation criterion is met. This trial was closed in September 2009. Approximately 160 patients were enrolled in this trial. Final data from this trial is expected to be available in the first half of 2010.

In March 2008, ArQule commenced patient dosing in a phase I/II clinical trial program with ARQ 197, administered in combination with erlotinib (Tarceva; OSI Pharmaceuticals) in patients with advanced non-small cell lung cancer (nsclc). The nsclc program consists of two trials. The first is a phase I trial to determine the safety, tolerability and a recommended phase II dose of ARQ 197 when administered in combination with erlotinib in this patient population, and also evaluate the PK profile and assess the preliminary antitumor activity of this combination therapy.

Indication

hepatocellular carcinoma (HCC), inoperable, second line • hepatocelluar carcinoma (HCC), advanced with cirrhosis, third line

Latest Status

Phase Ib (begin 1/09, closed 3/10) USA, Europe (Italy, Spain); phase II (begin 9/09, ongoing 8/10) USA, Europe (Belgium, Germany, Italy)

Clinical History

A multicenter (n=10), randomized, double blind, placebo control, phase II clinical trial (protocol ID: ARQ 197-215; NCT00988741) was initiated in September 2009, in the USA and in Europe (Belgium, Germany and Italy), to evaluate the safety and efficacy of ARQ 197 in treating patients with inoperable hepatocellular carcinoma (HCC) refractory to one prior systemic therapy. The trial’s primary objective is to determine TTP. Secondary objectives are to evaluate PFS, OS, objective response rate, disease control rate, and characterize safety and PK. According to the protocol, patients are randomly assigned in a 2:1 ratio to either ARQ 197 or placebo. Treatment assignment is stratified by ECOG PS, and vascular invasion status. The treatment with ARQ 197 or placebo is continued until progression of disease, unacceptable toxicity, or other discontinuation criteria. ARQ 197 (360 mg) or placebo is administered orally twice daily, once in the morning and once in the evening, about 12 hours apart, 1 hour prior or 2 hours after eating. A treatment cycle is defined as 4 weeks for both treatment arms. Cycles may be repeated every 4 weeks (28 days) based on toxicity and response. The dose may be reduced by the investigator if the patient can not tolerate it. After radiographic disease progression is documented, treatment assignment will be unblinded. Patients who were assigned to placebo arm and had documented radiographic disease progression will have the option tocross over to ARQ 197 and will be evaluated for objective response rate and disease control rate continuously. The trial is to enroll about 99 patients.

A multicenter (n=8), open label, phase Ib clinical trial (protocol ID: ARQ 197-114; NCT00802555) was initiated in January 2009, in the USA and Europe (Italy and Spain), to evaluate the safety of ARQ 197 in treating cirrhotic patients with hepatocellular carcinoma (HCC) who have been treated with <2 prior systemic regimens with liver disease severity categorized as Class A and B. The trial’s primary objective is to evaluate safety. Secondary objectives are to evaluate TTP, objective response rate, disease control rate, and to assess dynamic changes of hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and soluble c-Met in patients' peripheral blood. According to the protocol, patients are treated with 360 mg ARQ 197, twice daily, until disease progression, unacceptable toxicity, or other discontinuation criterion is met. This trial, to enroll about 25 patients was closed as of March 2010.

Indication

colorectal cancer, locally advanced or metastatic, second line

Latest Status

Phase I/II (begin 2/10) USA (combination)

Clinical History

A phase I/II clinical trial (protocol ID: NCT01075048), designed to evaluate the safety of ARQ 197 administered in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer (CRC) harboring the wild-type Kras gene, was initiated in February 2010, in the USA. Pending the successful completion of the phase I safety run-in portion of the trial, the randomized, double blind, placebo-controlled phase II portion of the trial will compare ARQ 197 in combination with irinotecan and cetuximab to placebo with the same two drugs. The primary objective of the trial is PFS. Estimated enrollment is 150 patients.

Indication

germ cell cancer, relapsed or refractory

Latest Status

Phase II (begin 1/10, ongoing 8/10) USA

Clinical History

A phase II clinical trial (protocol ID: ARQ 197-A-U251; NCT01055067) was initiated in January 2010, in the USA, at Memorial Sloan-Kettering Cancer Center, under PI Darren Feldman, MD, with single agent ARQ 197 in patients with relapsed or refractory germ cell tumors (GCT), including testicular and non-central nervous system (non-CNS) tumors. The primary outcome of this trial is to determine the objective response rate in patients with relapsed or refractory GCT treated with ARQ 197. Secondary objectives include determination of PFS, OS, and safety and tolerability of ARQ 197 in this population.

Patent/Legal Issues

In October 2009, the European Medicines Evaluation Agency (EMEA) designated ARQ 197 as an orphan medical product for the treatment of soft tissue sarcoma.

Market Opportunities

Approximately 930,000 new cases of gastric cancer are diagnosed annually, and approximately 700,000 people die of the disease worldwide. Gastric cancer is the second leading cause of cancer death worldwide, and the disease is more common in East Asian countries such as Japan and Korea than in western countries.

Germ cell tumors are the most common malignancy diagnosed in men between the ages 15 and 35, in the USA each year. Despite overall high cure rates, up to 30% of patients with advanced GCT not respond to initial chemotherapy with or without surgery. Because to their young age at diagnosis, death from testicular cancer represents the single greatest source of life years’ lost of any non-childhood malignancy. No standard therapy exists to provide disease control in patients following failure of high dose chemotherapy.

According to the American Cancer Society (ACS), lung cancer is the leading cause of cancer death for both men and women. Nsclc accounts for about 85% to 90% all lung cancer. In 2008, ACS estimates that there will be about 215,000 new cases of lung cancer in the USA and 162,000 people will die from this disease.

MiT tumors, which include clear cell sarcoma (CCS), alveolar soft part sarcoma (ASPS) and translocation-associated renal cell carcinoma (RCC), are linked biologically through a common chromosomal abnormality that is responsible for the overexpression of c-Met resulting in the development of these tumors. Tumors with this abnormality are resistant to current therapies and, in the absence of successful surgical resection, are invariably fatal.

Current as of

August 08, 2010