ARQL » Topics » Clinical Trials

These excerpts taken from the ARQL 10-K filed Mar 17, 2008.

Clinical Trials

        We initiated a Phase 2 proof-of-principle program with ARQ 501 consisting of three separate clinical trials during 2006: monotherapy trials in leiomyosarcoma and in head and neck cancer, and a combination therapy trial with gemcitabine in pancreatic cancer. The primary endpoints for each of the Phase 2 trials with ARQ 501 was an objective response rate of 15 percent. Objective response rate was defined as the sum of complete responses and partial responses, and in the case of the leiomyosarcoma study, stable disease lasting more than 4 months was also considered a partial response.

        Data from the pancreatic cancer trial showed a 16 percent objective response rate among evaluable patients treated with ARQ 501 and gemcitabine combination therapy, thus meeting the protocol-defined endpoint as agreed upon by Roche and us. Data from the leiomyosarcoma study showed a 17.5 percent objective response rate among evaluable patients to monotherapy treatment with ARQ 501, thus meeting the protocol-defined endpoint as agreed upon by Roche and us. Data from the head and neck cancer study showed a 2 percent objective response rate, thus failing to meet its endpoint.

        We have also analyzed six-month survival data from the pancreatic cancer trial, comparing survival time among patients treated with ARQ 501 and gemcitabine with historical survival data from patients treated with gemcitabine monotherapy alone. We have shared this data with Roche under our agreement, and we expect to have analyzed twelve-month survival data from this trial in mid-2008.

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        As defined in our Roche collaboration agreement, Roche has an option to license worldwide rights for the development and commercialization of all products resulting from the E2F-1 program in the field of cancer therapy based on our delivery of a clinical data package from one of the Phase 2 monotherapy trials and the combination therapy trial with ARQ 501, as well as a recommended Phase 2 dose for a second-generation E2F-1 product.

        We initiated patient recruitment in the Phase 1 trial with ARQ 171 in December 2006. ARQ 171, which is believed to have the same mechanism of action as ARQ 501, has been shown to have greater potency in preclinical tests. In November 2007, we announced that symptomatic and asymptomatic QTc prolongation, a potentially dangerous cardiac rhythm abnormality, has been observed in this trial. These observations were made based on electrocardiograms (EKGs) from patients who received doses of ARQ 171 from 380 to 760 mg/m2. We subsequently reviewed EKGs from all other patients treated with ARQ 171. We are completing this review and analysis of data, and we have decided not to enroll additional patients until we have fully assessed these observations.

        We are also proceeding with the pre-clinical development of another second-generation E2F-1 compound, ARQ 761. Progress in the pre-clinical and Phase 1 clinical development of ARQ 761, as well as clarity regarding the status of ARQ 171, will inform our decisions relating to the choice of the second-generation E2F-1 compound for additional clinical development and the determination of the clinical pathway and indications for this compound. We believe this information will guide Roche's decision regarding their further participation in the E2F-1 program.

Clinical Trials





        We initiated a Phase 2 proof-of-principle program with ARQ 501 consisting of three separate clinical trials during 2006:
monotherapy trials in leiomyosarcoma and in head and neck cancer, and a combination therapy trial with gemcitabine in pancreatic cancer. The primary endpoints for each of the Phase 2 trials
with ARQ 501 was an objective response rate of 15 percent. Objective response rate was defined as the sum of complete responses and partial responses, and in the case of the leiomyosarcoma
study, stable disease lasting more than 4 months was also considered a partial response.



        Data
from the pancreatic cancer trial showed a 16 percent objective response rate among evaluable patients treated with ARQ 501 and gemcitabine combination therapy, thus meeting
the protocol-defined endpoint as agreed upon by Roche and us. Data from the leiomyosarcoma study showed a 17.5 percent objective response rate among evaluable patients to monotherapy treatment
with ARQ 501, thus meeting the protocol-defined endpoint as agreed upon by Roche and us. Data from the head and neck cancer study showed a 2 percent objective response rate, thus failing to
meet its endpoint.



        We
have also analyzed six-month survival data from the pancreatic cancer trial, comparing survival time among patients treated with ARQ 501 and gemcitabine with historical
survival data from patients treated with gemcitabine monotherapy alone. We have shared this data with Roche under our agreement, and we expect to have analyzed twelve-month survival data from this
trial in mid-2008.



6









        As
defined in our Roche collaboration agreement, Roche has an option to license worldwide rights for the development and commercialization of all products resulting from the
E2F-1 program in the field of cancer therapy based on our delivery of a clinical data package from one of the Phase 2 monotherapy trials and the combination therapy trial with ARQ
501, as well as a recommended Phase 2 dose for a second-generation E2F-1 product.



        We
initiated patient recruitment in the Phase 1 trial with ARQ 171 in December 2006. ARQ 171, which is believed to have the same mechanism of action as ARQ 501, has been shown to
have greater potency in preclinical tests. In November 2007, we announced that symptomatic and asymptomatic QTc prolongation, a potentially dangerous cardiac rhythm abnormality, has been observed in
this trial. These observations were made based on electrocardiograms (EKGs) from patients who received doses of ARQ 171 from 380 to 760 mg/m2. We subsequently reviewed EKGs from all
other patients treated with ARQ 171. We are completing this review and analysis of data, and we have decided not to enroll additional patients until we have fully assessed these observations.



        We
are also proceeding with the pre-clinical development of another second-generation E2F-1 compound, ARQ 761. Progress in the pre-clinical and
Phase 1 clinical development of ARQ 761, as well as clarity regarding the status of ARQ 171, will inform our decisions relating to the choice of the second-generation E2F-1 compound
for additional clinical development and the determination of the clinical pathway and indications for this compound. We believe this information will guide Roche's decision regarding their further
participation in the E2F-1 program.



This excerpt taken from the ARQL 10-K filed Mar 9, 2006.
CLINICAL TRIALS

ARQ 501

Phase 2 clinical program.   The Phase 2 program will comprise two trials of ARQ 501 alone (“monotherapy studies”) in leiomyosarcoma (a sarcoma of smooth muscle) and in head and neck cancer, and two combination studies, with gemcitabine in pancreatic cancer and with paclitaxel in ovarian cancer. The leiomyosarcoma study was initiated and screening of patients began in early 2006. The protocol will study the Objective Response Rate in approximately 30 patients in second-line treatment of persistent, recurrent or metastatic disease at approximately 15 sites. The head and neck cancer study and the pancreatic cancer study are anticipated to begin during the middle of 2006, and the ovarian cancer study will follow.

The Phase 2 program is designed to generate preliminary efficacy data to support future regulatory registration studies. Initiation of the Phase 2 program follows the establishment of recommended dosage levels and regimens based on our Phase 1 monotherapy and combination therapy clinical trials with ARQ 501.

Phase 1 study in monotherapy.   Our ARQ 501 Phase 1 monotherapy dose-escalation study in patients with advanced solid tumors took place at the Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center and Massachusetts General Hospital and Mary Crowley Medical Research Center. We presented interim results for this trial at the annual meeting of the American Society of Clinical Oncology (“ASCO”) in May 2005. The data were presented by the Principal Investigator of the study, Dr. Geoffrey I. Shapiro of the Dana-Farber Cancer Institute/Harvard Medical School, and Dr. Chiang J. Li, ArQule’s Chief Scientific Officer. Data reflects trial status as of March 24, 2005. The poster presentation reported interim results that demonstrate clinical tolerability, favorable pharmacokinetics, and evidence of anti-tumor activity of ARQ 501 in patients with advanced solid tumors who had failed chemotherapy. Out of 16 patients who were evaluable for efficacy, 62.5% showed either tumor regression (one partial response, two minor responses) or disease stabilization (seven patients).

The Phase 1 monotherapy study was designed to determine the clinical tolerability, recommended Phase 2 dose and pharmacokinetics (i.e. blood level) of ARQ 501 when given intravenously to patients with advanced solid tumors. As of March 24, 2005, the study had enrolled a total of 32 patients who had failed prior regimens of chemotherapy, ranging from one to 15 courses per patient. Of the 26 patients who were evaluable for pharmacokinetic analysis, 20 patients had received ARQ 501 as a one hour infusion, and six patients had received ARQ 501 on different infusion regimens. Adverse events have been mild or self-limited. Hemolytic anemia and hyperbilirubinemia were noted as drug-related serious adverse events, which were transient and clinically manageable.

Researchers evaluated the tumors per RECIST criteria at study week 8 and every subsequent eight weeks. Evidence of anti-tumor activity was observed in 10 out of 16 (62.5%) evaluable patients as of March 24, 2005. This included one patient with a partial response (greater than 30% tumor reduction), two patients with minor responses, and seven with disease stabilization ranging from eight to 32 weeks. The partial response was seen with a patient with leiomyosarcoma. The minor responses were seen in a patient with metastatic parotid adenocarcinoma (21% reduction at 14 weeks) and a patient with metastatic adrenal carcinoma (18% reduction at 19 weeks).

Phase 1 study in combination with Taxotere.   In December 2004, we initiated an open label, dose escalation Phase 1 study of ARQ 501 in combination with Taxotere for patients with advanced solid tumors

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at the Mary Crowley Medical Research Center in Dallas, Texas. The objectives of this study were to determine the safety profile (clinical tolerability) of ARQ 501 in combination with Taxotere and a recommended dose to be used in Phase 2 clinical trials. This trial was initiated because of the synergistic effect of the combination of ARQ 501 and Taxol that was observed in animal studies. In these animal combination studies the tumors were completely eradicated. Taxotere is one of the most common chemotherapeutic agents and is used against a wide range of solid tumors. We enrolled patients with various forms of advanced solid tumors in this trial, some of whom may have previously been treated with Taxotere.

Phase 1b/2 study in combination with gemcitabine.   In January 2005, we announced the enrollment of the first patient in a Phase 1b/2 study in combination with gemcitabine at the M.D. Anderson Cancer Center in Houston, Texas. The Phase 1b component is an open label dose escalation study, enrolling patients with advanced cancer, some of whom may have previously received gemcitabine. This component is being followed by a Phase 2 study exploring the use of ARQ 501 and gemcitabine in patients with newly diagnosed pancreatic cancer.

Preclinical findings.   Our findings show ARQ 501 causes rapid and sustained elevation in the checkpoint regulatory protein E2F1. Based on preclinical findings, we believe that ARQ 501 has the potential for improved activity and reduced toxicity over other molecular approaches and traditional cancer chemotherapy. The compound has demonstrated anti-cancer activity in mice when applied as both a single agent and in combination with chemotherapeutics. In addition to its selectivity for tumor cells over normal cells, ARQ 501 is active against tumor cells with a broad range of genetic defects. We believe this is particularly advantageous for treatment of solid tumors, where individual tumor masses are comprised of highly heterogeneous cancer cells.

ARQ 197

Phase 1 study.   We began to enroll patients in a Phase 1 clinical trial with ARQ 197 in early 2006, following our submission of an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) in November 2005. This is an open label, dose escalation trial that will include patients with multiple tumor types. Its objectives are to determine the tolerability, safety and a recommended dosing regimen of ARQ 197 for future Phase 2 trials. Additionally, the trial will seek to define the pharmacokinetic profile of ARQ 197 and to collect preliminary data on anti-tumor activity.

Preclinical findings.   Our findings have shown that ARQ 197 can inhibit c-Met in a wide range of human tumor cell lines, including breast cancer, pancreatic cancer, colon cancer and lung cancer. It has also shown anti-tumor activity against several types of xenografted human tumors in mice. We believe ARQ 197 induces cancer cell death primarily through the activation of apoptotic mechanisms.

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