December 2009

Clinical Trials News

An ESUN Resource

Calls for Participation
Request for Volunteers for Ewing's Sarcoma/PNET Research Study at Children's Hospital Los Angeles

Children's Hospital Los Angeles is taking a fresh look at the role of genetics as a risk factor for Ewing's Sarcoma.   The Hospital is now collecting blood samples from patients with Ewing's Sarcoma and their families in search of evidence that DNA sequence changes associated with Ewing's Sarcoma/PNET may be inherited.

In a recent request for volunteers, Melissa Warden, M.S. states "In particular, copy number variations, which are large gains and losses of DNA sequence, are known to play a role in many human diseases, and we believe they may also be important in the development of Ewing's Sarcoma. By identifying a genetic susceptibility risk factor to Ewing's Sarcoma, we hope to improve our understanding of this disease, which could lead to improvement in treatment of future patients."

Anyone interested in participating in the study can contact Melissa by email at mwarden@chla.usc.edu or call her at (323) 361-5642.  The Hospital will cover the costs of blood collection and shipping.

 

Clinical Trial for patients with advanced, dedifferentiated liposarcoma to be announced

Infinity Pharmaceuticals is planning to initiate a Phase 2 clinical study to evaluate the efficacy and safety of IPI-504 (retaspimycin hydrochloride), an investigational Hsp90 inhibitor,  in patients with advanced, dedifferentiated liposarcoma.   They hope to start enrolling patients by early 2010.  Trial participants must have received at least one but no more than two prior chemotherapies.  Patients could have been treated with an unlimited number of targeted drugs or therapies that are not chemotherapies.  They plan to enroll approximately 40 patients at 6-8 centers in the United States (at this time there is no plan to have sites outside of the U.S.). Hsp90 supports and stabilizes cancer-causing proteins.  Inhibiting Hsp90 destabilizes these proteins, which stops tumor growth and  causes cancer cell death.  Hsp90 chaperone inhibition may represent an important new strategy for treating patients with cancer. For more information, contact Suzanne Sheirr at 617 453 1249 in Cambridge, Massachusetts.

 

Study Results
ZIOPHARM Presents Positive Palifosfamide Sarcoma Randomized Phase II Interim Data At CTOS

On November 9th, ZIOPHARM Oncology, Inc. presented positive interim data from the multicenter randomized Phase II trial of palifosfamide (ZymafosTM, ZIO-201) treating patients with unresectable or metastatic soft tissue sarcoma at the 15th Annual Connective Tissue Oncology Society (CTOS) Meeting. A panel of international sarcoma experts, and the Company's Medical Advisory Board determined that the data are compelling and sufficient to proceed to a pivotal study in support of product registration and to conclude enrollment in the trial.

The randomized Phase II trial treats patients with unresectable or metastatic soft tissue sarcoma in the front- and second-line setting. Patients are randomized either to doxorubicin (the only currently FDA-approved agent in sarcoma) or to palifosfamide in combination with doxorubicin. As of the October 5th cut-off date, there were 67 patients randomized to the trial, with 65 treated and 61 eligible for analysis. The 61 patients were evaluated for progression-free survival (PFS) with 20 documented PFS events (doxorubicin alone = 14 events; palifosfamide + doxorubicin = 6 events). With this analysis of all randomized and eligible patients, the hazard ratio is 0.63 favoring palifosfamide + doxorubicin (two-sided Wilcoxon-Gehan p-value = 0.026), statistically supporting that palifosfamide prolongs PFS by at least 50%.

The median PFS for doxorubicin is 4.4 months, the median PFS for palifosfamide + doxorubicin has not yet been reached; the 1st quartile PFS was 1.5 months for doxorubicin vs. 3.5 months for palifosfamide + doxorubicin (PFS more than doubled at this level). PFS is a biologically important end point in sarcoma, and has been well demonstrated to be a relevant measurement of the effect of treatment on outcome.

The interim safety data indicate that the addition of palifosfamide does not add to the toxicity of single agent doxorubicin. The most frequently reported side effects in both arms of the study include neutropenia and fatigue, hypokalemia, nausea, anemia, leucopenia, and alopecia. Palifosfamide is easily administered as an out-patient treatment, and generally well-tolerated.

"These interim results are very promising, indicating a potentially new drug to help control this life-threatening disease with acceptable safety and quality of life," commented George Demetri, MD, Director of the Center for Sarcoma and Bone Oncology and the Ludwig Center at the Dana-Farber Cancer Institute and Harvard Medical School, and a member of ZIOPHARM's Medical Advisory Board. "These data are not only encouraging for sarcoma but hopefully palifosfamide may also work in treating other cancers. This is particularly interesting if the oral form is successful in the clinic," added Lawrence Einhorn, MD, Distinguished Professor at the Simon Cancer Center of Indiana University Medical Center, Lance Armstrong Foundation Chair in Oncology, former President of ASCO and also a member of ZIOPHARM's Medical Advisory Board.

The Company is in the process of finalizing a registration trial plan in soft tissue sarcoma for review by the appropriate U.S. and international regulatory authorities.

 

Oncolytics Biotech(R) Inc. Collaborators Present Positive Phase II Sarcoma Trial Results At CTOS

On November 7th, Oncolytics Biotech Inc. announced updated results from a Phase II study of intravenous REOLYSIN(R) in patients with sarcomas metastatic to the lung in a poster presentation at the 15th Annual Connective Tissue Oncology Society (CTOS) Meeting. The poster presentation, entitled "A Phase II Study of Intravenous REOLYSIN (Wild-type Reovirus) in the Treatment of Patients with Bone and Soft Tissue Sarcomas Metastatic to the Lung", was delivered by Dr. Kamalesh Sankhala, part of principal investigator Dr. Monica Mita's team at the Institute of Drug Development (IDD), the Cancer Therapy and Research Center at the University of Texas Health Science Center, (UTHSC), San Antonio, Texas.

The investigators reported that the treatment has been well tolerated to date, and that 19 of 44 evaluable patients experienced stable disease ranging from two to 20 months, resulting in a total clinical benefit rate (complete response + partial response + stable disease) of 43%. The response objective for the study was three or more patients having prolonged stabilization of disease (greater than 6 months) or better, for the agent to be considered. The trial exceeded its established objective with six patients experiencing stable disease for more than six months. Two patients have experienced stable disease for more than 19 months. One has synovial cell sarcoma that relapsed following surgery, while the other has Ewing's Sarcoma and had previously progressed following multiple treatments.

"We were very happy to participate in the study," said Dr. Mita. "REOLYSIN is a promising option for patients with sarcoma as shown by the results of this study. As a single agent the virus had a clinical benefit rate of 43% and it was very well tolerated. Further studies combining REOLYSIN with chemotherapy are contemplated in order to integrate the virus in the panoply of agents used for sarcoma treatment."

"These results are consistent with what we observed on an interim basis when we reported data on the first 16 patients back in June 2008," said Dr. Brad Thompson, President and CEO of Oncolytics. "It is encouraging that we are observing stable disease in a range of sarcomas and the clinical benefit is not isolated to any specific type."

 

Threshold Pharmaceuticals Presents Interim Data From a Phase 1/2 Clinical Trial of TH-302 at CTOS

On November 6th, Threshold Pharmaceuticals, Inc. announced clinical trial results related to Threshold's clinical stage hypoxia-activated prodrug, TH-302 at the 15th Annual Connective Tissue Oncology Society (CTOS) Meeting. The trial is investigating TH-302 in combination with doxorubicin in patients with soft tissue sarcoma who have not received prior doxorubicin. Twelve patients have had at least one evaluable post-treatment tumor assessment, including 3 (25%) with a partial response (PR) as measured by RECIST (Response Evaluation Criteria In Solid Tumors). Two of the PRs are confirmed, including one patient who has remained on study for 33 weeks. One of the PRs was unconfirmed due to progression at the subsequent assessment. Five of the 12 patients continue to receive TH-302 after receiving TH-302 for 3 to 13 three-week cycles. Seven (58%) patients achieved stable disease while 2 (17%) had progressive disease. Additional patients are being enrolled to better define the extent of the tumor response activity.

"For sarcoma patients, median survival is about one year regardless of stage of disease, so we are definitely in need of new agents to help these patients. We believe that TH-302 may 'complement' doxorubicin, the standard of care in sarcoma, and treat that portion of the tumor that typically does not respond to this traditional chemotherapy agent," said John Curd, M.D., Threshold's chief medical officer. "This clinical trial has thus far established that TH-302 can be safely combined with full doses of doxorubicin, and the preliminary data suggests that TH-302 may add to the activity and durability of doxorubicin."

TH-302 continues to be tolerated and there have been no new unexpected adverse events in the 14 patients assessed for safety. Nausea was the most commonly reported adverse event and was reported in 8 (57%) patients. After observing significant, but not dose limiting toxicity at a TH-302 dose of 240 mg/m2, prophylactic growth factor support was initiated. Two dose limiting toxicities, grade 3 cellulitis with grade 4 neutropenia and grade 4 thrombocytopenia, were observed in 2 of 4 patients treated at a TH-302 dose of 340 mg/m2. The maximum tolerated dose (MTD) was then established at 300 mg/m2. Skin toxicity is common with 9 of 14 (64%) patients having at least one skin adverse event. All were grade 1 or 2 with the exception of the one patient with grade 3 cellulitis. Eight (57%) patients had a mucosal adverse event; all were grade 1 or 2.

The 403 trial is a Phase 1/2, multicenter, dose escalation trial to determine the safety, efficacy and pharmacokinetics of TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. The trial was initiated in September 2008. The trial will enroll up to 36 patients including 12 patients treated at the MTD as part of the dose expansion component of the trial. TH-302 is administered intravenously on days 1 and 8 of a 21 day cycle. Doxorubicin is dosed according to its package insert (75 mg/m2 on day 1 of the 21 day cycle). The Phase 1/2 clinical trial has completed the dose escalation component, reached the MTD and is currently enrolling patients in the dose expansion cohort.

The Company has two additional ongoing clinical trials of TH-302. The Company is in the process of completing a Phase 1/2 clinical trial of TH-302 in combination with various chemotherapies in patients with advanced solid tumors. The Company is also continuing a Phase 1/2 clinical trial of TH-302 as monotherapy in patients with advanced solid tumors.

 

Orphan Drug Status
European Medicines Evaluation Agency Grants ARQ 197 Orphan Drug Designation

On October 14th, ArQule, Inc. announced that the European Medicines Evaluation Agency (EMEA) has designated ARQ 197 as an orphan medical product for the treatment of soft tissue sarcoma. Under the guidelines of the EMEA, medicinal products are designated as orphan drugs when they are used to treat illnesses affecting small numbers of patients, such as soft tissue sarcoma. Such designation provides for incentives for investment in the research and development of such drugs, including exclusive distribution rights throughout the European Union for ten years, during which period no other product with the same active ingredient would be authorized for use for the same therapeutic application.

ArQule is conducting a Phase 2 clinical trial with ARQ 197 in a sub-group of soft tissue sarcoma known as MiT (Microphthalmia Transcription Factor)-associated tumors. The designation of ARQ 197 as an orphan medical product in soft tissue sarcoma, combined with the evaluation of clinical data from this trial expected to be available in early 2010, will inform the decisions related to the advancement of the program.

 

New Clinical Trials for Sarcomas

The Liddy Shriver Sarcoma Initiative maintains searchable abstracts of clinical trials for sarcomas. The following studies have been added to open clinical trials since the last issue of ESUN was published:

Phase III

Phase II

Phase I or Phase I/II

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