The Virtual Window: Clinical Trial Reports--June 2007

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â–ºPHASE I CuraGen, TopoTarget Begin Study of HDAC Inhibitor Candidate as Combination Therapy for Soft Tissue Sarcomas

CuraGen Corporation and TopoTarget A/S initiated a Phase I/II evaluation of the efficacy and safety of intravenous belinostat (PXD101) in combination with doxorubicin for the treatment of soft tissue sarcomas (STS).

“The antitumor activity of belinostat we observed in preclinical models, combined with previously generated clinical results suggest there is activity of belinostat for the treatment of STS and leads us to believe that the combination of belinostat and doxorubicin could benefit patients with this disease,” commented Frank Armstrong, MD, President and Chief Executive Officer of CuraGen Corporation.

This open-label, multi¬center study will enroll 24 patients with solid tumors for whom no standard therapy exists to define the maximal tolerated dose. The primary objectives for the trial are to determine the maximum tolerated dose and to assess the anti-tumor activity of belinostat and doxorubicin combination treatment. Secondary endpoints include the time to disease progression, overall survival, and duration of response. The pharmacokinetic profile and aspects of pharmacodynamic activity of belinostat will also be evaluated, the companies stated.

For the Phase II trial, the company plans to enroll an additional 20 to 40 STS pa¬tients who have not received prior chemotherapy.

Belinostat is a small molecule HDAC inhibitor being investigated in the treatment of solid and hematologic malignancies either as a single-agent or in combination with other active anti-cancer agents. It is currently in Phase II development for the treatment of T-cell lymphoma, ovarian cancer, and multiple myeloma and in Phase I for colorectal cancer and solid tumors.

â–º PHASE I Ambrilia’s Therapeutic Peptide Shows Clinical Activity in Metastatic Prostate Cancer Patients

Ambrilia Biopharma Inc. reported that a Phase I/II trial indicates that the drug PCK3145 has clinical activity in metastatic prostate cancer patients.

The study was conducted at the Memorial Sloan Kettering Cancer Centre in New York City with 28 metastatic hormone refracto¬ry patients and led by co-investigators Drs. Susan Slovin and Howard Scher. The researchers found that this therapeutic peptide increased PSA doubling time (PSADT). The study also confirms down-regulation of MMP-9, a matrix metalloproteinase enzyme involved in facilitating tumor metastasis, and disease stabilization as assessed by time to radiographic progression in several patients, according to Ambrilia.

While the elevated MMP-9 plasma levels were reduced in most of the patients, 10 out of the 28 patients showed an increase in PSADT from 1.5 fold to 5 fold.

“We are greatly encouraged by these recent findings on the potential clinical benefits of PCK3145 in late stage prostate cancer patients”, said Stephen Sudovar, Ex-ecutive Chairman and Interim CEO of Ambrilia. “The safety profile together with the quantitative results on PSADT, MMP-9 as well as stabilization of the metastatic process, we believe, warrant further development of this product.”

PCK3145 is a synthetic 15-mer peptide that is derived from the natural sequence of amino acids of the prostate secretory protein (PSP94), one of three predominant proteins found in human seminal fluid. PSP94 expression in the prostate is down regulated in patients with advanced prostate cancer, and believed to be a survival mechanism for the cancer cells. The mechanism of action and receptor for PCK3145 suggests PCK3145 to be a signal transduction inhibitor with multiple ways to restrict disease development, Abrilia reports.

â–º PHASE II Alchemia’s Precursory Evaluation of mCRC Study Presents Positive Efficacy Data

In a preliminary review, Alchemia Limited’s found that HyCAMP™ did not improve diarrhea incidence, its primary endpoint, in patients with metastatic colorectal cancer, compared to irinotecan. It did, however, increase median progression-free survival.

In the randomized trial, 80 patients who had previously failed treatment with 5-fluoro uracil were eligible to receive up to eight cycles of chemotherapy in the form of irinotecan or HyCAMP intravenously. The primary endpoint was the evaluation of incidence of late grade 3 or 4 diarrhea. Alchemia found a lower than expected incidence of diarrhea in the control arm. In regard to its secondary safety endpoints, the company saw no major differences in overall adverse events between the two treatment arms. The secondary efficacy endpoint was also met with median progression free survival for HyCAMP patients at 5.2 months compared to 2.4 months for the irinotecan arm. Patients on HyCAMP re¬ceived a median of six cycles of therapy compared to two for irinotecan alone.

Thus far, “the findings have far exceeded our expectations in that we did not expect to achieve a statistically significant improvement in efficacy from such a small number of patients” commented principal investigator Peter Gibbs.

Alchemia expects to complete the trial by the end of May. “We will be moving as quickly as possible to discuss our plans for future studies with the FDA,” said Alchemia CEO at the time Dr. Tracie Ramsdale, who has been succeeded by Dr. Peter Smith. “We are hopeful that these results will enable us to move forward to a pivotal Phase III study earlier than originally anticipated.”

â–º PHASE II IsoRay’s Cesium-131 Established as Front-Line Treatment for Early-Stage Prostate Cancer

Cesium-131 has proven to be a safe prostate brachytherapy isotope, according to IsoRay Medical. “This marks a major milestone in the brachytherapy field, providing high level of confidence in the effectiveness of Cesium-131 for physicians and patients,” stated Dr. Steven Kurtzman, medical director for IsoRay Medical and a principal with the San Francisco area-based Silicon Valley Urology Center.

Cesium-131, according to IsoRay, is the first breakthrough treatment in fighting prostate cancer in more than 20 years. Investigators of this seven-institution investigation concluded that Cesium-131 “has come into widespread use; and the clinical results of this trial are mature enough to be of immediate, important, practical use to practitioners.”

The study, conducted by Dr. Bradley Prestidge and Dr. William Bice, principal investigators at the Texas Cancer Clinic, measured the typical urinary and rectal responses of Cesium-131 for prostate cancer therapy. They found a correlation between dosimetry and urinary and rectal responses. The study reportedly concluded these responses are most often resolved back to baseline within four to six months.

Dr. Prestidge and Dr. Bice, presented their results at the 28th American Brachytherapy Society Annual Meeting, held in Chicago between April 29th and May 1. Their talk addressed 80 of the 100 study patients, with an average pretreatment PSA of 6.75. These participants were treated exclusively with brachytherapy. CT imaging was used to evaluate dosage and affect of the isotope on targeted areas. Evaluations were performed two weeks following the patients’ implant procedure.

Advantages of Cesium-131 treatment over Palladium-103 and Iodine-125 include higher energy and shorter half-life if 9.7 days, according to IsoRay. It delivers 90% of the prescribed dose to the prostate in just 33 days compared to 58 days for Palladium and 204 for Iodine, the company added. Cesium-131 also reportedly has a higher biologically effective dose.

â–º PHASE III BDSI Closer to Filing NDA for Delivery Technology in Breakthrough Cancer Pain Market

BioDelivery Sciences International, Inc. (BDSI) has found that its delivery technology used with fetanyl in cancer patients with breakthrough pain had statistically significant results in its Phase III trial.

BEMA™ Fentanyl met both primary and secondary efficacy endpoints. On April 25, 2007, BDSI reported positive results in its primary efficacy target, SPID 30 (Summary of Pain Intensity Difference at 30 minutes), compared to placebo. Then, on May 14, the company said that it achieved a key secondary endpoint, SPID 15 (Summary of Pain Intensity Difference at 15 minutes).

BEMA Fentanyl consists of a small, dissolvable polymer disc formulated with the opioid narcotic fentanyl for application to the buccal membranes. Upon administration, BDSI explained, BEMA Fentanyl is de¬signed to deliver a rapid, reliable dose of drug across the mucous membranes.

“These additional efficacy results continue to define the profile of BEMA Fentanyl in treating breakthrough cancer pain,” Mark Sirgo, PharmD, President and CEO of BDSI, commented. “Based on the combination of what we believe is a convenient and comfortable delivery form with the early pain intensity reduction demonstrated in our study, we remain confident that BEMA Fentanyl has the potential to play an important role in the future treatment of breakthrough cancer pain.”

BDSI believes that fentanyl applied with its BEMA disc technology could meet the market need for new narcotics. The company also thinks it will be well suited for breakthrough cancer pain in opioid-tolerant patients.

In 2006, franchise sales for the market leader in rapid-acting fentanyl products were a reported $659 million, while treating less than 50,000 of the estimated 500,000 cancer patients with breakthrough pain, according to BDSI. “We believe that the efficacy and safety profile of BEMA Fentanyl is well suited to penetrate the 90% of the market that is not served by existing products” commented Dr. Sirgo. “Based on this, and assuming NDA acceptance and approval by FDA and that our development and commercialization activities continue as planned, we continue to believe that we will ultimately reach our annual peak sales projection of $250 million for the treatment of breakthrough cancer pain.”

BDSI expects to submit the NDA during the third quarter of 2007. The company first will conduct a pre-NDA meeting with the FDA on June 28, 2007 to discuss results of the efficacy trial, along with the safety data and other requirements for the NDA submission.

â–º PHASE III Tarceva Sees Continued Positive Clinical Data and Spurs Growth for OSi

Journal of Clinical Oncology

OSI Pharmaceuticals, Inc. published results in the April 24 issue of the showing that adding Tarceva® (erlotinib) to gemcitabine chemotherapy improves survival when administered as first-line therapy to patients with advanced pancreatic cancer.

“This is the first study in 10 years to demonstrate an improvement in survival in pancreatic cancer,” notes Malcolm Moore, Study Chair and Chief of Medical Oncology and Hematology at Princess Margaret Hospital, University of Toronto. “As a physician I’m delighted to have additional treatment options for my patients.”

Tarceva was approved by FDA in November 2004 for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one chemotherapy regimen. Then, in November 2005, treatment of first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer in chemotherapy-naïve patients was added to its label.

Tarceva is co-promoted with Genentech and Roche and is under investigation for new uses. OSI is conducting Phase III evaluations of this drug as a first-line treatment of NSCLC as well as a therapy for adjuvant non-small cell lung, ovarian, and colorectal cancer.