Novacea's ASCENT Phase 2 Results Look Promising

February 20, 2007 -- A large, randomized Phase 2 trial reports today that standard chemotherapy for men with metastatic androgen-independent prostate cancer (AIPC) was enhanced for patients who received a new formulation of high-strength vitamin D, Novacea's DN-101 (AsentarT). The group that received the drug before each chemotherapy session showed some increase in survival. Those given the drug also had reduction of some common side effects of the chemotherapy and of advanced prostate cancer, notably, fewer blood clots.

The study, called ASCENT (AIPC Study of Calcitriol Enhancing Taxotere), is the first placebo-controlled randomized trial to test intermittent, high-dose calcitriol (the natural agonist of of the vitamin D receptor) in late-stage prostate cancer treatment.

Calcitriol is the most potent natural ligand or activator of the vitamin D receptor (also known as the calcitriol receptor). Animal studies and other evidence suggest that glitches in the vitamin D receptor are involved in prostate cancer. Medical observation suggested to some oncologists, including Dr. Toammasz Beer at Oregeon Health Sciences University, that giving prostate cancer patients "pulsed" super-doses of calcitriol before chemotherapy might enhance their treatment, perhaps by reactivating the vitamin D receptor on prostate cancer cells.

DN-101 (AsentarT) is a new formulation of calcitriol which Dr. Beer and colleagues helped design to deliver a highly concentrated oral dose in easy to take form. Some men with advanced prostate cancer have been prescribed off-label high doses of an older brand of oral calcitriol, called Rocaltrol, which is approved and widely used for patients on dialysis. To achieve a dose high enough to combine effectively with chemotherapy, though, prostate cancer patients would have to swallow close to a hundred pills the day before their chemo session. And until ASCENT, no large, randomized study had been done to find out whether this regimen is beneficial.

ASCENT tested DN-101 (Asentar) plus docetaxel (Taxotere) vs. placebo plus docetaxel in men with progressive metastatic androgen-independent prostate cancer (AIPC). Two hundred fifty patients participated in the trial at 48 sites in the United States and Canada. All patients had adequate kidney and other organ function. All of the patients received weekly docetaxel 36 mg/m 2 intravenously for 3 weeks of a 4-week cycle. Half of them received 45 µg DN-101, the other half, a dummy drug. The primary end point was prostate-specific antigen (PSA) response within 6 months of enrollment, defined as a 50% reduction confirmed at least 4 weeks later. Secondary endpoints were overall survival and "skeletal morbidity-free survival" as well as safety and tolerability of the trial treatment.

The investigators report in JCO that that DN-101 may help advanced prostate cancer patients live longer while experiencing fewer chemotherapy-associated side effects and fewer complications of their cancer. "This study suggests that DN-101 treatment was associated with improved survival," they conclude, "but this will require confirmation because survival was not a primary end point."

ASCENT Results

Adding Asentar (DN-101) the day before Taxotere had no dramatic effect on the mens' PSA's but appeared to extend survival and reduce risk of blood clots and other side effects of chemotheerapy for advanced prostate cancer. Taking account of patients' baseline hemoglobin and general health and energy levels on entering the trial, the ASCENT says, analysis showed a statistically significant improvement in survival in the plus Taxotere group over the Taxotere plus placebo group.

Two ways of expressing survival gain are used Firstly, patients who received the combination of Asentar (DN-101) plus Taxotere were estimated to have gained six months in "median survival," the study reports. Median survival is the midpoint between shortest and longest survival times achieved following participation in a study. This cannot be finalized until the longest-surviving patients have died. If that point has not be reached, an estimate is made based on known reduction of risks. "Median survival has not been reached for the DN-101 arm," the study authors say, "and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months for placebo." Put another way, the authors say, patients in the Asentar group saw their risk of death lowered by about a third (ratio of 0.67 in a multivariate analysis that included baseline hemoglobin and performance status).

Overall PSA responses trended slightly in favor of Asentar, occuring in about ten percent more of patients receiving the Asentar plus Taxotere combination versus Taxotere plus placebo. . Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients. Overall, PSA response rates were 63% and 52% (placebo).

Reduction in Chemo Adverse Events

Another significant outcome observed in the ASCENT trial was that men taking Asentar also experienced a reduction in blood clots. Blood clots are a serious complication in advanced cancers and affect between 15 and 20 percent of all cancer patients.

Overall, no increase in serious toxicity was seen with the addition of Asentar to Taxotere, the study authors say. Asentar-treated patients less fatigue ( 8% v 16%), infection (8% v 13%), and hyperglycemia (6% v 12%).. They had slightly more instances of neutropenia (10% 8%). The incidence of any grade 3 or 4 adverse events was 70 percent in Taxotere plus placebo-treated patients and 58 percent in Asentar plus Taxotere-treated patients. Serious adverse events, generally those requiring hospitalization, were observed in 41 percent of Taxotere plus placebo-treated patients and 27 percent of Asentar plus Taxotere-treated patients. The most common adverse events observed with the treatment of Asentar included low-grade elevation of calcium and creatinine in the blood. One case of kidney stones was also reported.

In a press release today John G. Curd, M.D., president and chief medical officer at Novacea., said: "We believe the large number of patients (250) and the randomized design of the ASCENT Phase 2 trial provide us with valuable data regarding the efficacy and safety observations associated with Asentar treatment. In preparation for this publication, we have continued to conduct sensitivity analyses and remain very impressed with the consistency and robustness of the overall survival and other endpoints. The ASCENT trial results strongly support the ongoing international 900-patient confirmatory Phase 3 trial (ASCENT-2) for which we expect to complete enrollment by the end of 2007. This trial is intended to serve as the main clinical study in the marketing application for Asentar."

Sources and Links:

The study is published in Journal of Clinical Oncology , Vol 25, No 6 (February 20), 2007: pp. 669-674. Double-Blinded Randomized Study of High-Dose Calcitriol Plus Docetaxel Compared With Placebo Plus Docetaxel in Androgen-Independent Prostate Cancer: A Report From the ASCENT

Tomasz M. Beer,, Christopher W. Ryan,, Peter M. Venner, Daniel P. Petrylak, Gurkamal S. Chatta,, J. Dean Ruethe,, Charles H. Redfern, Louis Fehrenbacher, Mansoor N. Saleh, David M. Waterhouse, Michael A. Carducci, Daniel Vicario, Robert Dreicer, Celestia S. Higano, Frederick R. Ahmann, Kim N. Chi, W. David Henner, Alan Arroyo, Fong W. Clow

From the Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR; Columbia Presbyterian Medical Center, New York, NY; University of Pittsburgh, Pavillion Hellman Cancer Center, Pittsburgh, PA; Sharp HealthCare; San Diego Cancer Center, Vista; Kaiser Permanente Medical Center, Vallejo; Novacea Inc, South San Francisco, CA; Georgia Cancer Specialists, Tucker, GA; Oncology Hematology Care, Cincinnati; The Cleveland Clinic Foundation, Cleveland, OH; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD; Seattle Cancer Care Alliance, Seattle, WA; University of Arizona Cancer Center, Tucson, AZ; Cross Cancer Institute, Edmonton; Tom Baker Cancer Centre, Calgary, Alberta; and the University of British Columbia Cancer Agency, Vancouver Centre, Vancouver, British Columbia, Canada

The research was paid for by Novacea Inc and sanofi-aventis (manufacturer of Taxotere). Oregon Health & Science University (OHSU) and Tomasz M. Beer have declared a significant financial interest in Novacea Inc, a company that may have a commercial interest in the results of this research and technology. This potential conflict was reviewed and a management plan approved by the OHSU conflict of interest in research committee and the integrity program oversight council was implemented. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of their article.

About Novacea

(source: company statement)

Novacea, Inc. is a biopharmaceutical company focused on in-licensing, developing and commercializing novel cancer therapies. Novacea has two product candidates in clinical trials, including Asentar™, which currently is in a Phase 3 clinical trial for androgen-independent prostate cancer, or AIPC. Novacea's second product candidate, AQ4N, is a hypoxia-activated prodrug and is being investigated in combination with radiation and chemotherapy in a Phase 1/2 clinical trial in brain tumors such as glioblastoma multiforme.