The Virtual Window: Clinical Trial Reports--April 2007

August 13, 2010
Querida Anderson, Prachi Patel-Predd

,
John D. Zoidis, MD

OBTN, April 2007, Volume 1, Issue 3

The Clinical Trials reported in this issue include: PHASE I: 1) Cell Genesys and Medarex Remain Positive on Combination Immunotherapy Study 2) Active Biotech Achieves Success with TASQ for Prostate Cancer PHASE II: 1) Myriad Initiates Evaluation of Brain Cancer Drug that Crosses the Blood-Brain Barrier 2) Second Lung Cancer Trial Adds Data to Novel Therapy PHASE III: 1) Nexavar Could Soon Add Primary Liver Cancer to its Label 2) Point Therapeutics Provides Clinical Update for NSCLC Studies

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THE VIRTUAL WINDOWClinical Trial Reports

â–º PHASE I

Cell Genesys and Medarex Remain Positive on Combination Immunotherapy Study

Cell Genesys, Inc. and Medarex, Inc. said that follow-up data from the ongoing phase I trial of Cell Genesys’ GVAX immunotherapy for prostate cancer, administered in combination with Medarex’ fully human anti-CTLA-4 antibody, ipilimumab (MDX-010) were positive.

“We continue to be encouraged by the interim results of this trial, which now include evidence for the durability of the anti-tumor

responses along with the frequency of such responses, observations which we believe have not been previously experienced

for a combination of immunotherapies in advanced prostate cancer,” stated Rob Dow, MD, chief medical officer of Cell Genesys.

“Moreover, we believe these findings provide further support for our ongoing phase III trials of GVAX immunotherapy for prostate

cancer.”

A maximum tolerated dose for the combination therapy has not yet been defined. Immunomonitoring studies showed that the combination therapy enhanced T-cell and dendritic cell activity, which was more pronounced at the higher dose levels.

To date, 12 patients with advanced prostate cancer completed treatment. Of the six patients treated in the two highest dose

groups, anti-tumor activity was observed in five. Prostate-specific antigen (PSA) declines of greater than 50% were maintained in four of these patients for at least six months. The longest response is reportedly ongoing at more than 12 months. Moreover, evidence of anti-tumor activity has been observed in three of the PSA responders, including improvement of multiple lesions on bone scan, resolution of abdominal lymph node disease by CT scan and improvement in pain due to bone metastases. Additionally, two patients have had stable disease on bone scan for at least three months.

This dose-escalation combination trial is currently expected to enroll a total of approximately 25 to 30 patients with metastatic

HRPC.

—Querida Anderson

Active Biotech Achieves Success with TASQ for Prostate Cancer

Active Biotech reported positive data from its phase Ib study of TASQ for the treatment of prostate cancer. By step-wise dose escalation, a safedose of 1 mg/day was achieved. This represents a doubling of the previously reported maximum tolerated dose level.

“We now have a very complete data set that constitutes a solid base to move into phase II clinical trials,” stated Sven Andreasson, president and CEO.

The ongoing 10-week study comprises patients with HRPC. All patients entering the study had rising serum levels of prostate-specific antigen (PSA). PSA measurements were recorded and PSA velocity (PSAV) was calculated after 28 days of treatment.

Out of six patients, five had greater than 50% decrease in PSAV compared to prior treatment. Of them, three exhibited a

decrease in absolute PSA levels.

The study is being performed at the urological clinics at the University Hospitals in Lund, Malmoe and Uppsala, Sweden. Phase

II studies are scheduled to start during 2007.

The objective of the TASQ project is to develop a pharmaceutical product that can be administered orally for the long-term treatment of prostate cancer. The market for prostate cancer is estimated at more than $3 billion a year, according to the company.

—Querida Anderson

Sunesis Initiates Phase I Trial of Small-Molecule CDK Inhibitor SNS-032

Sunesis Pharmaceuticals, Inc. reported on March 6 that the first patient in a phase I clinical trial of SNS-032 in advanced B-cell

malignancies has been dosed. SNS-032 is a novel, selective, and potent small-molecule inhibitor of cyclin-dependent kinase (CDK) 2, CDK7 and CDK9, and has been shown in preclinical and clinical studies to deplete cells of myeloid cell leukemia sequence 1 (MCL-1), a protein associated with cell survival, particularly in lymphomas and other B-lymphoid malignancies.

Daniel C. Adelman, MD, senior vice president of research and development at Sunesis elaborated: “Based on non-clinical and

phase I pharmacodynamic data of SNS-032 from our ongoing trial in patients with advanced solid tumors, we are eager to learn

more about this promising anticancer compound in patients with hematological cancers. We are enthusiastic about initiating

clinical trials in B-cell malignancies as we have seen evidence that SNS-032’s mechanism of action may be particularly well-suited to indications including multiple myeloma, chronic lymphocytic leukemia, and mantle-cell lymphoma.”

The phase I trial of SNS-032 is a dose-escalation study designed to evaluate the safety and tolerability, as well as the preliminary anti-tumor activity of the agent in patients with advanced B-cell malignancies. The trial will also be used to determine the maximum tolerated does in this setting, and will enroll 30 to 40 patients at three centers in the US. Preliminary results are expected by the end of 2007.

Sunesis has a solid pipeline of preclinical- and development-stage product candidates in oncology focused on novel pathways and targets, including inhibition of the cell-cycle and survival signaling. Sunesis is currently conducting phase I-II clinical trials in lung cancer, ovarian cancer, and acute myeloid leukemia for its lead compound, SNS-595.

—John D. Zoidis, MD

â–º PHASE II

Myriad Initiates Evaluation of Brain Cancer Drug that Crosses the Blood-Brain Barrier

Myriad Genetics, Inc. initiated the first phase II trial of Azixa™ in patients with brain cancer. The company expects to enlist the participation of approximately 50-70 centers in the US and Europe.

“We are pleased to continue the clinical development of this exciting compound,” said Adrian Hobden, PhD, president of Myriad.

“The ability of Azixa to cross the blood-brain barrier gives us hope that because it can reach the site of the disease, it could be

a more effective therapeutic than anything available today.”

The standard of care for patients with glioblastoma multiforme (GBM) is primarily surgery and whole brain radiation. The five-year survival rate of the disease has remained unchanged over the past 30 years and stands at less than 3%, according to

Myriad.

The study is designed to determine the safety profile of Azixa and the extent of its ability to improve the survival of patients with GBM, the most common form of primary brain cancer. The trial will compare the survival of patients treated with Azixa to those treated with oxaliplatin and those treated with Azixa plus oxaliplatin.

The trial will be an adaptive, open-label, multiple-dose study in patients with recurring or relapsed GBM. The first stage of the trial is designed to determine the safety and the maximum tolerated dose of Azixa in combination with oxaliplatin in approximately 16 patients. The maximum tolerated dose of Azixa alone was determined during the earlier phase I trials. The second stage of the trial will then assess the survival of patients treated with the Azixa/oxaliplatin combination therapy compared to Azixa alone or oxaliplatin alone.

—Querida Anderson

Second Lung Cancer Trial Adds Data to Novel Therapy

Antisoma said the second, confirmatory phase II trial of its non-small cell lung cancer drug candidate showed a 50% response

rate. Addition of AS1404 to chemotherapy was also well-tolerated.

“The high response rate and favorable tolerability profile in this study support earlier data suggesting that AS1404 has real potential as a novel therapy for lung cancer,” commented Dr. Mark McKeage of the University of Auckland, New Zealand, a key investigator in both AS1404 lung cancer studies.

This 30-patient trial tested a 1,800-mg/m² dose of AS1404 in combination with carboplatin and paclitaxel chemotherapy. Besides the 50% response rate, a further 43% of patients showed disease stabilization, while only 7% had progressive disease as their best response.

An earlier randomized controlled phase II study in lung cancer showed a fivemonth increase in median survival when 1,200 mg/m² AS1404 was added to carboplatin and paclitaxel. Initial data from controlled phase II trials in ovarian and prostate cancers also showed increased response rates.

“AS1404 now draws support from four phase II studies across three different cancers, an excellent position to be in as we prepare the drug for phase III trials,” pointed out Glyn Edwards, CEO.

—Querida Anderson

Adherex’ European Study Enhances Anticancer Candidate

Adherex Technologies’ phase Ib/II study of single-agent ADH-1 showed good results. ADH-1 targets N-cadherin, a protein present on certain tumor cells and established blood vessels that feed solid tumors.

The data includes 30 patients who received an aggregate of more than 200 doses, or 68 cycles, of ADH-1 given on a weekly schedule. Doses range from 150 to 2,400 mg/m². ADH-1 was well tolerated at all doses tested for periods of up to eight

months, displayed predictable pharmacokinetics, and demonstrated hints of antitumor activity in five patients with advanced,

chemotherapy-resistant cancer. A maximum tolerated dose has not yet been defined.

“This European data is consistent with our prior clinical experience, showing ADH-1 to be well tolerated over a broad dosage range with hints of anti-tumor activity in a variety of tumor types,” said William P. Peters, MD, PhD, chairman and CEO. “Given the unexpected level of synergy of ADH-1 in combination with chemotherapy that we have reported from our preclinical studies, the clinical development of this drug continues fully on track.”

In the European phase Ib/II study, three of 19 patients (16%) with ovarian/gynecological tumors experienced evidence of anti-tumor activity, one with an unconfirmed partial response (previously reported) and two with prolonged stabilization of their disease, which were previously rapidly progressive (eight and six months, respectively). Two other patients experienced stabilization of their disease, one with colorectal cancer and one with non-small cell lung cancer, each lasting three months.

—Querida Anderson

â–º PHASE III

Nexavar Could Soon Add Primary Liver Cancer to its Label

Bayer Pharmaceuticals Corporation and Onyx Pharmaceuticals, Inc., under the recommendation of an independent data

monitoring committee (DMC), decided to stop a phase III trial of Nexavar® in primary liver cancer and provide the patients

enrolled access to the drug. Given that there are limited approved systemic therapies for this disease, the companies say

they will continue discussions with health authorities worldwide regarding the next steps in filing for approval for the treatment

of hepatocellular carcinoma (HCC).

“The observed superiority in overall survival for Nexavar-treated patients over patients receiving placebo demonstrates the

efficacy of Nexavar in advanced primary liver cancer,” said Dr. Jordi Bruix, co-principal investigator and head of the Barcelona

Clinic Liver Cancer Group, Liver Unit, Hospital Clinic Barcelona, Spain. Onyx’ shares rose 80% to reach $24.15 the day after the results were reported.

The DMC reviewed the safety and efficacy data from the companies’ pivotal phase III trial in patients with primary liver cancer.

It concluded that the trial met its primary endpoint resulting in superior overall survival in those patients receiving Nexavar

(sorafenib) tablets versus those receiving placebo. The DMC also noted that there was no demonstrated difference in serious

adverse event rates between the two treatment arms.

Hepatocellular carcinoma is the fifth most common cancer in the world and is responsible for about 90% of the primary

malignant liver tumors in adults.

Nexavar is an oral multi-kinase inhibitor that targets the tumor cell and tumor vasculature. It is currently approved in nearly 50 countries, including the US, for the treatment of advanced kidney cancer.

—Querida Anderson

A Minor Setback for Glufosfamide

Threshold Pharmaceutical Inc.’s glufosfamide, which had received orphan drug status from the FDA late last year, has not met its primary efficacy endpoint in a phase III clinical trial. The primary endpoint of the trial was the overall survival in metastatic pancreatic cancer patients, measured as time from randomization for the trial until death. The drug, which was being tested as a second-line treatment, did not show a statistically significant improvement of overall survival as compared to best supportive care (BSC). At present, there are no approved second-line treatments for advanced pancreatic cancer.

The randomized, open-label trial evaluated 303 patients who had relapsed after a gemicitabine-containing chemotherapy

treatment. Of the patients, 148 received just BSC while the others received 4,500 mg/m² of glufosfamide every three weeks

combined with BSC. Best supportive care includes all medical or surgical interventions except treatment with systemic therapies that are intended to kill cancer cells. The primary endpoint of overall survival, which was evaluated after the 261st death, was not statistically significant.

“While we were hoping that overall survival would be close to 50% better in the glufosfamide-treated group, it was only 18% higher in this group,” said Threshold Pharmaceuticals’ chief executive officer Barry Selick. The median survival of patients treated with glufosfamide was greater: 105 days compared with 84 days for patients receiving BSC alone.

“While there was a trend toward efficacy with glufosfamide, unfortunately the trial did not meet its efficacy endpoint,” Selick

said. “Based upon the activity seen in this and previous studies, we remain committed to our ongoing trials with glufosfamide.”

—Prachi Patel-Predd

Point Therapeutics Provides Clinical Update for NSCLC Studies

Point Therapeutics, Inc. provided a clinical update on its two phase III trials in stage IIIb/IV non-small cell lung cancer (NSCLC)

in a press release on March 1. The evaluation consists of two randomized, placebo-controlled, double-blind phase III studies

in the second-line and third-line setting.

The first trial evaluates talabostat and pemetrexed (Alimta®, Eli Lilly) versus placebo and pemetrexed. The second study evaluates talabostat and docetaxel (Taxotere ®, Sanofi-Aventis) versus placebo and docetaxel.

Each study was intended to enroll approximately 400 patients, with an estimated 200 patients per treatment arm. Enrollment in the talabostat/pemetrexed study is on schedule with full enrollment expected in the Q2 of 2007 and results projected in the Q4 of 2007. In the talabostat/docetaxel study, enrollment is currently behind schedule.

“In my experience, many studies of docetaxel in NSCLC are enrolling slowly, primarily due to the increasing use of pemetrexed in the second- and third-line treatment setting, and the increasing use of docetaxel in the front-line setting,” said Dr. Chandra Belani, a professor of medicine in the division of hematology/oncology at the University of Pittsburgh School of Medicine, co-director of the Lung and Esophageal Cancer Program at the University of Pittsburgh Cancer Institute and a consultant for Point. “It is becoming increasingly difficult for sponsors to enroll large studies using docetaxel as a comparator due to this shifting treatment paradigm.”

Given these factors, the company is considering other options, such as initiatives to speed the rate of enrollment and downsizing the total number of patients enrolled in the trial while increasing the treatment effect needed to demonstrate

statistical significance.

—Querida Anderson