Clinical Trial Reports: May 2007

THEVIRTUALWINDOW Clinical Trial Reports

PHASE I

Adherex Initiates Combination Trial of ADH-1 and Melphalan for Melanoma Treatment

Adherex Technologies Inc. initiated a phase I trial of the combination of systemic ADH-1 plus isolated limb infusion melphalan for the treatment of melanoma. The study, which will be conducted at Duke University Medical Center, is expected to enroll up to 25 patients with N-cadherin positive melanoma and conclude in the second half of 2007, according to Adherex.

“Melanoma is a disease with an extremely poor prognosis,” said William P. Peters, MD, PhD, chairman and CEO. “Where the current treatment options are so limited, if our preclinical observations of significant and unexpected synergy of ADH-1 in combination with melphalan translate into humans, it would present the opportunity for an accelerated approval strategy and also the possibility for a major advance in the treatment of melanoma.”

The evaluation will explore escalating doses of ADH-1 in combination with standard doses of melphalan.

Erimos Initiates Evaluation of First-In-Class Small Molecule Therapy for Glioma Brain Tumors

Erimos Pharmaceuticals announced that patient dosing has commenced for its lead product candidate, terameprocol (EM-1421), for the treatment of recurrent, highgrade glioma brain tumors that are unresponsive to conventional therapy.

“Although major progress has been made in understanding how to treat brain tumors, we are very excited to have the opportunity to add a potential new treatment for this distressing disease, especially one that appears to have such low toxicity,” said Stuart A. Grossman, MD, study chairman.

Terameprocol, a derivative of nordihydroguaiaretic acid, is a novel chemical entity exclusively licensed from The Johns Hopkins University. This first-in-class small molecule drug is designed to target abnormal tumor cells while causing little or no toxicity to healthy cells, according to Erimos. It is designed to prevent the production and activation of survivin, a protein that is produced excessively in tumor cells, thus preventing cell replication and enhancing the body’s ability to eliminate abnormal cells through apoptosis.

The open-label, phase I/II study is designed to determine the safety and maximum tolerated dose of terameprocol when administered to adult patients as well as to assess the anti-tumor activity of the regime. The trial will also investigate the pharmacokinetic properties of terameprocol. Approximately 30 adult patients will be enrolled and will be drawn from a population with progressive or recurrent glioma after primary treatment with surgery, radiation therapy and/or chemotherapy, and/or with no standard therapy available.

PHASE II

ChemGenex Treats First Patient in CML Trial

ChemGenex Pharmaceuticals treated the first patient in a phase II/III study to evaluate whether Ceflatonin can provide clinical benefit to patients with chronic myeloid leukemia (CML) who have failed or are intolerant to tyrosine kinase inhibitor treatments (TKIs).

CML patients routinely receive treatment with imatinib mesylate (Gleevec) and dasatinib (Sprycel), TKIs that are approved in the US and Europe. Patients who are resistant or intolerant to the approved TKIs have limited treatment options, according to ChemGenex.

The CML-203 study is designed to evaluate the efficacy of Ceflatonin (homoharringtonine or HHT) in CML patients who have failed or were intolerant to treatment with two or more prior TKIs. It complements the ongoing CML-202 evaluation of CML patients with the T315I point mutation and will recruit CML patients from chronic, accelerated and blast-phase disease states.

“Initiation of the CML-203 study represents the achievement of another important milestone for ChemGenex,” said Greg Collier, PhD, ChemGenex’s managing director and chief executive officer. “This is a companion study to our ongoing CML-202 study, which will form the basis of our initial new drug application, or NDA. CML-203 should provide the basis for filing a supplementary NDA, thereby expanding the potential market for the drug.”

The first patient was enrolled into CML-203 at the M.D. Anderson Cancer Center in Houston, Texas. ChemGenex is expanding the study to an estimated 15 centers through the US and Europe. It anticipates that 50 to 75 patients will be enlisted into CML-203, and that initial data from the study will become available in the first half of 2008. The primary endpoint for the study will be hematologic response rate, and cytogenetic response rate will be one of the secondary endpoints assessed.

Cleveland BioLabs Phase II Hormone-Refractory Prostate Cancer Trial Advances to Next Phase

Cleveland BioLabs, Inc. reported that it will begin enrolling patients in a phase II study for Curaxin CBLC102 in advanced, hormone-refractory (androgen-independent) prostate cancer. The FDA has assigned orphan-drug status to treatments for androgen-independent prostate cancer.

“CBLC102’s historic safety profile has proven consistent and the hormone-refractory prostate cancer trial is advancing in line with our expectations,” commented Cleveland BioLabs President and chief executive officer, Michael Fonstein, PhD “CBLC102 is the most advanced compound in our anti-cancer (Curaxin) pipeline and presents a significant and unique market opportunity as a potential oral therapy for cancer.”

Curaxin CBLC102 is a safe, oral drug used in the past to treat malaria that demonstrates efficacy in vitro, in animal models and in live tumors removed from patients.

According to the trial protocol, enrollment of subjects of the main cohort may be initiated only if a limited number of subjects of the first cohort experience a certain severity of adverse events, explains Cleveland. The company said that it achieved this criterion, enabling enrollment. The first 15 subjects of the main cohort will be enrolled and monitored for PSA response throughout their treatment regimen. As soon as PSA response is achieved in at least one subject, the remaining 13 subjects may be admitted.

The phase II study will involve a total of 31 patients with advanced, refractory prostate cancer. Primary endpoints for the study are reduction in PSA levels, reduction in tumor size, and disease-free survival. The duration of the study is two years, however certain preliminary data may be available earlier. The study is being conducted at the University of Chicago, the Cleveland Clinic and the University Hospitals of Cleveland.

The company plans to start additional phase II studies of Curaxin CBLC102 in renal cell carcinoma and multiple myeloma in 2007.

Helix Shows Positive Results in Treatment of HPV-induced, Low-Grade Cervical Lesions

Helix BioPharma Corp. reported positive results from its phase II study of topical interferon alpha-2b in women with human papilloma virus- (HPV) induced, low-grade cervical lesions.

“Treated patients responded well, both in terms of efficacy and safety to this new investigational therapeutic,” said Achim Schneider,

MPH, principal investigator for the study and director of the department of gynaecology at the Charite University Hospital in Berlin. “Helix’s product shows real promise as a practical and effective pharmaceutical means of preventing cervical cancer development in women presenting with HPV-induced cervical lesions.”

The study showed a clinically efficacious response to treatment in nearly half of the treated patients. In addition, the candidate demonstrated an excellent safety profile with no significant local intolerance or drug-related serious adverse event observations, according to Helix.

A total of 41 women with confirmed HPV-induced, low-grade squamous intraepithelial lesions (LSIL) of the cervix were studied across four sites in Germany. The treatment arm consisted of 21 women, who received topical interferon alpha-2b, self-administered intravaginally three times per week for a period of six weeks with a follow-up evaluation at 12 weeks. The results were compared to 21 separately studied women who received no treatment whatsoever over the same study period.

The primary endpoint and main outcome for both groups was the Pap-response rate defined. Pap smear normalization was considered to occur if the patient’s Pap smear improved to group II or better from any of Pap smear groups IIW through IIID.

PHASE III

Amgen and ImClone’s Competing EGFr-targeting Drugs Battle It Out in the Clinic

Recently, Amgen and ImClone both with marketed drugs for epidermal growth factor receptor- (EGFr) expressing cancers, reported mixed phase III data. Results from Amgen, Inc.’s Vectibix trial and ImClone Systems’ Erbitux studies weighed in on each other’s current and projected market value.

Amgen pulled Vectibix from an evaluation along with another biologic drug plus chemotherapy in metastatic colorectal cancer (mCRC). On the other hand, while Erbitux from ImClone and Bristol-Myers Squibb (BMS) may not have been successful in adding a new cancer indication to its label, it could probably gain further hold of the squamous cell carcinoma of the head and neck (SCCHN) market.

Sales of Vectibix, introduced in September, were reportedly $39 million in the fourth quarter. The blockbuster status predicted by many analysts, however, hinges on Vectibix being approved as a first-line therapy for mCRC patients. Currently, Vectibix is approved as a third-line treatment for patients with EGFr-expressing mCRC.

Erbitux is indicated for the treatment of EGFR-expressing mCRC in combination with irinotecan for patients who are refractory to irinotecan-based chemotherapy, and as a single agent for patients who are intolerant to irinotecan-based therapy.

Amgen stopped Vectibix treatment in the phase III evaluation of the drug in combination with standard chemotherapy and Avastin for the treatment of first-line metastatic mCRC. Avastin is approved for first- and second-line treatment of mCRC but targets the vascular endothelial growth factor (VEGF) receptor. Amgen believed that the combination of two drugs targeting different molecular pathways known to contribute to malignancy was interesting because multiple redundant pathways are evident in many types of cancer.

“We had hoped that adding Vectibix to the current US standard-of-care for patients newly-diagnosed with mCRC would improve outcomes without excessive added toxicity,” said Roger M. Perlmutter, MD, PhD, executive vice president of Research and Development at Amgen. “Unfortunately, it appears that adding Vectibix to Avastin, when used in combination with oxaliplatin- or irinotecan-based chemotherapy, increased toxicity, without improving efficacy.”

A preliminary review of data, done after the first 231 events (death or disease progression), revealed a statistically significant difference in progression-free survival and overall survival in favor of the control arm. Amgen’s reported continued evaluation of Vectibix as a single biologic combined with chemotherapy in phase III first- and second-line registrational trials will be critical in realizing the predicted value.

ImClone and BMS reported improved survival of patients with recurrent and/or metastatic SCCHN treated with a combination of Erbitux and chemotherapy in a phase III evaluation. “When ERBITUX was approved for head and neck cancer, it was not only hailed as the first new treatment for the disease in 45 years, but it was also the first drug approved to show a survival benefit in this population,” pointed out Martin Birkhofer, MD, vice president, Oncology Global Medical Affairs, BMS. “Just one year later, this study adds to the growing body of clinical evidence with Erbitux in these patients.”

Erbitux, ImClone’s only product, generated worldwide sales of $1.1 billion in 2006. It is already approved as a single agent against recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed. Also, in combination with radiation therapy, it is indicated for the treatment of locally or regionally advanced SCCHN.

The randomized, multi-center study studied more than 400 patients treated with Erbitux in combination either with cisplatin plus 5-fluorouracil (5-FU) or carboplatin plus 5-FU, compared to patients treated with cisplatin plus 5-FU or carboplatin plus 5-FU alone. While this trial took Erbitux one step forward in the treatment of SCCHN, it did not see a similar advance in pancreatic cancer. On April 10, the companies said that a phase III evaluation of Erbitux plus chemotherapy in patients with locally advanced unresectable or metastatic pancreatic cancer did not significantly improve overall survival. These results sent its shares down more than 7.5%.

The Southwest Oncology Group (SWOG) conducted the study. This open-label, randomized trial compared Erbitux plus gemcitabine to gemcitabine alone in more than 700 patients with pancreatic cancer in the first-line treatment setting. “This study was designed to examine the phase II results we previously observed for Erbitux in patients with pancreatic cancer,” stated Eric K. Rowinsky, MD, chief medical officer and senior vice president of ImClone Systems. “We still consider pancreatic cancer to be of the utmost priority and we intend to pursue additional evaluations with Erbitux including a pilot study of Erbitux and bevacizumab with or without gemcitabine, as well as our pipeline agents, to improve the outcome for patients with pancreatic cancer.”