Allos Therapeutics, Inc. announced enrolment of the first patient in PROPEL, a pivotal multi-centre phase 2 study of the company's unique next generation antifolate PDX (pralatrexate) with vitamin B12 and folic acid supplementation in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).
"The initiation of this pivotal trial is an important milestone in the development of PDX and has the potential to be a significant driver of the company's future growth," said Paul L. Berns, president and chief executive officer. "Clinical experience to date suggests that PDX has the potential to provide meaningful therapeutic benefit to a difficult to treat, drug resistant patient population with high unmet medical need."
PROPEL (Pralatrexate in Patients with Relapsed Or Refractory PEripheral T-cell Lymphoma) is a Phase 2, international, multi-centre, open-label, single-arm study that will seek to enrol 100 evaluable patients with relapsed or refractory PTCL who have progressed after at least one prior treatment. Patients will receive 30 mg/m2 of PDX once every week for six weeks followed by one week of rest per cycle of treatment. The primary endpoint of the study is objective response rate (complete and partial response). Secondary endpoints include duration of response, progression-free survival and overall survival.
In August 2006, the company announced that it reached agreement with the US. Food and Drug Administration (FDA) under the Special Protocol Assessment process (SPA) on the design of this pivotal phase 2 trial. The SPA process allows for FDA evaluation of a clinical trial protocol intended to form the primary basis of an efficacy claim in support of a new drug application, and provides a binding agreement that the study design, including trial size, clinical endpoints and/or data analyses are acceptable to the FDA. The company currently anticipates that patient enrolment at approximately 35 centres in the US, Canada and Europe will take approximately 18 to 24 months to complete. Owen A. O'Connor, M.D., Ph.D., Head of the Laboratory of Experimental Therapeutics for Lymphoproliferative Malignancies, Lymphoma and Development Chemotherapy Services, Memorial Sloan-Kettering Cancer Centre, will serve as the international study chair.
Interim results from a Phase 1/2 study of PDX in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) and Hodgkin's disease, which is currently on-going at Memorial Sloan-Kettering Cancer Centre, demonstrated preliminary evidence of activity in patients with various subtypes of aggressive and chemotherapy resistant T-cell lymphoma. As reported at the 2005 American Society of Haematology Annual Meeting, four of seven evaluable patients with T-cell lymphoma achieved a complete response following treatment with PDX, despite having failed multiple prior therapies. The addition of vitamins to the treatment regimen appeared to successfully mitigate the previously established dose limiting toxicity of stomatitis.
PDX is a novel, small molecule chemotherapeutic agent that inhibits dihdrofolate reductase (DHFR), a folic acid (folate) dependent enzyme involved in the building of DNA and other processes. PDX was rationally designed for improved transport into tumour cells via the reduced folate carrier (RFC-1), and greater intracellular drug retention. These biochemical features, together with preclinical data in a variety of tumours, suggest that PDX has an enhanced potency and improved toxicity profile relative to methotrexate and other related DHFR inhibitors.
Peripheral T-cell lymphomas, or PTCLs, are a biologically diverse and uncommon group of blood cancers that account for approximately 10% to 15 per cent of all cases of non-Hodgkin's lymphoma, or about 6,700 patients annually. The average five year survival rate for PTCL patients is approximately 25%. There are currently no pharmaceutical agents approved for use in the treatment of relapsed or refractory PTCL.