Hana Biosciences announced today the clinical trial initiation of PT-523 to evaluate this compound as a single agent in relapsed non-small cell lung cancer (NSCLC). Lung cancer continues to carry the poorest prognosis of cancer, with a five-year survival rate of just 10 -15 per cent.
Lung cancer is the leading cause of cancer deaths in the US and worldwide. According to the American Cancer Society, over 173,000 new cases and 160,000 deaths were reported in the US alone in 2004. Non-small cell lung cancer accounts for about 80 per cent of all incidence of lung cancer. Non-small cell lung cancer is a group of lung cancers that includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.
PT-523 is a potentially exciting anticancer product because it works to an established and proven mechanism of action, overcoming resistance typically associated with this class of therapies and selectively binds to the key target enzyme.
The compound belongs to a novel, non-classical antifolate class that is a water-soluble, nonpolyglutamatable analogue of aminopterin. Potential advantages of PT-523 include increased targeting to tumour cells, better tolerability and a superior resistance profile over existing therapies.
PT-523 is 10-fold more efficiently transported by the membrane-bound transporter RFC into cells, 10-fold more tightly bound to the target enzyme, DHFR, and 10 to 100-fold more efficacious in a wide variety of tumour cell lines and animal models compared to methotrexate (MTX). PT-523 has also demonstrated efficacy in MTX resistant tumour models.
The new study will focus specifically on relapsed non-small cell lung cancer patients using a more common dosing schedule for lung cancer treatment. The Phase I component of the new study is a multi-centre, multi-national trial, which will first determine the dose, safety, tolerability, pharmacokinetics and preliminary efficacy of PT-523 in NSCLC patients (second and third line patients).
The Phase II component will utilise the maximally tolerated dose (MTD) in the same schedule, with the primary efficacy endpoint being overall survival. Secondary endpoints will include time-to-progression (TTP), progression-free survival (PFS), response rate (RR), and safety/tolerability.
The trial is expected to enrol between 80-120 patients over the next 12 to 15 months. Several leading clinical research sites in the US and Eastern Europe are expected to participate in the trial.
"With five year overall survival currently at 10-15 per cent, improving the standard of care for non-small lung cancer patients is an important priority for the oncology community," said Ravi Salgia, one of the lead investigators on the new study.
>Hana is planning trials with PT-523 in gynaecologic cancers and lymphoid leukaemias to see if the compound expresses the same anticancer properties.
At the moment surgery, chemotherapy, and radiation are typically used to treat lung cancer. The best treatment option is determined based on the type and stage of lung cancer, and the patient's performance status.
However, one of the emerging areas of treatment which s shown positive results are the Epidermal Growth Factor Receptor (EGFR) Blockade Agents. EGFR is often over-expressed on malignant cells, including 40 to 80 per cent of patients with non-small cell lung cancers (NSCLC).
The consequence of over-expression of EGFR in tumours is an uncontrolled signal transduction through the receptor, which leads to increased proliferation, tumour growth, and metastasis. This understanding has lead to the hypothesis that blocking EGFR can stop the growth of lung cancers.
Iressa was approved in May 2003 to treat advanced cases of non-small cell lung cancer (NSCLC). Iressa inhibits tumour cell growth by interfering with the EGFR enzyme tyrosine kinase. Early studies demonstrated that a few patients with lung cancer who had received previous treatments had a decrease in the size of their tumours when given Iressa alone and in combination with other chemotherapy drugs.
Cetuximab is another EGFR blockage agent under investigation. Cetuximab is a monoclonal antibody that competes with EGF for binding to its receptor. It has shown anti-tumour effect when used alone and in combination with chemotherapy and radiation. Further clinical trials are in progress.