Cell Therapeutics, Inc. announced the preliminary results of a phase II study of paclitaxel poliglumex (Opaxio) combined with temozolomide (TMZ) and radiotherapy (RT) in patients with newly diagnosed high-grade gliomas. The study was presented by Drs  Suriya Jeyapalan, Heinrich Elinzano and Mark Goldman, Assistant Professors of Neurology and Neurosurgery, Brown University Oncology Group at the 2010 Scientific Meeting of the Society of Neuro-Oncology in Montreal, Canada. The trial demonstrated a high rate of complete and partial responses (CR and PR) and, an encouragingly high rate of 6 month Progression-Free Survival (PFS).

“Standard therapy for patients with malignant brain tumours, like Glioblastoma Multiforme (GBM) employs a chemotherapy drug called temozolomide (TMZ) and radiation therapy (RT) and results in a PFS of 54 per cent at 6 months. Paclitaxel Poliglumex (PPX) is one of the most potent radiation sensitizers reported in the literature, selectively increasing tumour sensitivity to radiation up to 8 to 10 fold in animal models. This is the first clinical trial evaluating the safety and effectiveness of the addition of PPX to standard TMZ and radiation for patients with GBM,” said Dr Suriya Jeyapalan. “We were impressed by the high rate of complete and overall responses and importantly the durability of responses with the 6 month progression free survival being substantially longer than that reported with TMZ and RT alone. Given that 55 per cent of GBM tumours express MGMT, a gene responsible for inactivating the effectiveness of allkylating chemotherapy agents like TMZ, we are exploring whether or not PPX results in this trial were associated with anti-tumour activity in this otherwise TMZ resistant population which could lead to an accelerated clinical development path for PPX in MGMT+ GBM.”

In the current study, 25 patients were enrolled with confirmed high-grade glioma, 17 had GBM or gliosarcoma. Patients received PPX with TMZ and RT for six weeks. The main toxicity was grade 4 thrombocytopenia and neutropenia in 6/25 patients, 5 patients of which were receiving concomitant medications which are known to be associated with thrombocytopenia; only 1 of 14 patients not receiving these concomitant medication developed grade 4 thrombocytopenia with PPX in combination with TMZ. Among the 22 evaluable patients, the overall response rate was 45 per cent (10 of 22) with 27 per cent (6 of 22) of patients achieving a complete response. With a median follow up of 10.2 months, 76 per cent of patients remained free from disease progression or death (so called progression free survival or PFS) at 6 months.

“These results are quite provocative when considering that standard of care with TMZ and RT results in a 6 month PFS of 54 per cent,” said Jack Singer, MD Chief Medical Officer at CTI. “Given the high rate of response and durable PFS observed in this trial and the role of MGMT in conferring resistance to TMZ in more than half of GBM patients treated with the standard of care regimen (TMZ+RT) it is important to investigate whether PPX is able to bypass MGMT resistance as this could identify a genomically targeted population of patients with GBM for which PPX could provide meaningful durable responses and a potential additional accelerated route to approval.”

Epigenetic silencing of MGMT confers sensitivity of GBM tumours to alkylating agents like TMZ. Unfortunately almost 55 per cent of GBM tumours express MGMT, an enzyme that removes alkylating agents from DNA, thus preventing their DNA damaging effect. In an upcoming trial, The Brown University Oncology Group and Cell Therapeutics are planning to test PPX with radiation in the subset of patients with GBM and MGMT positive (non-silenced MGMT expression). This subset of patients, comprising 55 per cent of patients with GBM, is resistant to standard treatment with temozolomide. In contrast, PPX is not expected to be effected by MGMT expression. Therefore, the combination of PPX and RT may be more effective than standard TMZ/RT in patients with MGMT positive GBM.

Opaxio (paclitaxel poliglumex, CT-2103), which was formerly known as Xyotax, is an investigational, biologically enhanced, chemotherapeutic that links paclitaxel, the active ingredient in Taxol, to a biodegradable polyglutamate polymer, which results in a new chemical entity. When bound to the polymer, the chemotherapy is rendered inactive, potentially sparing normal tissue's exposure to high levels of unbound, active chemotherapy and its associated toxicities. Blood vessels in tumour tissue, unlike blood vessels in normal tissue, are porous to molecules like polyglutamate. Based on preclinical studies, it appears that OPAXIO is preferentially distributed to tumours due to their leaky blood vessels and trapped in the tumour bed allowing significantly more of the dose of chemotherapy to localize in the tumour than with standard paclitaxel. Once inside the tumour cell, enzymes metabolize the protein polymer, releasing the paclitaxel chemotherapy.

Headquartered in Seattle, CTI is a biopharmaceutical company committed to developing an integrated portfolio of oncology products aimed at making cancer more treatable.