Millennium's antibody-chemotherapeutic shows promise

Related tags Prostate cancer Cancer

Millenium Pharmaceuticals has announced final results from a
clinical trial of MLN2704, a novel antibody intended for the
chemotherapeutic treatment of advanced hormone-refractory prostate

There is currently a tremendous unmet medical need for treating prostate cancer, particularly for end-stage or androgen-independent prostate cancer for which therapeutic options are limited. MLN2704 is composed of a deimmunized monoclonal antibody (MLN591) directed at prostate specific membrane antigen (PSMA) conjugated to the chemotherapeutic agent DM1. MLN2704 binds to PSMA, which is rapidly internalised into the cell delivering a lethal dose of chemotherapy directly to prostate cancer cells.

Unlike the enzyme PSA which circulates in the blood, PSMA is a protein expressed on the cell surface of virtually all prostate cancer cells and its abundance on the cell surface increases as the disease progresses and becomes refractory to hormonal therapy. PSMA has little expression in normal tissues.

The single ascending dose phase I study of MLN2704, led by Howard Scher at Memorial Sloan-Kettering, New York and Mario Eisenberger at Johns Hopkins Oncology Center, Maryland enrolled 23 patients and examined the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics and immunogenicity of MLN2704. Patients received MLN2704 at doses ranging from 18 to 343mg/m2.

Responses in patients with measurable disease were evaluated based on the RECIST (Response Evaluation Criteria In Solid Tumors) criteria and confirmed four to six weeks after the first documentation of a complete or partial response. In addition, anti-tumour activity was evaluated based on a sustained PSA decline of at least 50 percent confirmed by two separate measurements at least four weeks apart. Dose escalation continued if no dose- limiting toxicity was observed.

The findings from this first in human MLN2704 single ascending dose trial indicated the molecule was well tolerated and produced sustained anti-tumour activity, including one patient who achieved a durable partial response in measurable disease for 11 months, as well as a sustained prostate specific antigen (PSA) decline of more than 50 per cent.

One additional patient, treated with a 343mg/m2 dose, achieved a PSA decline of more than 50 per cent that persisted for 24 weeks. Four other patients achieved stable disease.

Toxicities greater than grade three occurred in three patients including an episode of uncomplicated febrile neutropenia with lymphopenia and leukopenia, lymphopenia, and a transient grade three elevation in hepatic transaminases. No grade four toxicities were observed and no immunogenicity was observed despite repeat dosing.

"We are encouraged by these findings with MLN2704 in prostate cancer, and we are continuing to assess the dose and schedule,"​ said David Schenkein, senior vice president, clinical research at Millennium.

"These results allow us to continue to pursue this area of unmet medical need, and we are hopeful that further development can lead to new therapeutic options for patients with hormone-refractory prostate cancer."

According to the American Cancer Society, this year approximately 230,110 new cases of prostate cancer will be diagnosed in the United States and approximately 29,900 men will die of this disease. The five-year survival rate of men with prostate cancer is 98 percent with this percentage jumping to 100 percent if the cancer is found before it metastasises (spreads to another area of the body). Once the tumour spreads beyond the primary tumour, the five-year survival rate drops to 34 per cent.

The exact cause of prostate cancer is not yet known; however, scientists have identified certain risk factors, including family history of the disease, age, diet and race.

Related topics Preclinical Research

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