Molecular Medicine Israel

Clinical Trial Confirms Potential of Candidate Antimyeloma Drug

The candidate drug daratumumab, which is a monoclonal antibody that targets the cell surface molecule CD38 (cluster of differentiation 38), was shown to be a safe and effective treatment for multiple myeloma in a combined phase I/II clinical trial.

CD38 is a 45 kDa, type II transmembrane glycoprotein that associates with cell-surface receptors in lipid rafts, regulates cytoplasmic calcium ion flux, and mediates signal transduction in lymphoid and myeloid cells. CD38 is highly and uniformly expressed on myeloma cells and is expressed at relatively low levels on normal lymphoid and myeloid cells and in some tissues of nonhematopoietic origin, which makes it a potential target in the treatment of myeloma.

Daratumumab (HuMax-CD38, Genmab), a human IgG1kappa monoclonal antibody, binds to a unique CD38 epitope. Preclinical studies showed that daratumumab induced target-cell killing of CD38-expressing tumor cells by means of multiple mechanisms, including complement-mediated and antibody-dependent cell-mediated cytotoxic effects, antibody-dependent cellular phagocytosis, apoptosis, and to a lesser extent, inhibition of the enzymatic activity of CD38. The anti-myeloma activity of daratumumab in preclinical studies prompted the initiation of a phase I/II study involving patients with relapsed myeloma or relapsed and refractory myeloma.

Investigators at the Dana-Farber Harvard Cancer Center (Boston, MA, USA) conducted the phase I/II study with a group of multiple myeloma patients who had received at least two prior lines of therapy and whose disease had relapsed and no longer responded to treatment. Following an initial phase in which the dose of the drug was gradually increased, 72 patients were enrolled in the second phase, in which two doses were tested at different administration schedules – weekly, twice monthly, and monthly – for up to two years.

Results published in the August 26, 2015, online edition of the New England Journal of Medicinerevealed that the overall response rate was 36% in the cohort that received 16 milligrams per kilogram (15 patients had a partial response or better, including two with a complete response and two with a very good partial response) and 10% in the cohort that received eight milligrams per kilogram (three had a partial response). In the cohort that received 16 milligrams per kilogram, the median progression-free survival was 5.6 months, and 65% of the patients who had a response did not have progression at 12 months.

Reactions to the drug in the phase II trial were mild with no dose-dependent adverse events. The most common adverse events in about 5% of patients were pneumonia and thrombocytopenia.

“As a single-agent therapy, daratumumab showed significant promise against difficult-to-treat disease in our patients with advanced myeloma and who have few other therapeutic options,” said senior author Dr. Paul Richardson, professor of medicine at the Dana-Farber Harvard Cancer Center. “Because it targets a key receptor and works through different mechanisms than other available agents, it clearly has merited comprehensive testing in larger clinical trials. Preliminary results from these studies have been very encouraging.”

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