Sagar Lonial, MD
June 8, 2012
CHICAGO – The investigational oral proteasome inhibitor MLN9708 showed hints of promise in multiple myeloma patients who are relapsed or refractory to treatment, investigators in a small phase I study reported here.
Six of the 58 patients with multiple myeloma achieved at least an objective response, including one person who was found to have a stringent complete response, said Sagar Lonial, MD, of the Winship Cancer Institute at Emory University in Atlanta. That individual was naive to proteasome therapy and was a member of the study's expansion cohort.
"Preliminary data from this study suggest clinical activity in heavily pretreated relapsed and/or refractory multiple myeloma patients," Loniol said at the annual meeting of the American Society of Clinical Oncology.
He also said one patient achieved a near-complete response and another had a very good partial response. Overall, 32 patients achieved a stable disease state that has been durable for at least 17.3 months, he said.
Lonial noted that proteasome inhibition as an anticancer strategy has been validated with the first-in-class agent bortezomib (Velcade). "MLN9708 is an orally bioavailable potent, reversible specific inhibitor of the 20S proteasome," he said. "It is the first oral proteasome to enter clinical investigation in multiple myeloma."
In the phase I dose escalation and safety trial, groups of patients were tested at various doses of MLN9708 – ranging from 0.24 mg/m2 to 2.23 mg/m2 -- until the maximum tolerated dose could be established.
Adult patients with performance status of 0-2 were eligible for the trial if they had progressed following treatment with bortezomib; thalidomide or lenalidomide (Revlimid); or corticosteroids.
The researchers have enrolled 58 patients in the study – 26 in the dose-ranging study and 28 in the expansion cohorts. The median age of the patients was 65; 52% were men; 90% were white; and the median time since multiple myeloma diagnosis was 4.8 years. They had a median of four cycles of therapy – although one patient had 27 cycles, Loniol said.
At the data cutoff point on March 27, 2012, there were eight patients who remained on study.
Although all the patients in both the dose escalation study and the expansion cohort experienced some adverse events, none of the patients in the dose escalation left the study as a result. However, 12% of the patients in the expansion study discontinued the trial due to adverse events.
Those events included one case each of thrombocytopenia, pulmonary hypertension, pneumonia, orthostatic hypotension, and pruritic rash. One patient developed spinal cord compression due to progressive disease during the first cycle of treatment, and one patient developed bone pain in the third cycle of treatment that also required removal from the trial.
Lonial said 51 patients were evaluable for response. The study established 2.0 mg/kg as the maximum tolerated dose. "Oral MLN9708 generally was well tolerated," he said, noting especially that peripheral neuropathy was infrequent and mild, with no grade 3 or grade 4 peripheral neuropathy observed.
Irene Ghobrial, MD, assistant professor of medicine at the Dana Farber Cancer Institute/Harvard Medical School, Boston, said it was likely that when MLN9708 was combined with other drugs it would prove to be useful in treating patients with multiple myeloma.
"This agent is convenient to take and appears to have less toxicity than other agents we have now," she said. She predicted that it may be useful in maintenance therapy among high-risk multiple myeloma patients. "It is oral and it has fewer side effects, so this may be an area where we can use it,"said Ghobrial, who was selected to discuss the study at the presentation.
Lonial disclosed commercial interests with Bristol-Myers Squibb, Celgene, Merck, Millennium, Novartis and Onyx. Co-authors disclosed commercial interests with Celgene, Millennium, Ortho Biotech, ARIAD, Novartis, Sanofi, Deciphera, Genentech, Incyte, Onyx and Johnson & Johnson. Co-authors include employees of Millennium.
Ghobrial disclosed commercial interests with Novartis.
Original article can be found at: http://www.medpagetoday.com/MeetingCoverage/ASCO/33156