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Early Data for New Akt Inhibitor Show Promise in Myeloma

Value-Based Care in Myeloma - Clinical Trials, Multiple Myeloma
Caroline Helwick

Perifosine, a novel Akt inhibitor, has performed robustly in early-phase trials and is expected to make a substantial impact in the treatment of relapsed and refractory multiple myeloma.

A phase 3 randomized trial is actively enrolling patients in the United States, Europe, Canada, Israel, and South Korea. The study has been granted a special protocol assessment from the US Food and Drug Administration (FDA), according to Paul G. Richardson, MD, Director, Jerome Lipper Center for Multiple Myeloma, Dana-Farber Cancer Center, and Associate Professor of Medicine, Harvard Medical School. “This means that if the trial achieves its primary end point, the FDA is committed to approving perifosine in combination for the treatment of relapsed myeloma,” Dr Richardson told Value-Based Care in Myeloma.

How Perifosine Works

Perifosine (Karyx Biopharmaceuticals, Inc) is an orally bioavailable alkylphospholipid. It is known to affect tumor proliferation and metastasis, and has a different spectrum of cytotoxicity than conventional chemotherapeutic agents. Preclinically, perifosine has shown activity in a number of myeloma cell lines, including those resistant to many antimyeloma drugs; of interest is that its activity correlates with the inhibition of both Akt and NF-ĸB, with activation of JNK, making it an attractive partner with bortezomib and other novel agents.

“Perifosine enhances bortezomib-induced cytotoxicity and augments the activity of lenalidomide and dexamethasone as well. By doing so in a noncross-resistant fashion, it is really an interesting compound to develop as an agent in combination with others to overcome drug resistance,” Dr Richardson said. “In our phase 1/2 trial, the combination of perifosine and bortezomib produced outcomes that were better than our traditional experience in relapsed and refractory myeloma. It was also well tolerated in a daily dosing schema.”

Phase 1/2 Studies Encouraging

Dr Richardson spearheaded a phase 1/2 study in which patients received perifosine daily plus bortezomib and dexamethasone in 21-day cycles for up to 8 cycles (Richardson PG, et al. J Clin Oncol. 2011;29:4243-4249). Patients responding or showing no signs of progressive disease could continue treatment. Maintenance therapy permitted patients with stable disease or better to use the weekly schedule of bortezomib (days 1 and 8). The phase 1 portion of the study determined that 50 mg daily of perifosine was the optimal dose for phase 2 testing with bortezomib at 1.3 mg/m2.

The trial included 84 patients with relapsed or refractory disease (median age, 64 years) who had received an average of 5 previous lines of treatment (all had received bortezomib, with a median of 2 lines; two thirds of the patients had stage III disease by Durie-Salmon criteria at diagnosis). In 73 response-evaluable patients, the overall response rate (complete, nearly complete, partial and minimal responses) was 41%. This included a 65% response rate among the bortezomib-relapsed patients and a 32% response rate among bortezomib-refractory patients.

Median Survival Exceeded 3 Years

Median progression-free survival (PFS) was 8.3 months for patients achieving a complete or partial response, 7.7 months for those with a minimal response, and 6.4 months for the overall population. Median overall survival (OS) was impressive at 37 months, 27.7 months, and 25 months, respectively.

Dr Richardson commented on the prolonged survival time for patients with relapsed/refractory disease. “This quality of survival data and at this level of [data] maturity is quite unusual,” he said.

For patients whose disease had relapsed but was not yet refractory to bortezomib, the results were also encouraging, with 8.8 months PFS and 30.4 months OS.

Toxicities proved manageable, especially with appropriate dose reductions and supportive care. Grade 3 and 4 adverse events included thrombocytopenia (23%), neutropenia (15%), anemia (14%), pneumonia (12%), musculoskeletal pain (11%), and bleeding (10%).

“Overall, we consider perifosine a promising agent for the treatment of relapsed myeloma. It is generally well tolerated, and appears active in combination, with the former being especially important, because if we can keep patients on treatment longer, they seem to do better,” Dr Richardson said.

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Last modified: May 20, 2015
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