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Combo Therapy Improves Survival in Pancreatic Cancer Patients

Phase III trial evaluates irinotecan liposome injection

The results from a new phase III study have shown that the combination of MM-398 (irinotecan liposome injection, Merrimack Pharmaceuticals) with 5-fluorouracil (5-FU) and leucovorin achieved overall survival of 6.1 months — a 1.9-month improvement over the 4.2-month survival demonstrated by the control arm of 5-FU and leucovorin alone — in patients with metastatic pancreatic cancer who had received gemcitabine-based therapy.

The primary log-rank analysis of overall survival was statistically significant (P = 0.012), with a corresponding hazard ratio (HR) of 0.67. A statistically significant advantage for progression-free survival was also observed in the combination arm.

The most common grade-3 or higher adverse events in the combination arm were neutropenia (14.5%), fatigue (13.7%), diarrhea (12.8%), and vomiting (11.1%). Sepsis (3.4%) was the only serious life-threatening event that occurred with a more than 2% difference between the combination arm and the control arm.

The study also evaluated MM-398 in a monotherapy regimen. The investigational treatment had a 4.9-month median overall survival as monotherapy but did not achieve a statistically significant survival advantage compared with the 4.2 months in the control arm. The HR for overall survival was 0.99, with a corresponding P value of 0.942. In general, patients experienced a higher level of adverse events with the MM-398 monotherapy dose and treatment schedule compared with patients who received the combination of MM-398 with 5-FU and leucovorin.

The study results will be presented at the European Society for Medical Oncology World Conference on Gastrointestinal Cancer, to be held June 25–28 in Barcelona, Spain. A new drug application for the MM-398 combination regimen is expected to be submitted to the FDA in 2014.

The NAPOLI-1 (NAnoliPOsomaL Irinotecan-1) trial was a randomized, open-label, phase III study in patients with metastatic pancreatic cancer who had received prior gemcitabine-based therapy. The study evaluated two MM-398 regimens: 80 mg/m2 combined with 5-FU and leucovorin every 2 weeks, and 120 mg/m2 as monotherapy every 3 weeks. Each treatment arm was compared with a control arm of 5-FU and leucovorin. A total of 417 patients were randomly assigned to the three treatment groups. Each MM-398 regimen was compared with the control arm on the primary endpoint of overall survival. The patients were enrolled at sites in North America, South America, Europe, Asia, and Australia.

MM-398 (irinotecan liposome injection), also known as nal-IRI, is a nanoliposomal encapsulation of the chemotherapeutic agent irinotecan. The drug has demonstrated extended circulation in comparison with free irinotecan in the clinical setting. The activated form of irinotecan is SN-38, which functions by inhibiting topoisomerase I (an essential enzyme involved in DNA transcription and replication) and by promoting cell death.

MM-398 is also being evaluated in an ongoing phase II study in patients with metastatic colorectal cancer and in phase I studies in patients with Ewing's sarcoma and glioma. An additional phase I clinical trial is assessing a potential companion diagnostic for MM-398 in patients with multiple cancer types to determine which patients are most likely to benefit from treatment with the drug.

MM-398 is not approved for any indication by the FDA or any other regulatory agency.

Source: Merrimack Pharmaceuticals; May 1, 2014.

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