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New Pancreatic Cancer Treatment Shows Promise in Phase III Study
Positive results have been reported from a phase III study of MM-398 (irinotecan liposome injection, Merrimack Pharmaceuticals) in combination with 5-fluorouracil (5-FU) and leucovorin for the treatment of patients with metastatic pancreatic cancer who had received gemcitabine-based therapy.
The combination of MM-398 with 5-FU and leucovorin achieved overall survival of 6.1 months compared with 4.2 months in the control arm of 5-FU and leucovorin alone. This difference was statistically significant (P = 0.012), with a corresponding hazard ratio (HR) of 0.67.
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 greater than 2% difference between the combination arm and the control arm.
The phase III study also examined MM-398 as monotherapy. MM-398 alone achieved a 4.9-month median overall survival, but did not demonstrate 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 more severe adverse events with the MM-398 monotherapy dose and treatment schedule compared with patients treated with the combination of MM-398 with 5-FU and leucovorin.
The findings from this study will be presented at the European Society for Medical Oncology (ESMO) 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 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 against the control arm on the primary endpoint of overall survival. Patients were enrolled 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. It has demonstrated extended circulation in comparison to 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 an investigational agent that 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 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. The FDA has granted MM-398 an “orphan drug” designation in metastatic pancreatic cancer.
In the U.S., approximately 40,000 people die from pancreatic cancer annually, making it the fourth most common cause of cancer death. The 1-year and 5-year mortality rates are 73% and 94%, respectively.
Because the signs and symptoms of pancreatic cancer may not appear until the disease has metastasized, most patients are not candidates for surgery and receive chemotherapy as the mainstay of their treatment. There is no consensus on the standard of care for patients with metastatic pancreatic cancer who were previously treated with a gemcitabine-based therapy.
Source: Merrimack Pharmaceuticals; June 5, 2014.