Mifamurtide Study Demonstrates Improved Survival
IDM Pharma's Phase 3 mifamurtide (L-MTP-PE) clinical trial (INT-0133) is the largest study completed in this disease was a National Cancer Institute (NCI) funded cooperative group study conducted by the Children's Oncology Group (COG).
The COG's findings were based on long-term follow up of 662 patients with newly diagnosed non-metastatic osteosarcoma treated in the Phase 3 trial and demonstrated that the addition of L-MTP-PE to chemotherapy following surgery resulted in statistically superior Overall Survival (OS) the first stated aim of the study.
In the past two decades, there have been no treatment advances for patients with osteosarcoma, a rare and often fatal bone tumor that typically affects children and young adults.
"L-MTP-PE in combination with chemotherapy has demonstrated a significant long-term overall survival advantage in the largest Phase 3 clinical trial completed in patients with osteosarcoma," said Dr. Paul Meyers, vice chair, department of pediatrics at Memorial Sloan-Kettering Cancer Center and principal investigator of the Phase 3 trial. "These results are encouraging for children and young adults with osteosarcoma, considering the lack of progress for these patients in the last 20 years."
The JCO publication highlighting long-term follow up from this study formed the basis of the recent oral explanation to the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMEA), regarding the Marketing Authorization Application (MAA) for L-MTP-PE for the treatment of patients with non-metastatic, resectable osteosarcoma. Updated results from this study were previously presented at the Connective Tissue Oncology Society (CTOS) annual meeting in November 2007. In addition, the new JCO publication highlights the long-term OS data whereas a prior JCO publication in 2005 focused on an Event Free Survival (EFS) additional analysis.
"These findings of statistically superior overall survival in long-term patient follow-up validate the survival benefit offered by L-MTP-PE and underscore the desperate need for new treatments for osteosarcoma patients," said Timothy P. Walbert, president and chief executive officer, IDM Pharma. "We believe these findings were critical to the recent opinion from the Committee for Medicinal Products for Human Use in Europe and are a positive step toward bringing this important treatment to the European market and potentially gaining approval in the United States."
Study design and findings
The multicenter, open label, randomized, factorial, four parallel treatment group Phase 3 study was designed to evaluate the effects of patient outcome of the addition of L-MTP-PE to three-drug chemotherapy (cisplatin, doxorubicin, and methotrexate) or four-drug-chemotherapy (cisplatin, doxorubicin, methotrexate, and ifosfamide) in patients with newly diagnosed resectable osteosarcoma without metastatic disease.
Patients received one of four prospectively randomized treatments and all patients received identical cumulative doses of cisplatin, doxorubicin, and methotrexate and underwent definitive surgical resection of primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2x2 factorial design.
In the published analysis, the chemotherapy regimens without L-MTP-PE resulted in similar OS and EFS. Overall Survival after six years of follow-up in patients treated with chemotherapy and L-MTP-PE was 78%, compared to 70% in patients treated only with chemotherapy (p=0.03). The addition of L-MTP-PE to chemotherapy resulted in approximately 30% decrease in the risk of death. EFS, an additional analysis which includes the occurrence of secondary malignancies, after six years of follow-up in patients treated with chemotherapy and L-MTP-PE was 67% compared to 61% in patients treated only with chemotherapy (p=0.08).
Treatment with L-MTP-PE was generally well tolerated in all phases of study. Adverse events were mild to moderate in severity and included chills, fever, nausea, vomiting, myalgia, headache, tachycardia (fast heart rate), hypo- and hypertension, fatigue and shortness of breath, all of which are consistent events with the activation of monocytes and macrophages by L-MTP-PE and the flu-like symptoms that follow cytokine release. These side effects are readily prevented or treated with acetaminophen.