Mifamurtide in metastatic and recurrent osteosarcoma: A patient access study with pharmacokinetic, pharmacodynamic, and safety assessments

Abstract

Purpose This non-randomized, patient-access protocol, assessed both safety and efficacy outcomes following liposomal muramyl –tripeptide-phosphatidylethanolamine (L-MTP-PE; mifamurtide) in patients with high-risk, recurrent and/or metastatic osteosarcoma. Methods Patients received mifamurtide 2 mg/m2 intravenously twice-weekly ×12 weeks, then weekly ×24 weeks with and without chemotherapy. Serum concentration-time profiles were collected. Adverse events within 24 hours of drug administration were classified as infusion-related adverse events (IRAE); other AEs and overall survival (OS) were assessed. Results The study began therapy in January 2008; the last patient completed therapy in October 2012. 205 patients were enrolled; median age was 16.5 years and 143/204 (72%) had active disease. Mifamurtide serum concentrations declined rapidly in the first 30 minutes post-infusion, then in a loglinear manner 2–6 hours post-dose; t1/2 was 2 hours. There were no readily apparent relationships between age and BSA-normalized clearance, half-life, or pharmacodynamic effects, supporting the dose of 2 mg/m2 mifamurtide across the age range. Patients reported 3,415 IRAE after 7,122 mifamurtide infusions. These were very rarely grade 3 or 4 and most commonly included chills+fever or headache+fatigue symptom clusters. One and two year OS was 70.6% and 41.4%. Patients with initial metastatic disease or progression approximated by within 9 months of diagnosis (N=40) had similar 2-year OS (38.8%) as the entire cohort (41.4%) Conclusions Mifamurtide had a manageable safety profile; PK/PD of mifamurtide in this patient access study was consistent with prior studies. Two-year OS was 41.4%. A randomized clinical trial would be required to definitively determine impact on patient outcomes.

Pediatric Malignant Bone Tumors: A Review and Update on Current Challenges, and Emerging Drug Targets

“…This agent is currently approved for use in non-metastatic osteosarcoma in Europe, Mexico, South Korea, Switzerland, and Israel. 54 Monoclonal antibody therapy against the OS tumor antigen, GD2, is a new emerging therapy that will be investigated by the Children's Oncology Group. GD2 is a surface glycolipid that is expressed at high levels in osteosarcomas.…”

Advances in the management of osteosarcoma

“…Results from the metastatic cohort of INT0133 pointed in the same direction as in non-metastatic patients but were not statistically significant 49 . Come 2016, there is additional evidence that L-MTP-PE has a favorable safety profile: a patient access study of 200 patients reported 3,679 infusion-related adverse events after 7,482 infusions, commonly chills, fever, headache, and fatigue, but only rarely severe 50 . However, there have been no further trials which shed more light upon the potential efficacy of the drug, so uncertainties remain regarding its potential role.…”

Malignant Pediatric Bone Tumors - Treatment & Management

“…An access study (MTP-OS-403, NCT00631631) (Anderson et al 2014a ) for MTP in patients with relapsed and/or recurrent osteosarcoma was done after initial approval by the European Medical Agency and at the request of the US Food and Drug Administration. This study also helped better defi ne pharmacodynamics, pharmacokinetics, and safety profi le of this drug in osteosarcoma.…”