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

AbstractPURPOSE:
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/m(2) 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. Two hundred five patients were enrolled; median age was 16.0 years and 146/205 (71%) had active disease. Mifamurtide serum concentrations declined rapidly in the first 30 minutes post-infusion, then in a log-linear 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/m(2) mifamurtide across the age range. Patients reported 3,679 IRAE after 7,482 mifamurtide infusions. These were very rarely grade 3 or 4 and most commonly included chills + fever or headache + fatigue symptom clusters. One- and 2-year OS was 71.7% and 45.9%. Patients with initial metastatic disease or progression approximated by within 9 months of diagnosis (N = 40) had similar 2-year OS (39.9%) as the entire cohort (45.9%)
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 45.9%. A randomized clinical trial would be required to definitively determine impact on patient outcomes.
AuthorsP M Anderson, P Meyers, E Kleinerman, K Venkatakrishnan, D P Hughes, C Herzog, W Huh, R Sutphin, Y M Vyas, V Shen, A Warwick, N Yeager, C Oliva, B Wang, Y Liu, A Chou
JournalPediatric blood & cancer (Pediatr Blood Cancer) Vol. 61 Issue 2 Pg. 238-44 (Feb 2014) ISSN: 1545-5017 [Electronic] United States
PMID23997016 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2013 Wiley Periodicals, Inc.
Chemical References
  • Immunologic Factors
  • Phosphatidylethanolamines
  • Acetylmuramyl-Alanyl-Isoglutamine
  • mifamurtide
Topics
  • Acetylmuramyl-Alanyl-Isoglutamine (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)
  • Adolescent
  • Adult
  • Bone Neoplasms (drug therapy, mortality, pathology)
  • Child
  • Child, Preschool
  • Drug-Related Side Effects and Adverse Reactions
  • Female
  • Follow-Up Studies
  • Humans
  • Immunologic Factors (administration & dosage, pharmacokinetics, pharmacology)
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Metastasis
  • Neoplasm Recurrence, Local (drug therapy, mortality, pathology)
  • Osteosarcoma (drug therapy, mortality, pathology)
  • Phosphatidylethanolamines (administration & dosage, pharmacokinetics, pharmacology)
  • Prognosis
  • Safety
  • Survival Rate
  • Tissue Distribution
  • Young Adult

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