title: Mifamurtide in metastatic and recurrent osteosarcoma: a patient access study with pharmacokinetic, pharmacodynamic, and safety assessments.
abstract: OBJECTIVE
  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.
authors.affiliation: University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: P M
authors.initials: PM
authors.lastname: Anderson
authors.forename: P
authors.initials: P
authors.lastname: Meyers
authors.forename: E
authors.initials: E
authors.lastname: Kleinerman
authors.forename: K
authors.initials: K
authors.lastname: Venkatakrishnan
authors.forename: D P
authors.initials: DP
authors.lastname: Hughes
authors.forename: C
authors.initials: C
authors.lastname: Herzog
authors.forename: W
authors.initials: W
authors.lastname: Huh
authors.forename: R
authors.initials: R
authors.lastname: Sutphin
authors.forename: Y M
authors.initials: YM
authors.lastname: Vyas
authors.forename: V
authors.initials: V
authors.lastname: Shen
authors.forename: A
authors.initials: A
authors.lastname: Warwick
authors.forename: N
authors.initials: N
authors.lastname: Yeager
authors.forename: C
authors.initials: C
authors.lastname: Oliva
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: A
authors.initials: A
authors.lastname: Chou
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D012516:Osteosarcoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011379:Prognosis; D012449:Safety; D015996:Survival Rate; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D007155:Immunologic Factors; D010714:Phosphatidylethanolamines; C037144:mifamurtide; D000119:Acetylmuramyl-Alanyl-Isoglutamine
keywords: L-MTP-PE; biologic therapy; macrophage activation; mifamurtide; osteosarcoma; pharmacokinetics