title: Phase I study of safety and pharmacokinetics of the anti-MUC16 antibody-drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer or unresectable pancreatic cancer.
abstract: MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody-drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE).
  
  
  
  This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3-3.2 mg/kg) or weekly (Q1W, 0.8-1.6 mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken.
  
  
  
  Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC.
  
  
  
  DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required.
  
  
  
  NCT01335958.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston joyce_liu@dfci.harvard.edu.
authors: J F
authors: JF
authors: Liu
authors: Division of Gynecologic Oncology, Stephenson Oklahoma Cancer Center at the University of Oklahoma Health Sciences Center, Oklahoma City.
authors: K N
authors: KN
authors: Moore
authors: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.
authors: M J
authors: MJ
authors: Birrer
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston.|Department of Oncology, New England Cancer Care Specialists, Kennebunk.
authors: S
authors: S
authors: Berlin
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston.
authors: U A
authors: UA
authors: Matulonis
authors: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville.
authors: J R
authors: JR
authors: Infante
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston.
authors: B
authors: B
authors: Wolpin
authors: Early Development, Genentech, South San Francisco, USA.
authors: K A
authors: KA
authors: Poon
authors: Early Development, Genentech, South San Francisco, USA.
authors: R
authors: R
authors: Firestein
authors: Early Development, Genentech, South San Francisco, USA.
authors: J
authors: J
authors: Xu
authors: Early Development, Genentech, South San Francisco, USA.
authors: R
authors: R
authors: Kahn
authors: Early Development, Genentech, South San Francisco, USA.
authors: Y
authors: Y
authors: Wang
authors: Early Development, Genentech, South San Francisco, USA.
authors: K
authors: K
authors: Wood
authors: Early Development, Genentech, South San Francisco, USA.
authors: W C
authors: WC
authors: Darbonne
authors: Early Development, Genentech, South San Francisco, USA.
authors: M R
authors: MR
authors: Lackner
authors: Early Development, Genentech, South San Francisco, USA.
authors: S K
authors: SK
authors: Kelley
authors: Early Development, Genentech, South San Francisco, USA.
authors: X
authors: X
authors: Lu
authors: Early Development, Genentech, South San Francisco, USA.
authors: Y J
authors: YJ
authors: Choi
authors: Early Development, Genentech, South San Francisco, USA.
authors: D
authors: D
authors: Maslyar
authors: Early Development, Genentech, South San Francisco, USA.
authors: E W
authors: EW
authors: Humke
authors: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville.
authors: H A
authors: HA
authors: Burris
mesh_terms: D000328:Adult; D000368:Aged; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage* / Q000009:adverse effects; D018394:CA-125 Antigen / Q000235:genetics / Q000276:immunology; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000888:Antibodies, Anti-Idiotypic; D018394:CA-125 Antigen; C000625656:DMUC5754A; D018796:Immunoconjugates; C451759:MUC16 protein, human; D008565:Membrane Proteins
keywords: DMUC5754a; MUC16; antibody–drug conjugate; ovarian cancer; pancreatic cancer