title: Phase I Study of DMOT4039A, an Antibody-Drug Conjugate Targeting Mesothelin, in Patients with Unresectable Pancreatic or Platinum-Resistant Ovarian Cancer.
abstract: DMOT4039A, a humanized anti-mesothelin mAb conjugated to the antimitotic agent monomethyl auristatin E (MMAE), was given to patients with pancreatic and ovarian cancer every 3 weeks (0.2-2.8 mg/kg; q3w) or weekly (0.8-1.2 mg/kg). A 3+3 design was used for dose escalation followed by expansion at the recommended phase II dose (RP2D) to evaluate safety and pharmacokinetics. Antitumor response was evaluated per RECIST 1.1 and serum CA19-9 or CA125 declines. Tumor mesothelin expression was determined by IHC. Seventy-one patients (40 pancreatic cancer; 31 ovarian cancer) were treated with DMOT4039A. For the q3w schedule (n = 54), the MTD and RP2D was 2.4 mg/kg, with dose-limiting toxicities of grade 3 hyperglycemia and grade 3 hypophosphatemia at 2.8 mg/kg. For the weekly schedule (n = 17), the maximum assessed dose was 1.2 mg/kg, with further dose escalations deferred because of toxicities limiting scheduled retreatment in later cycles, and therefore the RP2D level for the weekly regimen was determined to be 1 mg/kg. Across both schedules, the most common toxicities were gastrointestinal and constitutional. Treatment-related serious adverse events occurred in 6 patients; 4 patients continued treatment following dose reductions. Drug exposure as measured by antibody-conjugated MMAE and total antibody was generally dose proportional over all dose levels on both schedules. A total of 6 patients had confirmed partial responses (4 ovarian; 2 pancreatic) with DMOT4039A at 2.4 to 2.8 mg/kg i.v. q3w. DMOT4039A administered at doses up to 2.4 mg/kg q3w and 1.0 mg/kg weekly has a tolerable safety profile and antitumor activity in both pancreatic and ovarian cancer.
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine and Developmental Therapeutics Program, University of Colorado Cancer Center, Aurora, Colorado. colin.weekes@ucdenver.edu.
authors.forename: Colin D
authors.initials: CD
authors.lastname: Weekes
authors.affiliation: University Medical Center Groningen, University of Groningen, the Netherlands.
authors.forename: Laetitia E
authors.initials: LE
authors.lastname: Lamberts
authors.affiliation: Mayo Clinic, Scottsdale, Arizona.
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.affiliation: VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Johannes
authors.initials: J
authors.lastname: Voortman
authors.affiliation: Mayo Clinic, Rochester, New York.
authors.forename: Robert R
authors.initials: RR
authors.lastname: McWilliams
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine and Developmental Therapeutics Program, University of Colorado Cancer Center, Aurora, Colorado.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Diamond
authors.affiliation: University Medical Center Groningen, University of Groningen, the Netherlands.
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.affiliation: VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Henk M
authors.initials: HM
authors.lastname: Verheul
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine and Developmental Therapeutics Program, University of Colorado Cancer Center, Aurora, Colorado.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Lieu
authors.affiliation: Mayo Clinic, Jacksonville, Florida.
authors.forename: George P
authors.initials: GP
authors.lastname: Kim
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Yulei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Suzie J
authors.initials: SJ
authors.lastname: Scales
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Divya
authors.initials: D
authors.lastname: Samineni
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Flavia
authors.initials: F
authors.lastname: Brunstein
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: YounJeong
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Genentech Inc., South San Francisco, California.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Maslyar
authors.affiliation: Mayo Clinic, Jacksonville, Florida.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Colon-Otero
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D018450:Disease Progression; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D000090204:Mesothelin; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010984:Platinum / Q000627:therapeutic use; D019233:Retreatment; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D058851:GPI-Linked Proteins; D018796:Immunoconjugates; D010984:Platinum; D000090204:Mesothelin