Phase I Study of MEDI3726: A Prostate-Specific Membrane Antigen-Targeted Antibody-Drug Conjugate, in Patients with mCRPC after Failure of Abiraterone or Enzalutamide

  • Clin Cancer Res. 2021 Jul 1;27(13):3602-3609. doi: 10.1158/1078-0432.CCR-20-4528.
Johann S de Bono  1 ,  Mark T Fleming  2 ,  Judy S Wang  3 ,  Richard Cathomas  4 ,  Manuel Selvi Miralles  5 ,  John Bothos  5 ,  Mary Jane Hinrichs  5 ,  Qu Zhang  5 ,  Peng He  5 ,  Marna Williams  5 ,  Anton I Rosenbaum  6 ,  Meina Liang  6 ,  Kapil Vashisht  5 ,  Song Cho  5 ,  Pablo Martinez  5 ,  Daniel P Petrylak  7
Affiliations
  • 1. Institute of Cancer Research, Surrey, United Kingdom. [email protected].
  • 2. Virginia Oncology Associates, Norfolk, Virginia.
  • 3. Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Florida.
  • 4. Kantonsspital Graubünden, Chur, Switzerland.
  • 5. AstraZeneca, Gaithersburg, Maryland.
  • 6. AstraZeneca, South San Francisco, California.
  • 7. Yale Comprehensive Cancer Center, New Haven, Connecticut.
PMID: 33795255 DOI: 10.1158/1078-0432.CCR-20-4528
Abstract

Purpose: MEDI3726 is an antibody-drug conjugate targeting the prostate-specific membrane antigen and carrying a pyrrolobenzodiazepine warhead. This phase I study evaluated MEDI3726 monotherapy in patients with metastatic castration-resistant prostate Cancer after disease progression on abiraterone and/or enzalutamide and taxane-based chemotherapy.

Patients and methods: MEDI3726 was administered at 0.015-0.3 mg/kg intravenously every 3 weeks until disease progression/unacceptable toxicity. The primary objective was to assess safety, dose-limiting toxicities (DLT), and MTD/maximum administered dose (MAD). Secondary objectives included assessment of antitumor activity, pharmacokinetics, and immunogenicity. The main efficacy endpoint was composite response, defined as confirmed response by RECIST v1.1, and/or PSA decrease of ≥50% after ≥12 weeks, and/or decrease from ≥5 to <5 circulating tumor cells/7.5 mL blood.

Results: Between February 1, 2017 and November 13, 2019, 33 patients received MEDI3726. By the data cutoff (January 17, 2020), treatment-related adverse events (TRAE) occurred in 30 patients (90.9%), primarily skin toxicities and effusions. Grade 3/4 TRAEs occurred in 15 patients (45.5%). Eleven patients (33.3%) discontinued because of TRAEs. There were no treatment-related deaths. One patient receiving 0.3 mg/kg had a DLT of grade 3 thrombocytopenia. The MTD was not identified; the MAD was 0.3 mg/kg. The composite response rate was 4/33 (12.1%). MEDI3726 had nonlinear pharmacokinetics with a short half-life (0.3-1.8 days). The prevalence of antidrug antibodies was 3/32 (9.4%), and the incidence was 13/32 (40.6%).

Conclusions: Following dose escalation, no MTD was identified. Clinical responses occurred at higher doses, but were not durable as patients had to discontinue treatment due to TRAEs.

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