Phase I Study of MEDI3726: A Prostate-Specific Membrane Antigen-Targeted Antibody-Drug Conjugate, in Patients with mCRPC after Failure of Abiraterone or Enzalutamide.
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Embargo End Date
ICR Authors
Authors
de Bono, JS
Fleming, MT
Wang, JS
Cathomas, R
Miralles, MS
Bothos, J
Hinrichs, MJ
Zhang, Q
He, P
Williams, M
Rosenbaum, AI
Liang, M
Vashisht, K
Cho, S
Martinez, P
Petrylak, DP
Fleming, MT
Wang, JS
Cathomas, R
Miralles, MS
Bothos, J
Hinrichs, MJ
Zhang, Q
He, P
Williams, M
Rosenbaum, AI
Liang, M
Vashisht, K
Cho, S
Martinez, P
Petrylak, DP
Document Type
Journal Article
Date
2021-07-01
Date Accepted
2021-03-29
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.
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2021
Rights
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Collections
Research Team
Prostate Cancer Targeted Therapy Group
Prostate Cancer Targeted Therapy Group
Prostate Cancer Targeted Therapy Group