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

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.

An Immune-Related lncRNA Signature to Predict the Biochemical Recurrence and Immune Landscape in Prostate Cancer

“…Generally, prostate cancer is considered poorly immunogenic. 58 To date, the ICB has yet to be FDA-approved for the management of prostate cancer, and the results of ICB clinical trials in prostate cancer have not been satisfactory. Phase III trials of CTLA-4 and PD-1 blockers in prostate cancer patients did not observe any difference in overall survival compared with placebo.…”

Targeting signaling pathways in prostate cancer: mechanisms and clinical trials

“… 319 , 320 The first clinical trial of MEDI3726 observed a high incidence of treatment-related adverse events. 321 A phase 2 clinical trial demonstrated that PSMA-MMAE showed some activity with regards to PSA decline and circulating tumor cell reduction in patients with mCRPC, but it also included significant treatment-related toxicities, such as neutropenia and neuropathy. 317 Interestingly, the phase 2 clinical trial of BIND-014 (a novel PSMA-ADC) in patients with chemotherapy-naive mCRPC suggest that BIND-014 is well tolerated and patients are likely to benefit from the treatment.…”

Drug resistance in metastatic castration-resistant prostate cancer: an update on the status quo

“…A Phase II trial (NCT01695044) was performed by Petrylak et al [147] , a Phase I trial (NCT02991911) by de Bono et al [148] , and a Phase I/II multiple escalating dose trial by Milowsky et al [149] tested different PSMA-ADCs. The different trials showed that, although these drug conjugates had some activity in mCRPC, their effect was accompanied by significant adverse events (such as neutropenia and neuropathy), which led to the discontinuation of some of these treatments.…”