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Phase 1/2 multiple ascending dose trial of the prostate-specific membrane antigen-targeted antibody drug conjugate MLN2704 in metastatic castration-resistant prostate cancer.

ABSTRACT: This phase 1/2 study evaluated the dose-limiting toxicity and maximum tolerated dose of MLN2704, a humanized monoclonal antibody MLN591 targeting prostate-specific membrane antigen, linked to the maytansinoid DM1 in patients with progressive metastatic castration-resistant prostate cancer.A total of 62 patients received MLN2704 at ascending doses on 4 schedules: weekly (60, 84, 118, and 165mg/m2; 12 patients); every 2 weeks (120, 168, 236, and 330mg/m2; 15 patients); every 3 weeks (330 and 426mg/m2; 18 patients); and on days 1 and 15 of a 6-week schedule (6-week cycle, 330mg/m2; 17 patients). The primary efficacy endpoint was a sustained ?50% decline from baseline prostate-specific antigen (PSA) without evidence of disease progression. Toxicity, pharmacokinetics, immunogenicity, and antitumor activity were assessed.Neurotoxicity was dose-limiting. Overall, 44 patients (71%) exhibited peripheral neuropathy: 6 (10%) had grade 3/4. Neurotoxicity rates remained high despite increasing the dosing interval to 3 (13 of 14; one grade 3) and 6 weeks (16 of 17; three grade 3). MLN2704 pharmacokinetics were dose-linear. Rapid deconjugation of DM1 from the conjugated antibody was seen. In all, 5 patients (8%) experienced ?50% decline in PSA; 5 (8%) had PSA stabilization lasting?90 days. Only 2 of 35 patients on the 3- and 6-week schedules achieved a PSA decline of >50%.MLN2704 has limited activity in metastatic castration-resistant prostate cancer. Disulfide linker lability and rapid deconjugation lead to neurotoxicity and a narrow therapeutic window.

SUBMITTER: Milowsky MI

PROVIDER: S-EPMC5464417 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Phase 1/2 multiple ascending dose trial of the prostate-specific membrane antigen-targeted antibody drug conjugate MLN2704 in metastatic castration-resistant prostate cancer.

Milowsky Matthew I MI Galsky Matthew D MD Morris Michael J MJ Crona Daniel J DJ George Daniel J DJ Dreicer Robert R Tse Kin K Petruck Jesika J Webb Iain J IJ Bander Neil H NH Nanus David M DM Scher Howard I HI

Urologic oncology 20161017 12

<h4>Background</h4>This phase 1/2 study evaluated the dose-limiting toxicity and maximum tolerated dose of MLN2704, a humanized monoclonal antibody MLN591 targeting prostate-specific membrane antigen, linked to the maytansinoid DM1 in patients with progressive metastatic castration-resistant prostate cancer.<h4>Patients and methods</h4>A total of 62 patients received MLN2704 at ascending doses on 4 schedules: weekly (60, 84, 118, and 165mg/m<sup>2</sup>; 12 patients); every 2 weeks (120, 168, 23 ...[more]

PMID: 27765518

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Project description:BACKGROUND:Therapeutic cancer vaccines have shown activity in metastatic castration-resistant prostate cancer (mCRPC), and methods are being assessed to enhance their efficacy. Ipilimumab is an antagonistic monoclonal antibody that binds cytotoxic T-lymphocyte-associated protein 4, an immunomodulatory molecule expressed by activated T cells, and to CD80 on antigen-presenting cells. We aimed to assess the safety and tolerability of ipilimumab in combination with a poxviral-based vaccine targeting prostate-specific antigen (PSA) and containing transgenes for T-cell co-stimulatory molecule expression, including CD80. METHODS:We did a phase 1 dose-escalation trial, with a subsequent expansion phase, to assess the safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of the PSA-Tricom vaccine. Patients with mCRPC received 2×10(8) plaque-forming units of recombinant vaccinia PSA-Tricom subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of 1×10(9) plaque-forming units, starting on day 15. Intravenous ipilimumab was given monthly starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Our primary goal was to assess the safety of the combination. This study is registered with ClinicalTrials.gov, number NCT00113984. FINDINGS:We completed enrolment with 30 patients (24 of whom had not been previously treated with chemotherapy) and we did not identify any dose-limiting toxic effects. Grade 1 and 2 vaccination-site reactions were the most common toxic effects: three of 30 patients had grade 1 reactions and 26 had grade 2 reactions. 21 patients had grade 2 or greater immune-related adverse events. Grade 3 or 4 immune-related adverse events included diarrhoea or colitis in four patients and grade 3 rash (two patients), grade 3 raised aminotransferases (two patients), grade 3 endocrine immune-related adverse events (two patients), and grade 4 neutropenia (one patient). Only one of the six patients previously treated with chemotherapy had a PSA decline from baseline. Of the 24 patients who were chemotherapy-naive, 14 (58%) had PSA declines from baseline, of which six were greater than 50%. INTERPRETATION:The use of a vaccine targeting PSA that also enhances co-stimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipilimumab. Randomised trials are needed to further assess clinical outcomes of the combination of ipilimumab and vaccine in mCRPC. FUNDING:US National Institutes of Health.

Dataset Information

Phase 1/2 multiple ascending dose trial of the prostate-specific membrane antigen-targeted antibody drug conjugate MLN2704 in metastatic castration-resistant prostate cancer.

Publications

Phase 1/2 multiple ascending dose trial of the prostate-specific membrane antigen-targeted antibody drug conjugate MLN2704 in metastatic castration-resistant prostate cancer.

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