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

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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%. CONCLUSIONS: MLN2704 has limited activity in metastatic castration-resistant prostate cancer. Disulfide linker lability and rapid deconjugation lead to neurotoxicity and a narrow therapeutic window.

Single therapeutic and supratherapeutic doses of sacubitril/valsartan (LCZ696) do not affect cardiac repolarization.

PURPOSE: Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA class II-IV) and reduced ejection fraction. This study was aimed to evaluate the effect of single oral therapeutic (400 mg) and supratherapeutic (1200 mg) doses of LCZ696 on cardiac repolarization. METHOD: This randomized double-blind crossover study in healthy male subjects compared the effect of therapeutic and supratherapeutic doses of LCZ696 with placebo and moxifloxacin 400 mg (open-label treatment) as positive control. The primary assessment was mean baseline- and placebo-corrected QTcF (∆∆QTcF; Fridericia correction). Additional assessments included the ∆∆QTcB (Bazett's correction), PR interval, QRS duration, heart rate (HR), LCZ696 pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and safety. RESULTS: Of the 84 subjects enrolled, 81 completed the study. The maximum upper bound of the two-sided 90 % confidence interval for ∆∆QTcF for LCZ696 400 mg and 1200 mg were <10 ms, and assay sensitivity was confirmed with moxifloxacin. No relevant treatment-emergent changes were observed in any of the ECG-derived parameters with LCZ696 or placebo, and the incidence of adverse events was comparable among the treatment groups. CONCLUSION: Single therapeutic and supratherapeutic doses of LCZ696 did not affect cardiac repolarization as defined by the E14 ICH guidelines.

Effects of age and sex on the pharmacokinetics of LCZ696, an angiotensin receptor neprilysin inhibitor.

LCZ696, a novel angiotensin receptor neprilysin inhibitor, is in development for the treatment of heart failure. Administration of LCZ696 results in systemic exposure to sacubitril (inactive prodrug of LBQ657), LBQ657 (neprilysin inhibitor), and valsartan (angiotensin II receptor blocker). We investigated the potential effects of age and sex on the pharmacokinetics of LCZ696 analytes (LBQ657 and valsartan) in an open-label, single oral dose (400 mg), parallel-group study in healthy subjects. Among 36 enrolled subjects, there were 19 male and 17 female subjects; 18 subjects were 18-45 years old (young), and 18 subjects were 65 years of age or older (elderly). Compared with young subjects, the AUCinf and T1/2 for LBQ657 were 42% and 30% greater, respectively, in elderly subjects. The Cmax for LBQ657 was similar between age groups. The AUCinf, Cmax, and T1/2 for valsartan were 30%, 24% greater, and 3.35 hours longer, respectively, in the elderly when compared with young subjects. All pharmacokinetic parameters of LCZ696 analytes (LBQ657 and valsartan) were similar between male and female subjects, indicating no effect on the pharmacokinetics of LCZ696 analytes based on sex. Considering the magnitude of change and its clinical significance, dose adjustment based on age or sex is not considered necessary.