Statistical Design for Arms A and B
toxicity, intra-dose
DISEASE, SECONDARY
The combination of paclitaxel and ipatasertib was determined to be safe and well tolerated in previous Phase Ib (PAM 4983g)Treatment Arms are shown in Treatment Arms showing patients included in the study (To confirm the RP2D obtained from the dose escalation, and for an initial assessment of response, correlatives, and PFS estimates, an additional cohort of patients was enrolled until the number treated and evaluable for DLT considerations at the recommended Phase II dose was 14 patients for Arm B and Arm A. All eligible patients who started treatment at the recommended Phase II dose were considered in the calculation of the RR.Arms A and B had an expected sample size of 14 patients, for an expected total sample-size of 28 patients. Protocol allowed for the addition of cohorts (6-8 patients) if level 1 was not well-tolerated (a lower dose was necessary).For Arm C safety-lead in, a 3-at-risk design was utilized to assess toxicity for the combination therapy. The DLT period was 1-cycle (28 days). Each participant remained on the dosing level according to the escalation dose level they were enrolled in, and intra-dose level escalations were not allowed, even if the MTD was defined at a higher dose level. If a patient came off study in the first 28 days for any reason outside of toxicity (unrelated AE, withdrawal of consent, progression of disease, etc), this patient was not considered as evaluable for DLT and this patient was replaced.When a maximum tolerable dose (MTD) level was defined by the dose escalation portion of the study, and the recommended Phase II dose (RP2D not to exceed the MTD) was selected, additional patients were accrued to confirm the tolerability of the regimen. The plan was for at least 12 patients to be treated at the RP2D to confirm tolerability. Additional patients beyond the 12 at the RP2D could be accrued if the total number of patients accrued did not exceed 21 patients. With 12 patients, any specific severe toxicity with 20% incidence would be observed with 93% probability.Survival endpoints were evaluated using Kaplan-Meier methods. Clinical activity was described based on the secondary objectives, with a description of the activity based on PD-L1 status. Other biological correlative studies were considered exploratory in the context of this limited Phase I study.