Planned study design.
thrombosis, tumor, DLTs, toxicity, toxicities, TEEs, chemotherapy-associated venous thromboembolism, PK/PD, DLBCL, PD
THROMBOSIS, DISEASE PROGRESSION, TUMOR, THROMBOEMBOLIC EVENT, ADVERSE EVENTS, EVALUABLE, REGRESSION, DIFFUSE LARGE B-CELL LYMPHOMA
DLBCL diffuse large B-cell lymphoma, PD pharmacodynamic, PK pharmacokinetic, po orally, qd once daily, RP2D recommended Phase 2 dose. Part 1 of this study included a dose-escalation cohort to assess the incidence of dose-limiting toxicities (DLTs) and adverse events, and a PK/PD cohort to characterize the PK/PD profile of GSK3368715 (Fig. The starting dose for the dose escalation cohort was 50 mg. Based on toxicity studies in dogs and preclinical studies of tumor regression in mice, tumor regression was observed at daily doses ranging from >75 mg/kg to 300 mg/kg (depending on tumor type), and 50 mg provided 16- and 33-fold safety margins for the steady state AUC and For each dosing group in the dose-escalation cohort, GSK3368715 was administered on day 1, no treatment was administered on days 2 and 3 (to characterize single-dose PK), and daily dosing continued thereafter until disease progression, unacceptable toxicity, or withdrawal of consent. Study treatment was dosed at approximately the same time of day (±4 h), with no food for 1 h before and 2 h after each dose. Evaluable patients for dose escalation received at least 21 days of study intervention and completed the postintervention follow-up visit.Due to a higher-than-expected incidence of thromboembolic events (TEEs) among the first 19 participants in the dose-escalation cohort, enrollment was paused at the 200-mg dose, and several measures were implemented to reduce the risk of TEE in subsequent patients enrolled in the study. The study resumed under a protocol amendment with the PK/PD cohort starting at a daily dose of 100 mg, and dose escalation was limited to 50-mg increments. The incidence and frequency of TEEs were added to the DLT criteria (grade 2 TEE requiring systemic anticoagulation or ≥grade 3 TEE) with extended monitoring to 8 weeks or until study discontinuation, whichever occurred first. Further, eligibility criteria were modified to exclude patients at high risk of thrombosis (ie, Khorana score ≥3 or prior medical history of TEE). Patients with a Khorana score of 2 were considered for prophylactic anticoagulation if deemed appropriate by the investigator. Khorana score is a risk assessment model based on clinical and laboratory parameters to classify the risk for chemotherapy-associated venous thromboembolism (Supplemental Table The study was halted prior to initiation of part 2 due to a comprehensive risk/benefit analysis. No recommended Phase 2 dose was determined and no food effect analysis was performed as planned in part 1.