Avatrombopag for chemotherapy-induced thrombocytopenia in gastrointestinal malignancies (ACT-GI): A multicenter, U.S., randomized, double-blind, placebo-controlled clinical trial.

3580 Background: Chemotherapy-induced thrombocytopenia (CIT) is a frequent complication of chemotherapy. Persistent CIT (not adequately resolved by day 1 of the following cycle) may lead to reduction or delay in treatment. There are no FDA approved therapies for CIT. Aim: To evaluate the safety and efficacy of avatrombopag (AVA), an oral thrombopoietin receptor agonist, to treat persistent CIT and prevent its recurrence in GI cancer. Methods: ACT-GI (NCT05772546) was a multicenter, randomized, double-blind, placebo-controlled, investigator-initiated trial of GI cancer patients with persistent CIT (platelets [Plt] <85×10 9 /L on day 1 of a scheduled chemotherapy cycle). Patients were randomized 1:1 to AVA 40 mg daily or placebo and treated for two on-study phases. In the lead-in phase, patients were treated up to 2 weeks while chemotherapy was held. Patients proceeded to the on-cycle phase and resumed chemotherapy only if their Plt recovered to ≥100×10 9 /L. In the on-cycle phase, patients received a single full-dose chemotherapy cycle with continued study drug. The primary endpoint was successful correction of CIT and prevention of recurrence (achieving Plt ≥100×10 9 /L within the lead-in period AND prevention of CIT recurrence (Plt ≥100×10 9 /L) at end of the cycle). Results: Efficacy: ACT-GI was closed to enrollment by the DSMB, for overwhelming efficacy, at a prespecified interim analysis when 20 patients in each arm completed the double-blind period. 16 of 23 patients (70%; 95% CI 47% to 87%) in the AVA arm achieved the primary endpoint versus 4/24 patients (17%; 95% CI 5% to 37%) in the placebo arm (Z=3.67, P<0.001). 74% and 88% of patients had stage IV cancer in AVA and placebo arms, respectively. 44/47 patients completed study drug; 2 discontinuations were due to physician decision and 1 was due to an adverse event. Plt improvement to ≥100×10 9 /L during lead-in was achieved by 83% of patients in the AVA arm vs. 46% of patients in the placebo arm. The median (IQR) Plt at the end of the on-cycle treatment period was 157 (136-202) in the AVA arm vs 72 (68-134) in the placebo arm. In the AVA arm there were two clinically relevant bleeding events (intestinal stoma site bleed at Plt 105×10 9 /L and intracranial hemorrhage). No patient received platelet transfusion. Safety: AEs and serious AEs (SAEs) occurred in 74% and 13% of patients in the AVA arm and 46% and 0% of patients in the placebo arm, respectively. No SAEs were study drug-related. There were no treatment-related AEs leading to death or discontinuation of study drug. Conclusions: In this randomized, placebo-controlled trial, AVA demonstrated safety, tolerability, and efficacy in treatment and prevention of persistent CIT in GI cancers. These findings are promising for a common, serious condition that prevents delivery of full-dose, on-time cancer-directed therapy. Clinical trial information: NCT05772546 .