Avatrombopag Versus Placebo for Persistent Chemotherapy-Induced Thrombocytopenia in GI Cancers: The Phase II ACT-GI Trial

PURPOSE Chemotherapy-induced thrombocytopenia (CIT) is a challenging and common complication of cytotoxic chemotherapy in patients with GI cancers. There is no widely available approved treatment. Avatrombopag is a potent, second-generation oral thrombopoietin receptor agonist promising for CIT management. METHODS We conducted a multicenter, randomized, double-blind, investigator-initiated US trial of avatrombopag or placebo (1:1) in GI cancer patients with persistent CIT (platelets ≤85 × 10 9 /L on day 1 of a chemotherapy cycle despite adequate time to recover from the prior cycle). The primary end point was successful correction of CIT and prevention of recurrence (defined as recovery of platelets to ≥100 × 10 9 /L, no chemotherapy dose modification/delay, and prevention of CIT recurrence [platelets ≥100 × 109/L] at end of the on-study cycle). RESULTS The trial was closed to enrollment by the data and safety monitoring board at the planned interim analysis after meeting prespecified stopping criteria for efficacy. Sixteen of 23 patients (70% [95% CI, 47 to 87]) receiving avatrombopag achieved the primary end point versus 4/24 patients (17% [95% CI, 5 to 37]) receiving placebo ( Z = 3.67, P < .001). The median (IQR) platelet count at the end of the on-cycle treatment period was 157 (136-202) × 10 9 /L with avatrombopag versus 72 (68-134) × 10 9 /L with placebo. Adverse events (AEs) and serious AEs occurred in 78% and 17% of patients receiving avatrombopag and 46% and 0% of patients receiving placebo, respectively. No serious AEs were study drug-related. There were no treatment-related AEs leading to death or discontinuation of study drug. CONCLUSION In this randomized, placebo-controlled trial, avatrombopag was efficacious in the management of persistent CIT in patients with GI cancers. These findings are promising for a common, challenging oncologic complication that prevents delivery of full-dose, on-time, cancer-directed therapy.