A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Avatrombopag for the Treatment of Chemotherapy-Induced Thrombocytopenia in Patients with Solid Tumors

Background: Chemotherapy-induced thrombocytopenia (CIT) is a common complication in cancer patients receiving myelosuppressive chemotherapy. Not only can it increase the risk of bleeding, but it also complicates cancer treatment due to chemotherapy delays, dose reductions, and discontinuation, potentially resulting in sub-optimal treatment outcomes. There are currently no FDA approved medications available to manage CIT in the US and Europe. While platelet transfusions are used to rescue patients with very low platelet levels, they are associated with risks of viral and bacterial infections. Avatrombopag is an orally administered thrombopoietin (TPO) receptor agonist that mimics the biologic effects of TPO, resulting in increased platelet production. Avatrombopag is approved for the treatment of thrombocytopenia in patients with chronic liver disease (CLD) scheduled to undergo a procedure, and in adults with chronic immune thrombocytopenia (ITP) that have had an insufficient response to a prior therapy. Pre-clinical data as well as clinical data in patients with CLD and ITP suggest that Avatrombopag is a promising candidate for treatment of thrombocytopenia of diverse etiologies, including CIT.

Study design and method: This is a phase 3 randomized, double-blind, placebo-controlled, multi-national (United States, Russia, Ukraine, Poland, China, Serbia, Hungary), study evaluating the efficacy and safety of oral Avatrombopag for the treatment of CIT in 120 adult patients with NSCLC, SCLC, bladder, or ovarian cancer (NCT03471078). To be eligible for the study, patients must have experienced severe thrombocytopenia (platelet counts (PC) <50x10⁹/L) during their current chemotherapy regimen (the qualifying cycle defined as "cycle X"), , and receiving a 21- or 28-day chemotherapy regimen including one or more of the following agents/class of agents: gemcitabine, 5-FU, carbo- or cisplatin, anthracyclines, or alkylating agents. Main exclusion criteria include history of chronic platelet or bleeding disorders, thrombocytopenia due to an etiology other than CIT, >2 prior lines of myelosuppressive chemotherapy, prior history of CIT (PC <75 x10⁹/L) in the previous 6 mo , history of hematologic malignancies, known clinically significant acute or active bleeding within 7 days of screening andrecent history of significant cardiovascular disease. Eligible patients will be randomized in a 2:1 ratio to receive either 60 mg Avatrombopag or placebo once daily for 5 days prior to and for 5 days immediately after the subsequent chemotherapy dose (cycle X+1). Cycle X+2 is an observational period with no study drug administered. The primary endpoint is the proportion of patients not requiring a platelet transfusion, a chemotherapy dose reduction by ≥15% ordelay by ≥4 days due to thrombocytopenia. Secondary endpoints include duration of platelet count <50x10⁹/L after Avatrombopag treatment and through chemotherapy treatment cycle X+2, change in platelet count from baseline (nadir) to cycle X+1 (nadir), proportion of patients who do not have clinically relevant bleeding after Avatrombopag treatment and through chemotherapy treatment cycle X+2, proportion of patients who do not receive a platelet transfusion after treatment with Avatrombopag and through chemotherapy treatment cycle X+2 and incidence of adverse events. The treatment effect will be tested between Avatrombopag and placebo using the Cochran-Mantel-Haenszel test, adjusting for number of eligible chemotherapy agents (1, or ≥2). The study will consist of three periods: the double-blind treatment period and observational period of appr 8 to 9 weeks, an optional open label extension period for cycle X+3 (which may continue until the patients' current chemotherapy regimen ends), and a long-term follow-up period of up to 5 years.

Summary: The study aims to evaluate the efficacy of Avatrombopag, an orally administered thrombopoietic agent, in increasing platelet counts to avoid platelet transfusions, chemotherapy dose delays and dose reductions in patients with solid tumors and severe CIT. This study has recently concluded enrollment as of June 2020.