An open-label, dose-ranging study to assess the safety, efficacy, and pharmacokinetics of eltrombopag in treating thrombocytopenia in patients with advanced sarcomas receiving doxorubicin and ifosfamide.

Abstract

TPS334 Background: Doxorubicin and ifosfamide are active in the treatment of sarcomas; however, this regimen is associated with grade 3/4 chemotherapy-induced thrombocytopenia (CIT), which may necessitate chemotherapy dose reductions and dose delays with the consequence of less disease control. Thrombocytopenia can also increase the risk of hemorrhage. CIT is primarily managed with dose reductions, dose delays, and platelet transfusions, each of which has significant limitations. Eltrombopag, an oral, small molecule thrombopoietin receptor agonist, increases platelet counts in patients with chronic immune thrombocytopenic purpura, chronic liver disease, and hepatitis C infection. This study will evaluate the safety and effectiveness of eltrombopag in patients with cancer. Methods: This open- label, nonrandomized, phase I, 2-part, sequential cohort, dose-escalation study will evaluate the safety and efficacy of eltrombopag when administered to patients receiving doxorubicin/ifosfamide. Eligible adult patients have locally advanced (with high risk for relapse) or metastatic soft tissue sarcoma, ECOG/Zubrod performance status of 0 or 1, have received ≤1 previous chemotherapy, and are candidates for doxorubicin/ifosfamide chemotherapy on a 21-day cycle. Patients will receive once-daily eltrombopag for 5 days prior to and 5 days after chemotherapy in cycles 2 to 6 to identify an optimal biologic dose (OBD). At least 3 patients will be enrolled into each of the following dose levels: 75, 100, 150, 200, 300 mg eltrombopag. An additional 3 patients will be enrolled if 1 patient experiences a ≥ grade 3 toxicity related to eltrombopag. Progression to the next dose level will be based on safety and pharmacokinetics data. Once the OBD is identified, that dose will be tested in additional patients on the aforementioned schedule and also on a schedule of eltrombopag daily on each of the 10 days following chemotherapy dosing in cycles 2 to 6. The primary endpoint is safety and tolerability as assessed by adverse events, changes from baseline in vital signs, and clinical laboratory parameters. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline