Results of a phase I dose escalation study of eltrombopag in patients with advanced soft tissue sarcoma receiving doxorubicin and ifosfamide

Sant P Chawla, Arthur Staddon, Andrew Hendifar, Conrad A Messam, Rita Patwardhan, Yasser Mostafa Kamel, Sant P Chawla, Arthur Staddon, Andrew Hendifar, Conrad A Messam, Rita Patwardhan, Yasser Mostafa Kamel

Abstract

Background: The objective of this Phase I dose escalation study was to explore the safety and tolerability of eltrombopag, an oral, nonpeptide, thrombopoietin receptor agonist, in patients with advanced soft tissue sarcoma (STS) and thrombocytopenia due to treatment with doxorubicin and ifosfamide (AI) combination chemotherapy.

Methods: Patients aged 18 or older with histologically confirmed, locally advanced or metastatic STS were treated with 1 cycle of AI followed by AI with eltrombopag starting at Cycle 2, using 2 different dosing schedules. The study design included an eltrombopag dose escalation phase starting at 75 mg daily to determine the optimal biological dose (OBD).

Results: Eighteen patients were enrolled and 15 received at least 1 dose of chemotherapy; 3 patients withdrew prior to receiving eltrombopag. Seven, 4, and 1 patients received 75 mg, 100 mg, and 150 mg eltrombopag daily, respectively. No dose-limiting toxicities were reported. Due to slow recruitment, the study was closed prior to identifying an OBD. The most common hematologic adverse events (AEs) were thrombocytopenia (80%), neutropenia (73%), and anemia (67%). The most common nonhematologic AEs were fatigue (53%), alanine aminotransferase increased, constipation, and nausea (47% each). Eleven of 12 patients who received eltrombopag completed at least 2 chemotherapy cycles; all had increased platelet counts on Day 1 of Cycle 2 (cycle with eltrombopag) compared to Day 1 of Cycle 1 (cycle without eltrombopag).

Conclusions: Although data are limited, safety data were consistent with the known toxicities of AI combination chemotherapy or the side effect profile of eltrombopag seen in other studies. Available data suggest a potential pre- and post-chemotherapy dosing scheme for eltrombopag when administered with AI chemotherapy, and support further investigation of eltrombopag treatment in patients with chemotherapy-induced thrombocytopenia.

Trial registration: ClinicalTrials.gov NCT00358540.

Figures

Figure 1
Figure 1
Summary of Patient Disposition. Of 18 patients enrolled, 3 withdrew before receiving any chemotherapy and 15 received at least 1 chemotherapy dose (safety population). Of these 15 patients, 3 withdrew before receiving a first dose of eltrombopag during Cycle 2. Seven, 4, and 1 patients received at least 1 dose of 75 mg, 100 mg, and 150 mg eltrombopag, respectively.
Figure 2
Figure 2
Day 1 Pre-Chemotherapy Platelet Counts for Cycle 1 and Cycle 2 for Individual Patients Who Received Eltrombopag and Completed at Least 2 Cycles (n = 11). Patients indicated with an asterisk (*) received eltrombopag for 10 days post-chemotherapy beginning in Cycle 2; all other patients received eltrombopag beginning in Cycle 2 for 5 days pre- and 5 days post-chemotherapy.
Figure 3
Figure 3
Platelet Nadirs in Cycle 1 and Cycle 2 of Treatment for Individual Patients Who Received Eltrombopag and Completed at Least 2 Cycles (n = 11). Patients indicated with an asterisk (*) received eltrombopag for 10 days post-chemotherapy beginning in Cycle 2; all other patients received eltrombopag beginning in Cycle 2 for 5 days pre- and 5 days post-chemotherapy.

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