A novel PrECOG (PrE0901) dose-escalation trial using eltrombopag: enhanced platelet recovery during consolidation therapy in acute myeloid leukemia

Abstract

High-dose cytarabine (HiDAC) consolidation for acute myeloid leukemia (AML) induces transient profound myelosuppression and potential morbidity/mortality. PrE0901 was a phase I multi-center trial evaluating the safety/toxicity of eltrombopag in AML patients receiving HiDAC consolidation. We used a standard 3 + 3 design employing a unique dose-escalation/de-escalation strategy. One hundred four patients were screened, 54 declined participation, 35 were deemed medically ineligible, and 14 were treated on study. Three patients were treated in cohorts 1–4 and two were treated in cohort 5. Eltrombopag + HiDAC was well-tolerated and no dose-limiting toxicities were observed. Median time to platelet recovery of all patients treated was 22.5 (range 16–43) days. Observationally, eltrombopag 150 mg once daily starting on day 3 of consolidation demonstrated the fastest and most consistent platelet recovery (median 19 days). Further investigation is needed to define the optimal role, dose, and schedule of eltrombopag in the treatment of chemotherapy associated myelosuppression.

Keywords:

• Acute myeloid leukemia
• AML
• consolidation
• eltrombopag
• thrombocytopenia
• TPO

Acknowledgments

PrECOG was established as a not-for-profit 501(c)(3) limited liability company (LLC) in 2006 as a subsidiary of the ECOG Research and Education Foundation. The mission of PrECOG is to design, implement, conduct and publish results for clinical trials that support the ever-evolving needs of patients with cancer and our underlying knowledge of cancer diseases.

Author contributions

SAS, JC, WR, MST, ML, and HL performed the research with significant contributions of patient enrollment, data generation, and data collection.

SAS, XVM, MST, ML, and HL designed the research study.

XVM analyzed the data.

SAS, XVM, JC, JMR, MST, WR, ML, and HL all made significant contributions to the writing of the manuscript.

Disclosure statement

SAS discloses consultancy/advisory board participation with AbbVie, ArcherDx, Astellas, Incyte, Jazz, Kite, Novartis, and Pfizer within three years prior to manuscript submission. SAS also discloses research funding from Sunesis.

HL discloses participation in a Speakers’ Bureau with Novartis.

JC discloses consultancy/advisory board participation with Pfizer, Incyte, Daiichi- Sankyo, and Jazz Pharmaceuticals. JC also discloses stock/stock options in BluebirdBio Inc.

WR discloses consultancy/advisory board participation with Merck and Spark Therapeutics. WR also discloses grants/grants pending with Merck and Seattle Genetics as well as institutional study support in the form of a grant from PrECOG, LLC.

XVM Discloses institutional grant support from PrECOG, LLC

MST discloses Board Membership with Abbvie, BioLineRx, Daiichi-Sankyo, Orsenix, KAHR, Rigel, Nohla, Delta Fly Pharma, Tetraphase, Oncolyze, Jazz Pharma, and Roche. MST also discloses institutional grants/grants pending with AbbVie, Cellerant, Orsenix, ADC Therapeutics, Biosight, and Glycomimetics. MST discloses participation in speakers bureaus with 14^th Annual Miami Cancer Meeting, St. Vincent Medical Center, ASH, Hemedicus, Jazz Pharmaceuticals, Univ of Miami Comprehensive Cancer Center, Medscape, NCCN, Univ of Toronto, NIH, Hammersmith Hospital, Prime Oncology, Penn State Cancer Institute, Vanderbilt-Ingram Cancer Center, ASCO, Mayo Clinic, and UC Davis. MST discloses royalties from UpToDate.

The authors (JMR, ML) have no relevant financial or other interests to disclose pertaining to the data or opinions contained within this manuscript.

PrECOG, LLC is the study Sponsor and oversaw conduct of the trial. Funding and study drug support were provided by GlaxoSmithKline (GSK) and Novartis. GSK reviewed and provided input to the final study design. Neither GSK nor Novartis were involved with the data analysis, interpretation, or writing of the manuscript. The final manuscript was reviewed by Novartis prior to submission.