Results from phase 1 of the MANIFEST clinical trial to evaluate the safety and tolerability of pelabresib in patients with myeloid malignancies

Abstract

Pelabresib (CPI-0610), a BET protein inhibitor, is in clinical development for hematologic malignancies, given its ability to target NF-κB gene expression. The MANIFEST phase 1 study assessed pelabresib in patients with acute leukemia, high-risk myelodysplastic (MDS) syndrome, or MDS/myeloproliferative neoplasms (MDS/MPNs) (NCT02158858). Forty-four patients received pelabresib orally once daily (QD) at various doses (24–400 mg capsule or 225–275 mg tablet) on cycles of 14 d on and 7 d off. The most frequent drug-related adverse events were nausea, decreased appetite, and fatigue. The maximum tolerated dose (MTD) was 225 mg tablet QD. One patient with chronic myelomonocytic leukemia (CMML) showed partial remission. In total, 25.8% of acute myeloid leukemia (AML) patients and 38.5% of high-risk MDS patients had stable disease. One AML patient and one CMML patient showed peripheral hematologic response. The favorable safety profile supports the ongoing pivotal study of pelabresib in patients with myelofibrosis using the recommended phase 2 dose of 125 mg tablet QD.

CLINICAL TRIAL REGISTRATION: NCT02158858

Keywords:

• Pelabresib
• BET inhibition
• myeloid malignancies

Acknowledgments

The authors would like to express their gratitude to the study participants, investigators, and trial staff. Constellation Pharmaceuticals (subsequently acquired by MorphoSys AG) provided funding for this study. The development of pelabresib was funded in part by the Leukemia and Lymphoma Society. Medical writing support was provided by Laura Travers of LiNK Health Group and funded by Constellation Pharmaceuticals (subsequently acquired by MorphoSys AG).

Author contributions

ES and ATF helped with patient recruitment, enrollment, and conduct of the study. All authors contributed equally to the development of this manuscript.

Ethics approval

This study was approved by the institutional review board at each participating site and was conducted in accordance with the principles of the Declaration of Helsinki. It was also overseen by an independent ethics review committee.

Patient consent

Written informed consent was obtained from each patient prior to study entry.

Disclosure statement

EMS received research funding to his institution from MorphoSys. ATF participates in advisory board/consulting with AbbVie, Agios/Servier, Amgen, Astellas, Blueprint, Celgene/Bristol Myers Squibb, Daiichi Sankyo, EnClear, Foghorn, Genentech, Immunogen, Kite, Kura Oncology, Mablytics, Menarini, MorphoSys, Novartis, Orum, Pfizer, PureTech, Remix, Rigel, Seattle Genetics, Takeda, and Trillium; consulting for Daiichi Sankyo, Forma, Ipsen, Menarini, Remix, Gilead, and Rigel, and receives clinical research funding from AbbVie, Agios/Servier, and Celgene/Bristol Myers Squibb. WAH has nothing to disclose. GC is employed by Constellation Pharmaceuticals, Inc., a MorphoSys Company, and is a current holder of stock options in a privately held company and stock options at MorphoSys AG. AF is employed by Constellation Pharmaceuticals, Inc., a MorphoSys Company. JKM participated in advisory boards for Astellas, Kura Oncology, Adicet Bio, Gilead, and Rigel Pharma.

Data availability statement

Data sharing requests by qualified researchers pertaining to the MANIFEST phase 1 study will be considered only for noncommercial use on a case-by-case basis (to be approved by MorphoSys; [email protected]), starting 12 months from acceptance of the manuscript and until 36 months thereafter; approval may be subject to a data access agreement.

Additional information

Funding

Constellation Pharmaceuticals (subsequently acquired by MorphoSys AG) provided funding for this study. The MANIFEST study was supported in part by funding from the Leukemia and Lymphoma Society. Medical writing support was provided by Laura Travers of LiNK Health Group and funded by Constellation Pharmaceuticals (subsequently acquired by MorphoSys AG).