A phase I study of panobinostat in children with relapsed and refractory hematologic malignancies

Abstract

Background: Panobinostat demonstrates activity against pediatric cancers in vitro. A phase I trial in children with refractory hematologic malignancies was conducted. Study design: The trial evaluated two schedules of oral panobinostat using 3 + 3 dose escalations in 28-day cycles. For children with leukemia, panobinostat was given once daily three days a week each week at 24, 30 and 34 mg/m2/day. For children with lymphoma, panobinostat was given once daily three days a week every other week at 16, 20 and 24 mg/m2/day. Cerebrospinal fluid (CSF) from Day 29 of the first cycle, when available, was evaluated for PK. The study was registered on clinicaltrials.gov (NCT01321346) Results: Twenty-two subjects enrolled with leukemia. Five enrolled at dose level 1, 6 at dose level 2, and 11 at dose level 3. There was one dose limiting toxicity (DLT) in the leukemia arm at dose level 3 (Grade 4 hypertriglyceridemia), but no maximum tolerated dose (MTD) was identified. No subjects required removal from protocol therapy for QTc prolongation. PK studies were available in 11 subjects with similar exposure in children as in adults. Four Day 29 CSF specimens were found to have panobinostat levels below the lower limit of quantification. Five subjects with lymphoma were enrolled and received study drug, and 4 were evaluable for DLT. A DLT was reported (Grade 3 enteritis) on the lymphoma arm. Conclusions: Panobinostat was tolerated in heavily pretreated pediatric subjects. Gastrointestinal effects were observed on this study. There were no cardiac findings. There were no responses.

Keywords:

• Acute leukemias
• lymphoma
• Phase I/II studies
• Oncology (Target Therapy)

Disclosure statement

Panobinostat is not labeled for pediatric acute leukemia or lymphoma.

Conflict of interest statement

Dr. Goldberg was a full-time faculty member at the University of Miami Miller School of Medicine and the study chair at the time of the study’s initiation, as well as the IND holder. He is currently employed full time by Oncorus, Inc., a biotechnology company in Cambridge, Massachusetts. Dr. Laetsch has consulted for Novartis, Loxo Oncology, Bayer, and Eli Lilly, and has research funding from Novartis, Bayer, and Pfizer. Dr. Thomson at time of study initiation was faculty at the University of Washington, Seattle Children’s Hospital. She is working at MedPace.

Acknowledgements

We acknowledge all patients and families who participated in this trial and the TACL Consortium’s scientific contribution to and participation in this study, including participating member institutions, investigators, research teams, and the TACL Operations Center.

Additional information

Funding

Trial support and funding were provided in part by the Stroud Family Research Fund and Novartis.