Phase 1 study of pomalidomide in children with recurrent, refractory, and progressive central nervous system tumors: A Pediatric Brain Tumor Consortium trial

Abstract

Background: Central nervous system (CNS) malignancies are the most common solid tumors among children, and novel therapies are needed to help improve survival. Pomalidomide is an immunomodulatory agent that displays antiangiogenic and cytotoxic activity, making it an appropriate candidate to explore in pediatric CNS tumors.

Methods: A phase 1 first in pediatric trial of pomalidomide was conducted in children with recurrent, progressive, and refractory CNS tumors. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) when given orally once daily for 21 consecutive days of a 28-day cycle. Once the MTD was established, 12 additional patients were enrolled on expansion cohorts based on age and steroid use.

Results: Twenty-nine children were enrolled and 25 were evaluable for dose-limiting toxicity (DLT). The MTD was 2.6 mg/m2 (dose level 2). Four DLTs were observed in three patients at dose level 3 (3.4 mg/m2 ) includeding grade 3 diarrhea, grade 3 thrombocytopenia, grade 3 lung infection, and grade 4 neutropenia. The most common adverse events were grade 1 and 2 myelosuppression. One patient with an oligodendroglioma had stable disease for nine cycles, and a second patient with an anaplastic pleomorphic xanthoastrocytoma achieved a sustained partial response. Immunologic analyses suggested that pomalidomide triggers immunomodulation.

Conclusions: The MTD of pomalidomide is 2.6 mg/m2 . It was well tolerated, and immune correlates showed a serum immune response. These data led to an industry-sponsored phase 2 trial of pomalidomide monotherapy in children with recurrent brain tumors (NCT03257631).

Keywords: IMiD agent; brain tumor; central nervous system tumor; pediatric; pomalidomide.

Conflict of interest statement

Conflict of Interest:

JF and KEW served on a pediatric advisory board for Celgene. IJD served as an unpaid consultant for Apexigen, served as a pediatric oncology steering committee member for AstraZeneca, pediatric advisory council member for Bristol-Myers Squibb, a consultant for Fennec and a pediatric advisory board member for Roche. GWR has previously consulted for Roche and Eli-Lilly. DAM is a co-founder of iOncologi, Inc., a biotechnology company specializing in immuno-oncology, holds patents that have been licensed to iOncologi, Inc., Annias Immunotherapeutics, Inc., Immunomic Therapeutics, Inc., and Celldex Therapeutics, Inc., and he has served as a consultant/advisor to Bristol-Meyers Squibb, Inc., Tocagen, Inc., Imvax, Inc., and Oncorus, Inc. All other authors report no conflict of interest.

© 2020 Wiley Periodicals LLC.

Figures

Figure 1:

Pharmacokinetic concentration-time curve for individual patients treated at the MTD (2.6 mg/m2).

Figure 2:

PFS and OS of all eligible patients enrolled (n=29)