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).

• Authors: Jason Fangusaro, Duane A Mitchell, Mehmet Kocak, Giles W Robinson, Patricia Ann Baxter, Eugene I Hwang, Jianping Huang, Arzu Onar-Thomas, Ira J Dunkel, Maryam Fouladi, Katherine E Warren
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 68 Issue 2 Pg. e28756 (02 2021) ISSN: 1545-5017 [Electronic] United States
• PMID: 33025730 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2020 Wiley Periodicals LLC.

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Thalidomide
• pomalidomide

Topics

• Adolescent
• Angiogenesis Inhibitors (pharmacokinetics, therapeutic use)
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Central Nervous System Neoplasms (drug therapy, mortality, pathology)
• Child
• Child, Preschool
• Dose-Response Relationship, Drug
• Female
• Humans
• Immunomodulation (drug effects)
• Male
• Thalidomide (analogs & derivatives, pharmacokinetics, therapeutic use)
• Young Adult