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

• Type of Material: Article
• Authors: Jason Fangusaro, Emory University; Duane A Mitchell, University of Florida; Mehmet Kocak, University of Tennessee Health Science Center; Giles W Robinson, St Jude Children’s Research Hospital; Patricia Ann Baxter, Baylor College of Medicine; Eugene I Hwang, Children’s National Health System; Jianping Huang, University of Florida; Arzu Onar-Thomas, St Jude Children’s Research Hospital; Ira J Dunkel, Memorial Sloan Kettering Cancer Center; Maryam Fouladi, Nationwide Children’s Hospital, Columbus; Katherine E Warren, Dana Farber Cancer Institute
• Language: English
• Date: 2020-10-07
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 Wiley Periodicals LLC
• Final Published Version (URL): http://dx.doi.org/10.1002/pbc.28756
• Title of Journal or Parent Work: PEDIATRIC BLOOD & CANCER
• Volume: 68
• Issue: 2
• Start Page: e28756
• End Page: e28756
• Keywords: LENALIDOMIDE; pomalidomide; MYELOMA; Science & Technology; Hematology; brain tumor; Oncology; IMiD agent; Pediatrics; central nervous system tumor; pediatric; Life Sciences & Biomedicine

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).