A Phase I/II Trial of Nivolumab plus Ipilimumab in Children and Young Adults with Relapsed/Refractory Solid Tumors: A Children’s Oncology Group Study ADVL1412

Kara L. Davis, Elizabeth Fox, Emasenyie Isikwei, Joel M. Reid, Xiaowei Liu, Charles G. Minard, Stephan Voss, Stacey L. Berg, Brenda J. Weigel, Crystal L. Mackall

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14 Scopus citations


Purpose: In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in childhood cancer. We conducted a phase I/II trial of nivolumab plus ipilimumab in children and young adults with recurrent/refractory solid tumors. Patients and Methods: ADVL1412, Part C assessed safety of nivolumab plus ipilimumab at two dose levels (DL): DL1 1 mg/kg of each drug and DL2 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Part D evaluated response at the recommended phase II dose (RP2D) in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Part E tested DL3 (1 mg/kg nivolumab plus 3 mg/kg ipilimumab) in Ewing sarcoma and rhabdomyosarcoma. Tumor response was measured using RECIST v1.1. Pharmacokinetics and PD-L1 expression on archival tissues were assessed. Results: Fifty-five eligible patients enrolled. Based on safety, tolerability, and similar drug exposure to the same doses administered in adults, DL2 was defined as the pediatric RP2D. Among 41 patients treated at the RP2D, 2 patients experienced dose-limiting toxicities during cycle 1, and 4 patients experienced toxicities beyond that period. Two patients had clinically significant sustained partial responses (1 rhabdomyosarcoma, 1 Ewing sarcoma) and 4 had stable disease. Among 8 patients treated at DL3, 3 dose-limiting toxicities (DLT) occurred, all immune-related adverse events; no objective responses were observed. Conclusions: The RP2D of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) is well tolerated in children and young adults with solid tumors and shows some clinical activity. Increased dose of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) was associated with increased toxicity without clinical benefit.

Original languageEnglish (US)
Pages (from-to)5088-5097
Number of pages10
JournalClinical Cancer Research
Issue number23
StatePublished - Dec 1 2022

Bibliographical note

Funding Information:
The research reported is supported by Bristol Myers Squibb (BMS Study ID CA209-070), the Children’s Oncology Group, the NCI of the NIH under award number UM1 CA228823, and the Cookies for Kids’ Cancer Foundation. C.L. Mackall is a member of the Parker Institute for Cancer Immunotherapy, which supports the Stanford University Cancer Immunotherapy Program. The work was also supported by the Virginia and D.K. Ludwig Fund for Cancer Research (C.L. Mackall) and by NCI 5P30CA124435 (C.L. Mackall). K.L. Davis was supported in part by the Stanford Maternal and Child Health Research Institute as the Anne T. and Robert M. Bass Endowed Faculty Scholar in Pediatric Cancer and Blood Diseases. J.M. Reid was supported in part by Grant Number P30 CA015083 from the NCI. E. Isikwei was supported by the National Institute of General Medical Sciences (NIGMS) grant T32GM 08685. We thank the patients and their families for making this study possible. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Funding Information:
K.L. Davis reports grants from Jazz Pharmaceuticals, as well as personal fees from Novartis Pharmaceuticals outside the submitted work. J.M. Reid reports grants from NIH during the conduct of the study. S.L. Berg reports grants from the Children’s Oncology Group during the conduct of the study; grants and other support from sponsors outside the submitted work; and a leadership position in the NCI-funded Children’s Oncology Group Developmental Therapeutics

Funding Information:
Committee/Pediatric Early-Phase Clinical Trial Network. C.L. Mackall reports grants, personal fees, and other support from Lyell Immunopharma; personal fees and other support from Syncopation Life Sciences, Link Cell Therapies, Ensoma, Mammoth, and Apricity Bio; and personal fees from Immatics, Nekar, Neoimmune Tech, Bristol Myers Squibb, and GlaxoSmithKline outside the submitted work. C.L. Mackall also reports multiple patents related to immunotherapy. No disclosures were reported by the other authors.

Publisher Copyright:
© 2022 American Association for Cancer Research.


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