In the phase I/II ADVL1412 study reported in The Lancet Oncology, Davis et al identified the phase II dosage of nivolumab monotherapy in children and young adults with relapsed or refractory solid tumors or lymphoma. Objective responses were observed in patients with lymphoma, but not in those with solid tumors.

Study Details

In the multicenter trial, eligible patients for the dose-confirmation phase of the study were age 1 to 18, with solid tumors that had measurable or evaluable disease. Eligible patients for the dose-expansion phase were age 1 to 30, with measurable disease in cohorts of rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, neuroblastoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and melanoma. Patients in the dose-confirmation phase received nivolumab at 3 mg/kg on days 1 and 15 of a 28-day cycle, with de-escalation for dose-limiting toxicities to establish the recommended phase II dose. Patients in the dose-expansion phase received the recommended phase II dose.

A total of 85 patients were enrolled between February 2015 and December 2018, with 75 being fully evaluable for toxicity.

Findings

Median follow-up was 30 days. In the dose-confirmation phase, 12 of 13 patients were evaluable for toxicity. No dose de-escalations were required, and no dose-limiting toxicities were observed. Nivolumab 3 mg/kg was confirmed as the pediatric recommended phase II dose.

Among 72 patients in the dose-expansion phase, 63 were evaluable for toxicity. Five (7%) patients had dose-limiting toxicities, consisting of grade 3 elevated lipase for more than 7 days (n = 1), grade 4 neutropenia (n = 1), grade 3 pain at tumor site (n = 1), grade 3 upper gastrointestinal hemorrhage (n = 1), and grade 2 enterocolitis infection (n = 1).  

Among all 75 evaluable patients, the most common overall toxicity was anemia (47%, grade 3 or 4 in 5 patients) and the most common nonhematologic toxicity was fatigue (37%, all grade 1 or 2).

Among all 74 patients evaluable for response, objective responses were observed in 3 (30%) of 10 patients with Hodgkin lymphoma and 1 (10%) of 10 patients with non-Hodgkin lymphoma, with all responders having programmed cell death ligand 1–positive disease.

No objective responses were observed in other tumor types. Best response of stable disease was observed in 11 (33%) of 33 patients in the sarcoma cohorts and 5 (50%) of 10 patients in the neuroblastoma cohort. No response was observed in the one patient with melanoma.

The investigators concluded, “Nivolumab was safe and well tolerated in children and young adults and showed clinical activity in [patients with] lymphoma. Nivolumab showed no significant single-agent activity in the common pediatric solid tumors. This study defines the recommended phase II dose and establishes a favorable safety profile for nivolumab in children and young adults, which can serve as the basis for its potential study in combinatorial regimens for childhood cancer.”

Crystal L. Mackall, MD, of the Department of Pediatrics, Stanford University, is the corresponding author for The Lancet Oncology article.  

Disclosure: The study was funded by Bristol-Myers Squibb, Children’s Oncology Group, National Institutes of Health, and Cookies for Kids Cancer Foundation. For full disclosures of the study authors, visit thelancet.com.