Phase 1 clinical trial of durvalumab in children with solid and central nervous system tumors.
Authors: Mascarenhas Leo , Levi Abrahm , Malvar Jemily , Haduong Josephine Hoatuyet , Jiang Yu , Donegan Sarah E. , Erdreich-Epstein Anat , Robison Nathan John , Tang Weifeng , Chi Yueh-Yun , Navid Fariba 
Published: June 2022

10029 Background: Immune checkpoint inhibitors targeting PDL-1 have shown clinical benefit in adults with cancer. We conducted a first in pediatrics, phase 1 clinical trial to assess safety, pharmacokinetics (PK), and pharmacodynamics of durvalumab in children with solid and central nervous system malignancies. Methods: This single center investigator-initiated trial enrolled eligible patients considered incurable with measurable/evaluable disease (exception: osteosarcoma in 3rd remission), no prior exposure to checkpoint inhibitors and adequate organ function on 2 dose levels: 10 mg/kg (DL1) and 15 mg/kg (DL2), utilizing a standard 3+3 design. The primary objectives were to assess safety and PK of durvalumab. Durvalumab was administered intravenously (IV) Q2 weeks for a maximum of 24 doses (12 cycles) on study or until disease progression/unacceptable toxicity. Patients were assessed for dose-limiting toxicity (DLT) in the first 28 days. The tolerable dose level was expanded to obtain PK on at most 6 patients age ≥12 years (yrs) and 6 patients < 12 yrs weighing < 35 kg). Soluble PDL-1 (sPDL1) and anti-drug antibody (ADA) levels were also assessed. Results: Fifteen patients (8M/7F) were enrolled (3 DL1, 12 DL2) with median age of 12.7 (2.9-16.6) yrs. Diagnoses included 5 osteosarcoma, 4 ependymoma and 1 each of glioblastoma, astrocytoma, rhabdomyosarcoma, synovial sarcoma, hepatoblastoma and adrenocortical carcinoma. Of the 14 patients evaluable for DLT, 3 were on DL1 and 11 on DL2. Only 1 DLT was observed, Grade (Gr) 3 intracranial hemorrhage (ICH). Median number of cycles administered was 3 (1-12). There were no treatment related deaths. There were 72 treatment-related adverse events (TRAEs) observed in 11 patients in a total of 73 cycles administered on the trial. The most common TRAE was AST elevation (7 instances in 4 patients). All TRAEs were < Gr 3 except for 1 instance each of Gr 3 AST elevation, anemia, and ICH. All 15 patients had PK, sPDL1 and ADA samples analyzed. PK for DL2 in patients ≥35 Kg and < 35 Kg were comparable to PK in adults dosed with durvalumab 10 mg/kg IV Q2W. Mean (SD) DL2 Cmax 292 (102) mg/mL, Ctrough 85.1 (27.7) mg/mL, AUC 2220 (986) day*mg/mL in pts ≥35 Kg and Cmax 442 (338), Ctrough 120 (123), AUC 2470 (1870) in pts < 12 yrs weighing < 35 kg. sPDL1 was completely suppressed in all patients 2 weeks after a single dose of durvalumab. No ADA were detected in any patients. Five patients (2 osteosarcoma, 3 ependymoma) completed > 6 cycles and 3 (1 osteosarcoma, 2 ependymoma) completed all 12 cycles of treatment. One objective response (PR) was seen in a patient with anaplastic ependymoma by RECIST1.1. Four patients were alive at the time of data cut-off with a median follow up of 30.5 (8.8-58.1) months. Conclusions: Durvalumab at 15 mg/kg IV Q2W was well tolerated in children with drug exposures comparable to adults receiving10 mg/kg IV Q2W. A signal for activity was noted in ependymoma where 3 of 5 children benefitted clinically. Clinical trial information: NCT02793466.