Safety and PK (pharmacokinetic) profile of niraparib (nir) + dostarlimab (dost) in pediatric patients (pts) with recurrent or refractory (RR) solid tumors: SCOOP study.

Francois Doz Institut Curie and University of Paris, Paris, France info_outline Francois Doz, Nicolas André, Pilar Guerra-García, Antonio Juan-Ribelles, Jaume Mora, Lucas Moreno, Nadège Corradini, Anne Huff, Courtney Nugent, Michele Snyder, Veronica Moroz, Danielle Wanik, Divya Gupta, Nidale Tarek, Alba Rubio-San-Simón

Authors Francois Doz Institut Curie and University of Paris, Paris, France info_outline Francois Doz, Nicolas André, Pilar Guerra-García, Antonio Juan-Ribelles, Jaume Mora, Lucas Moreno, Nadège Corradini, Anne Huff, Courtney Nugent, Michele Snyder, Veronica Moroz, Danielle Wanik, Divya Gupta, Nidale Tarek, Alba Rubio-San-Simón Organizations Institut Curie and University of Paris, Paris, France, Hôpital pour enfants de la Timone, Marseille, France, Hospital Universitario 12 De Octubre, Madrid, Spain, Hospital U i P La Fe, Valencia, Spain, Hospital Sant Joan de Deu de Barcelona, Barcelona, Spain, Vall d'Hebron University Hospital, Barcelona, Spain, Centre Léon Bérard; Institut d´Hématologie et d´Oncologie Pédiatrique, Lyon, France, GSK, Collegeville, PA, GlaxoSmithKline, Collegeville, PA, Hospital Infantil Universitario Niño Jesus, Madrid, Spain Abstract Disclosures Research Funding Pharmaceutical/Biotech Company GSK Background: Combination therapies may improve clinical outcomes in pediatric pts with tumors with single-agent resistance. Emerging preclinical and clinical data have shown a positive effect for combination PARP/immune checkpoint inhibition. The SCOOP study was designed to evaluate combination nir+dost in pediatric pts with non-central nervous system (CNS) RR solid tumors. Herein we present the safety, dose-limiting toxicities (DLTs), PK, and recommended phase 2 dose (RP2D) of nir+dost. Methods: SCOOP is a phase 1, multicenter, open-label, dose-escalation, and cohort-expansion study in pts aged ≥6 mo to <18 y with non-CNS tumor types reported to have a BRCA ness gene signature. Part 1A comprised multiple dose-level cohorts (0, 1A, 1B, and 2; Table) of pts ≥20 kg able to swallow nir tablets. The primary endpoint was determination of the RP2D of nir+dost based on DLT incidence during the first 2 cycles. Plasma concentrations were compared with simulated adult concentrations using population PK models. Results: A total of 23 pts with non-CNS RR solid tumors were enrolled with 16 evaluated for DLTs and 23 for PK analysis (see Table for dose-level cohorts and observed DLTs). Grade (Gr) ≥3 drug-related (DR) treatment-emergent adverse events (TEAEs) in part 1A included hematologic toxicities, decreased appetite, and fatigue, with DR serious TEAEs of immune-mediated encephalitis, headache, nausea, vomiting, cerebral hemorrhage, and hyponatremia. Observed plasma nir concentrations at 100 and 200 mg once daily (QD) in pediatric pts were similar to simulated adult concentrations at 200 or 300 mg QD. Observed dost concentrations at 7.5 mg/kg every 3 weeks (Q3W) in pediatric pts were in the expected range for adults at 500 mg Q3W. Conclusions: Observed DLTs were consistent with the individual safety profile of each drug; overall no unexpected safety issues were observed. Based on these results, nir 100 mg QD + dost 7.5 mg/kg Q3W was selected as the RP2D for the SCOOP expansion cohorts in neuroblastoma and osteosarcoma. Pts in the expansion study will receive nir+dost at the RP2D until disease progression. Clinical trial information: NCT04544995. Cohort Dosage DLTs observed 0 (n=11; 8 evaluable a ) Nir 100 mg QD + dost 3 mg/kg Q3W n=1; Gr 3 anemia requiring blood transfusion 1A (n=7; 6 evaluable a ) Selected as RP2D Nir 100 mg QD +dost 7.5 mg/kg Q3W n=1; Gr 3 vomiting, nausea, and anorexia and Gr 5 immune-mediated encephalitis 1B (n=5; 2 evaluable a,b ) Nir 200 mg QD + dost 3 mg/kg Q3W n=2; 1 Gr 4 thrombocytopenia requiring transfusion, 1 Gr 3 cerebral hemorrhage 2Did not open for enrollment as 1B was not deemed safe Nir 200 mg QD +dost 7.5 mg/kg Q3W a DLT-evaluable population comprises pts who completed the DLT observation period or experienced a DLT. b Two additional pts in cohort 1B experienced Gr 3 neutropenia leading to interruption and reduction of nir dose, resulting in inadequate dosing compliance.

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