A phase 1b study of crizotinib in combination with temsirolimus in pediatric ALK- or MET-aberrated relapsed or refractory neuroblastoma (ITCC-053): Results of the phase 1 part.

Abstract

10036 Background: Preclinical data in neuroblastoma (NBL) models provided evidence that the addition of an mTOR inhibitor with crizotinib may overcome the relative resistance to ALK inhibitors (Berry et al., 2012, Cancer Cell). The primary objective of this phase 1b trial was to establish the recommended phase 2 dose (RP2D) of crizotinib in combination with the mTOR inhibitor temsirolimus in pediatric NBL patients. Methods: Patients aged 1-21 years with relapsed/refractory ALK/MET aberrated NBL were eligible to enroll onto stratum 2 of the CRISP trial (EudraCT: 2015-005437-53, ITCC-053), sponsored by Erasmus MC. This was an open-label, non-randomized, two-stage phase 1b dose finding study. Crizotinib was dose escalated using the EWOC method in four dose levels (DL) ranging from 100 mg/m2 to 280 mg/m2 twice daily (BID) in 28 day cycles. Temsirolimus was administered intravenously in a fixed dose of 60 mg/m2/week. Both starting doses were reduced compared to the single agent RP2D because of an expected CYP3A4 interaction. Primary endpoint was dose limiting toxicity (DLT) during cycle 1. Radiological disease assessments and blood sampling for pharmacokinetics were scheduled per protocol. Results: Nine NBL patients were enrolled onto stratum 2 between 06-2018 and 12-2022. Eight patients with a median age of 7 years (range: 1-12) received trial treatment. The temsirolimus dose was reduced to 40 mg/m2 after the first 3 patients based on unexpected toxicity. DLTs occurred in 2/3 patients treated with crizotinib at DL2 (200 mg/m2 BID); grade 3 elevated ALT (alanine aminotransferase) and grade 3 gastritis (temsirolimus dose; see table). No DLT occurred in 5 patients treated with crizotinib DL1 (150 mg/m2 BID). Dose re-escalation of crizotinib to DL2 was considered not feasible. The RP2D was established at 150 mg/m2 BID crizotinib with 40 mg/m2 temsirolimus. Frequent grade 3 treatment-related adverse events were anorexia, gastritis, oral mucositis (n = 2) and anemia (n = 3). Treatment, toxicity and response are summarized in table. Conclusions: We established a RP2D of 150 mg/m2 BID crizotinib in combination with 40 mg/m2 temsirolimus. The expansion cohort is currently open for enrollment. Clinical trial information: EUCTR2015-005437-53 . [Table: see text]

Pediatric oncology drug development and dosage optimization

“…Model-based approaches for human studies ( 97 ) allow for utilizing all available data and determining the relationship between dose, exposure, and effect. The potential and application of various escalation approaches such as the Time-to-event Continual Reassessment Method (TiTE CRM), escalation with overdose control design (EWOC) and combined TiTE-EWOC are shown in ( 98 ), where EWOC design was used in a pediatric trial for irinotecan and gefitinib combination ( 99 ), and for crizotinib ( 100 ) and incorporating the examples to illustrate the practical implementation of model-based approaches (e.g., EWOC used in irinotecan and gefitinib) and the challenges they address.…”