A Multicenter, Study of the Safety and Pharmacokinetics of Intravenously Infused Berubicin in Pediatric Patients With Progressive, Refractory, or Recurrent High Grade Gliomas

This is a Phase 1, multicenter, open-label, dose escalation study of intravenous Berubicin in pediatric patients. The purpose of this first-in-pediatrics study is to examine the safety, tolerability, and PK of Berubicin and to estimate its MTD and/or RP2D when administered to pediatric patients with progressive, refractory, or recurrent HGG who have completed at least 1 standard line of therapy. This study will also make a preliminary assessment of the antitumor activity of Berubicin in this patient population. An exploratory evaluation of quality of life will also be performed.

This open-label, nonrandomized study is composed of a series of Dose Escalation Cohorts followed by an Expansion Cohort. The Dose Escalation Cohorts will utilize a standard "rules based" 3+3 design. A safety review committee (SRC) composed of, at a minimum, the principal investigators, the medical monitor(s), the sponsor's responsible medical officer (s), and an external expert in pediatric oncology will review all available study data at regular intervals and will make recommendations to the sponsor regarding dose escalations. Patients enrolled in the Expansion Cohort will be administered the MTD or RP2D identified during dose escalation. Safety, PK, efficacy, and quality of life evaluations will be performed for all patients throughout the study.

Berubicin will be administered as 1-hour infusions each day for 3 consecutive days followed by 18 days off drug (ie, 21-day cycles). The starting dose is based on population PK modeling of data from adult studies and will be 1.20 mg/m2 (Dose Level 1). During the study, PK data will be incorporated into a PK model on an ongoing basis and may be used to inform dose escalation decisions.

Dose Escalation and Stopping Rules: The Dose Escalation Cohorts will utilize a standard 3+3 design to determine an MTD and/or RP2D. All available information, including safety, PK, and efficacy, will be taken into account when making decisions regarding dose escalation. The 3 + 3 dose escalation procedures will be based on the following:

Enroll 3 patients initially. If no dose-limiting toxicities (DLTs; as defined in Safety Outcome Measures) occur, escalate dose to next dose level cohort.

If 1 patient out of 3 experiences a DLT, expand cohort up to 6 patients. If 1 patient out of 6 experiences a DLT, escalate to next dose level cohort. If ≥2 patients out of 6 experience a DLT, the MTD will have been exceeded; stop dose escalation, and review the next lower dose cohort. This may require enrollment of a further 3 patients if only 3 were dosed at a previous dose level.