POE16-01, A study of neratinib in children and adolescent and young adults with relapsed/refractory solid tumors or leukemias
This is a multi-center, open label, phase I/II trial evaluating the safety and efficacy of neratinib in
pediatric patients with relapsed/refractory malignancies. This trial is an investigator initiated trial
managed by the Pediatric Oncology Experimental Therapeutics Investigator s Consortium
(POETIC), which will hereafter be referred to as the Sponsor. In the phase I portion, the primary
objective will be to determine the dose limiting toxicity (DLT), the maximum tolerated dose
(MTD) and recommended phase 2 dose (RP2D) for neratinib in pediatric patients with
relapsed/refractory malignancies. There will be 2 cohorts of patients, which will accrue
separately: Cohort 1 will consist of patients with solid tumors including lymphoma and central
nervous system (CNS) malignancies, and will accrue first. Cohort 2 will consist of patients with
relapsed/refractory acute leukemia. Once an MTD has been determined in Cohort 1, Cohort 2
will begin enrolling with a limited dose-escalation design at the MTD found in cohort 1.
Additionally, an interim analysis will be performed after the completion of enrollment of Cohort 1
at which time the toxicity profile, PK and PD data will be reviewed to establish confidence
regarding the RP2D to be used for the starting dose of the leukemia cohort and for subsequent
dosing of solid tumor patients.
A rolling six dose escalation schema will be used with 3-6 subjects enrolled per dose level for
both cohorts. Patients are recommended to be admitted for the first 7 days of Cycle 1 to monitor
for diarrhea. If the patient is treated in an outpatient setting, they must be seen every 48-
72hours. Patients must be able to swallow tablets for eligibility onto the study. Neratinib will be
administered once a day either by mouth or via a pre-existing permanent gastrostomy tube.
Each cycle will consist of 28 days. There will be no interruption of dosing between Day 28 of
Cycle 1 and Day 1 of Cycle 2. Dose escalation is detailed in Appendix 2 and will continue until
MTD and RP2D is established. There will be no intra-patient dose escalation. It is anticipated
that the phase I part for Cohort 1 will be completed in 1 year. The phase I part for Cohort 2 is
anticipated to take less than a year to accrue since these patients will utilize a limited doseescalation
schema and will start accrual either at the MTD identified for Cohort 1 or, if
unacceptable toxicity is noted at the MTD in the interim analysis, one dose level below. We
anticipate accruing 9-12 patients in Cohort 2. The expected accrual for the phase 1 component
is 18-30 patients overall.
Once the MTD is established in Cohort 1, the phase II portion of the study will open for accrual
for solid tumors (including lymphoma and CNS malignancies) at the RP2D following a Simon
two stage design. These patients will accrue simultaneously with the accrual of Cohort 2
patients to the phase I portion. Once the MTD for Cohort 2 is identified, this dose level will be
moved into the phase II part of the study for leukemia patients only. The phase II part is
expected to accrue 12-29 patients over the course of 1.5 years, with the leukemia patients
expected to enter this phase while accrual for solid tumor is already occurring.