This is an open-label, phase I-II dose-escalation and expansion study designed to define the recommended dose of brigatinib as monotherapy in pediatric and young adult patients with ALK+ ALCL, IMT or other solid tumors and to evaluate the pharmacokinetics (PK), (long-term) safety, and efficacy of brigatinib in these children.
Patients must be 1 and < 26 years of age at the time of enrollment, and able to swallow brigatinib tablets at the time of enrollment, with a minimum weight of 10 kg. Note: for phase 1 only patients ≤18 years old will be eligible, A liquid formulation for children with a weight lower than 10 kg or for those that cannot swallow tablets is in development.
Patients must have a confirmed diagnosis of cancer histologically at baseline. In patients where a repeat biopsy at relapse (or moment of refractory disease) is considered not feasible by the treating physician, archived material from diagnosis needs to be available for central review.
Patients are required to provide prior results showing an activating ALK aberration in the tumor per local laboratory results, and material needs to be available for central laboratory confirmation of ALK status. For ALK+ ALCL, detection of ALK with immunohistochemistry (IHC) is sufficient for inclusion, all others require molecular evidence of a ALK fusion gene or mutation by FISH, PCR or NGS. ALK detection will be confirmed centrally with FISH.
Patients with relapsed/refractory (R/R) IMT must not be suitable for curative surgical resection without causing mutilation. Newly diagnosed patients with unresectable ALK+ IMT, or when surgery would imply severe mutilation may also be included, as well as metastatic disease.
Patients receiving systemic treatment with strong or moderate CYP3A inhibitors or inducers within 14 days or five half-life times whichever the less prior to the first dose of study drug (refer to Section 5.2 for a list of example medications).
Diagnosis of another concurrent primary malignancy.
Myocardial infarction or unstable angina within 6 months of study entry.
History of or presence of heart block, and/or clinically significant ventricular or atrial arrhythmias.
Sequential
Brigatinib
DrugBrigatinib is a second generation novel, orally administered, tyrosine kinase inhibitor (TKI) that potently inhibits activated variants of ALK and to a lesser extent ROS1.
Phase 1: assess the MTD/RP2D regimen
Phase 1: • To assess the MTD/RP2D regimen of brigatinib monotherapy when administered in pediatric and AYA patients with ALK+ ALCL or ALK+ solid tumors. Dose-limiting toxicities (DLTs) during the first course of therapy. The RP2D is defined as the dose that results in equivalent (approximately ±20% of the adult values) PK exposure to 180 mg QD with a 7 day lead in of 90 mg QD in adults and with 0 or 1 DLT in 6 patients.
Phase 1: to characterize the PK of brigatinib
Phase 1: • To characterize the PK of brigatinib administered as monotherapy in pediatric and AYA patients with ALK+ ALCL or ALK+ solid tumors: o maximum observed concentration (Cmax),
Phase 1: to characterize the PK of brigatinib
Phase 1: • To characterize the PK of brigatinib administered as monotherapy in pediatric and AYA patients with ALK+ ALCL or ALK+ solid tumors: o area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast).
Phase 1: to characterize the PK of brigatinib
Phase 1: * To characterize the PK of brigatinib administered as monotherapy in pediatric and AYA patients with ALK+ ALCL or ALK+ solid tumors: * time of first occurrence of maximum observed concentration (Tmax), T ½.
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Princess Maxima Center for Pediatric Oncology
Lead sponsor
Takeda
Collaborator
