Palbociclib in Combination with Chemotherapy in Pediatric and Young
Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia and
Lymphoma: A Children’s Oncology Group Study (AINV18P1)
Abstract
Background Cyclin D has been shown to play an essential role in
acute lymphoblastic leukemia (ALL) initiation and progression, providing
rationale for targeting the CDK4/6-cyclin D complex that regulates cell
cycle progression. Procedure The Children’s Oncology Group
AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in
combination with standard four-drug reinduction chemotherapy in children
and young adults with relapsed/refractory B- and T-cell lymphoblastic
leukemia (ALL) and lymphoma. Palbociclib (50 mg/m
2/dose) was administered orally once daily for 21
consecutive days, first as a single agent (days 1-3) and subsequently
combined with reinduction chemotherapy. This two-part study was designed
to determine the maximum tolerated dose (MTD) or recommended phase 2
dose (RP2D) followed by an expansion pharmacokinetic (PK) cohort.
Results Twelve heavily pretreated patients enrolled, all of
whom were evaluable for toxicity. One dose-limiting hematologic toxicity
(DLT) occurred at the starting dose of 50 mg/m 2/dose
orally for 21 days. No additional DLTs were observed in the dose
determination or PK expansion cohorts and overall rates of grade 3/4
non-hematologic toxicities were comparable to those observed with the
chemotherapy platform alone. Five complete responses were observed, two
among four patients with T-ALL and three among seven patients with
B-ALL. Pharmacokinetic studies showed similar profiles with both liquid
and capsule formulations of palbociclib. Conclusions
Palbociclib in combination with reinduction chemotherapy was well
tolerated with a RP2D of 50 mg/m 2/day for 21 days.
Complete responses were observed among heavily pretreated patients.