In a phase I/II Children’s Oncology Group study (AAML1421) reported in the Journal of Clinical Oncology, Cooper et al identified the phase II dose of CPX-351, a liposomal preparation of daunorubicin and cytarabine, and found that a regimen consisting of CPX-351 followed by fludarabine, cytarabine, and granulocyte-colony stimulating factor (G-CSF; FLAG) produced a high response rate in pediatric patients with relapsed acute myeloid leukemia (AML).
“The recommended phase II dose of CPX-351 is 135 units/m2/dose on days 1, 3, and 5. Toxicity was manageable, and protocol therapy was effective. Response rates are superior to prior published North American cooperative group clinical trials for children with AML in first relapse.”— Cooper et al
Tweet this quote
Study Details
The multicenter study (with sites in the United States and Canada) enrolled a total of 38 patients aged ≥ 1 to 21 years (including 6 with relapsed or refractory disease) in the dose-finding phase and 32 in first relapse in an efficacy phase. Dose level 1 for CPX-351 in the dose-finding phase was 135 units/m2 per dose on days 1, 3, and 5, with a single reduction in dose level to 100 units/m2 planned if the level 1 dose was not tolerated. All patients received CPX-351 in a 28-day first cycle of treatment and were to receive a second cycle of treatment with FLAG, consisting of fludarabine at 30 mg/m2 on days 1 to 5, cytarabine at 2,000 mg/m2 on days 1 to 5, and G-CSF at 5 mg/kg on days 1 to 5 and day 15 through an absolute neutrophil count > 500/mL. All patients received intrathecal cytarabine within 1 week of initiating cycle 1 of therapy and again within 1 week of initiating cycle 2. Response was assessed after each cycle.
Key Findings
During the dose-finding phase, one dose-limiting toxicity (grade 3 decrease in ejection fraction) was observed in six patients receiving the CPX-351 dosage of 135 units/m2 on days 1, 3, and 5, with this dosage being selected as the phase II dose and administered to all patients in the efficacy phase.
Of the total of 38 patients, 37 were evaluable for efficacy (1 was excluded due to protocol violation). Among the 37 evaluable patients, 10 did not proceed to the FLAG cycle after the CPX-351 cycle, including 7 with better than partial response who withdrew to receive allogeneic hematopoietic stem cell transplantation (HSCT), 1 who withdrew after partial response, and 1 with treatment failure.
Among 37 evaluable patients, 30 (81%) achieved response better than partial response, with complete remission in 20 (54%), complete remission with partial recovery of platelet count in 5 (14%), and complete remission with incomplete blood count recovery in 5 (14%). Response better than partial response was observed in 28 patients (76%) after the CPX-351 cycle.
No detectable residual disease was found on flow cytometry in 21 (84%) of 25 patients with complete remission/complete remission with partial recovery of platelet count. Among the 30 responders, 29 (97%) underwent HSCT as consolidation, with 20 (80%) of 25 with available data having no residual disease before HSCT.
Grade ≥ 3 adverse events during cycle 1 with CPX-351 occurred in 89% of 38 patients, with the most common being fever/neutropenia (45%), infection (47%), rash (40%), and QT prolongation (19%). No fatal adverse events occurred.
Among 27 patents receiving FLAG, grade ≥ 3 adverse events occurred in 52%, with the most common being QT prolongation (26%), febrile neutropenia (22%), and infections/infestations (19%).
The investigators concluded, “The recommended phase II dose of CPX-351 is 135 units/m2/dose on days 1, 3, and 5. Toxicity was manageable, and protocol therapy was effective. Response rates are superior to prior published North American cooperative group clinical trials for children with AML in first relapse.”
Todd M. Cooper, DO, of the Cancer and Blood Disorders Center, Seattle Children’s Hospital, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Institutes of Health National Clinical Trials Network and St. Baldrick’s Foundation. For full disclosures of the study authors, visit ascopubs.org.
