AAML1421 phase I/II trial of CPX-351 followed by FLAG in children with R/R AML

The treatment and long-term survival of childhood acute myeloid leukemia (AML) is often complicated by the cardiotoxicity of anthracycline use. CPX-351 is a liposomal preparation of daunorubicin and cytarabine maintained at a 1:5 molar ratio that has demonstrated safety and superior efficacy in adult patients with newly diagnosed, secondary AML, and has already been approved by the U.S. Food and Drug Administration (FDA) and the European Commission in these patients or those with myelodysplasia-related changes.¹

In a phase I/II study, AAML1421 (NCT02642965), Todd Cooper and colleagues investigated the use of CPX-351 followed by FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) in children with relapsed/refractory AML (R/R AML). They aimed to determine the recommended phase II dose (RP2D) of CPX-351 and estimate the response rate after two cycles of treatment in children with AML in first relapse.¹

Study design and patient characteristics¹

• AAML1421 is a Children’s Oncology Group (COG)-sponsored, phase I/II, open label, single arm study comprising of two parts:
  • a dose-finding phase
  • an efficacy phase
• Patients of 1–21 years of age with R/R AML were enrolled in the dose-finding phase (n = 6)
• Only patients with first relapse and no prior reinduction attempt were included in the efficacy phase (n = 32)
• A minimum of 5% leukemic burden in the marrow or a peripheral blood absolute blast count > 1,000/µL was required
• Patients who received more than the maximal cumulative anthracyclines delivered with de novo therapy (> 450 mg/m²) were excluded
• Two cycles of therapy were offered:
  • Cycle 1: CPX-351, starting at Dose Level 1; 135 units/m² on Days 1, 3, and 5, which was selected to maintain equivalent daunorubicin doses for comparisons with standard pediatric de novo AML induction regimens, and the European DaunoXome (DNX) trial.
  • Cycle 2: Fludarabine 30 mg/m² on Days 1–5; cytarabine 2,000 mg/m² on Days 1–5; and granulocyte colony-stimulating factor 5 µg/kg on Days 1–5 and Day 15 through absolute neutrophil count (ANC) > 500/µL
  • All patients received intrathecal cytarabine within 1 week of initiating each cycle
  • Additional intrathecal cytarabine was administered twice weekly after CPX-351 for 4–6 treatments in patients with any detectable leukemia in the cerebral spinal fluid at time of screening, and was allowed at the investigator’s discretion for patients at high risk for treatment failure in the central nervous system (CNS)
• Response was assessed after each cycle no earlier than Day 28, by bone marrow aspirate and biopsy, and lumbar puncture
• Dose-limiting toxicity assessment occurred during Cycle 1
  • If Dose Level 1 was deemed intolerable, a single dose reduction to the adult CPX-351 dose (100 units/m²) would occur
• Complete response (CR): attainment of a M1 marrow (< 5% blasts) with peripheral blood recovery of ANC ≥ 1,000/µL and platelets ≥ 100,000/µL
• CR with partial recovery of platelet count (CRp) or CR with incomplete blood count recovery (CRi) were defined as M1 marrow with either failure to recover platelets ≥ 100,000/µL or both platelets and/or ANC, respectively
• Partial response: an M2 bone marrow (5–25% blasts) and at least a 50% decrease in bone marrow blast percentage from baseline
• Treatment failure was defined as any of the following: an absolute increase of ≥ 20% marrow blasts, > 25% marrow blasts, an M1 marrow with circulating blasts, or development of extramedullary disease
• Best response: CR plus CRp
• Overall response rate: defined as CR plus CRp plus CRi
• Patient characteristics can be seen in Table 1
  • Median age at study entry was 11.9 years (range, 1.81–21.5)
  • Four patients (10.5%) had CNS 2 status and required additional intrathecal cytarabine, per protocol
  • 24 patients (63.2%) had relapsed < 1 year after first CR

Table 1. Baseline patient characteristics¹

CNS, central nervous system; CR1, complete response 1; HSCT, hematopoietic stem cell transplant
Characteristic	% of patients (n = 38)
CNS status
CNS 1	81.6
CNS 2	10.5
Unknown	7.9
Cytogenetics
Normal	13.2
Inv (16); t(8;21)	15.8
Monosomy 7	5.3
11q23	15.8
Del(7q)	5.3
3q and 13q	2.6
13q only	2.6
Other	15.8
Unknown	23.7
Disease status (length of CR1), days
< 180	13.2
180–365	50.0
> 365	36.8
Prior HSCT
Yes	26.3
No	73.7

 

Results¹

Dose-finding phase

• The RP2D was 135 units/m² on Days 1, 3, and 5
  • One of six patients experienced a dose-limiting toxicity of Grade 3 decrease in ejection fraction, though this patient had a prior history of cardiac dysfunction

Efficacy phase

• Toxicity was graded using Version 4 of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Adverse events (AEs) are shown in Table 2
  • The most common AEs were febrile neutropenia (44.7%), infection and infestations (44.7%), and maculopapular rash (39.5%)
  • There was no toxic mortality
  • One patient developed a Grade 3 reduction in ejection fraction after Cycle 1, which resolved with enalapril treatment
  • Two patients developed a Grade 2 reduction in ejection fraction after Cycle 1, and four patients developed this AE after Cycle 2, but all recovered during the follow-up

Table 2. Adverse events by treatment cycle¹

CTCAEv4, Common Terminology Criteria for Adverse Events, Version 4
CTCAEv4 adverse event, %	Cycle 1 (n = 38)	Cycle 2 (n = 27)
Febrile neutropenia	44.7	22.2
Oral mucositis	2.6	—
Fever	5.3	—
≥ 1 infections and infestations	44.7	18.5
Decreased ejection fraction	2.6	—
Prolonged QT electrocardiogram	18.4	25.9
Rash maculopapular	39.5	3.7
None	10.5	48.1

 

• After administration of 135 units/m² CPX-351, plasma exposures were similar to those observed in adults
  • Pharmacokinetic parameters: terminal phase half-life, clearance, and volume of distribution, for total cytarabine and daunorubicin were also similar to those observed in adults
• Treatment response by cycle can be seen in Table 3
  • 75% of evaluable patients achieved a CR, CRp or CRi with Cycle 1
  • One patient was not evaluable and received non-protocol therapy with a tyrosine kinase inhibitor on Day 15 of Cycle 1, before disease evaluation could be performed at an adequate time point
  • 11 patients withdrew after Cycle 1, of which seven patients went on to receive hematopoietic stem cell transplant (HSCT)
  • 96.7% of patients went on to receive HSCT as consolidation
  • 2-year overall survival for evaluable patients was 52.7%

Table 3. Treatment response by cycle¹

CR, complete remission; CRi, CR with incomplete blood count recovery; CRp, CR with partial recovery of platelet count; ORR, overall response rate; PR, partial response; TF, treatment failure; UE, unevaluable
Response, %	Cycle 1 (n = 38)	Cycle 2 (n = 27)	Best response (n = 38)
CR	37.8	48.1	54.1
CRp	5.4	25.9	13.5
CRi	32.4	7.4	13.5
PR	18.9	0.0	13.5
TF	5.4	18.5	5.4
UE	2.6	0.0	2.6
ORR	75.6	81.4	81.1

 

• Overall, 84% of patients that had a CR or CRp as best response, had no detectable residual disease by flow cytometry

Conclusions

The RP2D of CPX-351 in children with R/R AML is 135 units/m² on Days 1, 3, and 5, as this protocol was effective and demonstrated a manageable toxicity profile. Although there was some cardiac toxicity in terms of Grade 2/3 reduced ejection fraction, all patients recovered during follow-up, which further demonstrates the enhanced safety of this lysosomal preparation. Furthermore, the response rates were superior to those published by the North American Cooperative Group clinical trials for children with AML in first relapse. Taken together, these encouraging results provide the rationale for a randomized study of CPX-351 in children with de novo AML.