CPX-351 Exposure-Response Analyses for Efficacy and Safety in Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)

CPX-351 (Vyxeos^®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of daunorubicin and cytarabine at a synergistic 1:5 molar ratio, is approved by the US FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Separate studies at Cincinnati Children's Hospital (CCH) and by the Children's Oncology Group (COG) evaluated the efficacy and safety of CPX-351 in pediatric patients (pts). CPX-351 was administered by IV infusion on Days 1, 3, and 5 for the first induction only. The CCH study included 2 dose levels, 100 and 134 units/m², with 100 units/m² identified as the recommended phase 2 dose (RP2D); pts with multiple relapsed or refractory AML were included in the exposure-response (E-R) analyses. The COG study established an RP2D of 135 units/m²; the majority of pts in the E-R analyses had first-relapsed AML. E-R analyses were conducted to evaluate the relationship between plasma exposures to CPX-351 and efficacy or safety endpoints.

Plasma PK parameters of cytarabine and daunorubicin, including area under the curve up to 48 h post dose on Day 5 Cycle 1 (AUC₄₈), maximum concentration on Day 5 Cycle 1 (C_max), and concentration at 48 h post dose on Day 5 Cycle 1 (C₄₈), were derived from a previously developed population PK model for pediatric and adult pts. The efficacy endpoints were complete remission (CR), CR+CRp (partial platelet count recovery), or CR+CRp+CRi (incomplete hematologic recovery). Age, sex, bone marrow blast, white blood cell, and platelet counts at baseline were included in the covariate analysis. The safety endpoints included grade ≥3 TEAEs.

From the studies, both pediatric and adult pts were included in the E-R analyses for efficacy. Overall, the E-R efficacy population included 43 (53%) pediatric pts (1-17 y) and 38 (47%) adults (≥18 y); the majority were male (57%) and of white origin (63%). Of the 81 pts included in the analysis, 28 (31%), 16 (25%), and 1 (2%) pt achieved CR, CRp, and CRi, respectively; 39 (48%) pts had progressive disease or no response.

Various models were used to describe the relationship between probability of response (CR, CRi, or CRp) and exposure parameters (AUC₄₈, C_max, and C₄₈). C₄₈ of cytarabine was associated with the best statistical goodness-of-fit in the logistic regression model. The effect of cytarabine C₄₈ on the probability of response was statistically significant (P = 0.0144; odds ratio = 1.057). These results suggest the odds of response increased by ~6% for each 1-unit increment of cytarabine C₄₈ (ie, 1 μg/mL). The estimated probability of response was separated into exposure quartiles: 33% for Q1, 49% for Q2, 59% for Q3, and 83% for Q4. The cytarabine C₄₈ was mainly observed in Q1 and Q2 for the 100 units/m² dose and in Q3 and Q4 for the 134-135 units/m² doses. In a covariate analysis, none of the covariates tested explained the variability in response. AUC₄₈ of cytarabine and daunorubicin and C₄₈ of daunorubicin were also significantly correlated with probability of response to CPX-351. This was expected, as the PK of daunorubicin and cytarabine are highly correlated when administered as CPX-351. Logistic models were also developed to describe the relationship between probability of response and exposure parameters. Similarly, cytarabine C₄₈ was a significant predictor of the probability of CR or CRi. However, no logistic models were found to describe the relationship of probability of CR+CRp (or CR only) and exposure parameters. Although pt populations of the CCH and COG studies were different, a similar correlation was shown for exposures and efficacy in the CCH study, where higher exposures were associated with higher response rates.

Grade ≥3 TEAEs observed in pediatric pts were separated into exposure quartiles for C_max of cytarabine or daunorubicin. The probabilities of grade ≥3 TEAEs for quartiles of cytarabine C_max were 77% for Q1, 85% for Q2, 85% for Q3, and 71% for Q4. Similar results were observed with daunorubicin.

In these post hoc E-R analyses, higher CPX-351 doses were associated with higher plasma exposures, which led to a higher probability of response (CR+CRp+CRi) in pediatric pts with relapsed or refractory AML. There was no correlation of plasma exposures to grade ≥3 TEAEs. These analyses should be interpreted with caution due to the small sample size; however, they support use of the higher dose of 135 units/m².