CPX-351 Exposure-Response Analyses for Efficacy and Safety in Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)
Authors: Wang Qi , Gosselin Nathalie H. , Absalon Michael J. , Kolb E. Anders , Marier J.F. , Alonzo Todd A. , Faderl Stefan , Cooper Todd M. 
Published: November 2020

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 (Cmax), 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, Cmax, 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 Cmax of cytarabine or daunorubicin. The probabilities of grade ≥3 TEAEs for quartiles of cytarabine Cmax 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.

Disclosures
Wang: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Absalon:Jazz Pharmaceuticals: Research Funding. Faderl:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019).

OffLabel Disclosure:
Yes, in these studies, CPX-351 was evaluated in pediatric AML