CPX-351 ((Cytarabine:Daunorubicin) Liposome Injection, (Vyxeos)) Does Not Prolong Qtcf Intervals, Requires No Dose Adjustment for Impaired Renal Function and Induces High Rates of Complete Remission in Acute Myeloid Leukemia

Introduction: CPX-351 is a liposomal formulation of cytarabine and daunorubicin encapsulated at a fixed 5:1 molar ratio.  It is highly effective in patients with high-risk acute myeloid leukemia (AML).  This study evaluated the impact of CPX-351 (100 units/m²) on cardiac repolarization.

Methods: This open-label, Phase II, pharmacokinetic (PK) and pharmacodynamic (PD) study entered AML and acute lymphocytic leukemia (ALL) patients with good risk hepatic function (Child-Pugh scores <7), and normal cardiac function (LVEF≥50%, QTcF<470 ms).  Cardiac repolarization changes were assessed using conventional ECG and Holter monitor recordings.  PK was assessed during the first 21 days for total cytarabine, daunorubicin, Ara-U and daunorubicinol.  The relationship between CPX-351 PK, QTcF, and renal function using the equation to calculate the estimated glomerular filtration rate (eGFR) was evaluated.

Results:  Twenty-six patients entered the study and 21 were evaluable for QT interval change from baseline.  Evidence that CPX-351 prolongs the QTcF interval was not observed. The largest absolute and mean change from time-matched baseline was 12.56 and 8.03 ms, respectively (Day 1, hour 4). Mean QTcF change on Day 5 was unchanged from baseline.  QTcF intervals >480 ms were never observed and no consistent QTcF intervals >450 ms were noted.  Absolute QTcF increases between 30 and 60 ms were present in 4 of 25 patients and no changes >60 ms were observed.  CPX-351 plasma concentration vs. time curves for day 1 and 5 exhibited a volume of distribution approximately equal to the plasma volume with prolonged single-exponential elimination half-lives for cytarabine and daunorubicin of ≥24 hours.  The PK of CPX-351 was independent of renal function.  Patients with moderately impaired (eGFR=30-59 mL/min/1.73m²) renal function exhibited similar drug exposure as those with mild and normal renal function.

Table 1: Impact of renal function impairment on Day 5 CPX-351 PK parameters (mean, %CV):

Analyte	Renal Function		Cmax (ng/mL)	AUClast (ng*hr/mL)	AUCinf (ng*hr/mL)	T1/2 (hr)
Cytarabine	Normal (n=3)	Mean	59333	2893146	2902641	42.5
		%CV	28.7	68.8	69	34.1
	Mild (n=7)	Mean	58071	3599512	3606695	41.0
		%CV	31.9	52.4	52.4	21.8
	Moderate (n=3)	Mean	57333	3149303	3156738	38.0
		%CV	46.6	50.7	50.6	21.9
Daunorubicin	Normal (n=3)	Mean	25967	754646	870861	24.9
		%CV	23.1	63	65.3	56.0
	Mild (n=7)	Mean	28686	865034	1021420	30.5
		%CV	43.9	43.5	43.6	25.3
	Moderate (n=3)	Mean	21933	671542	814732	35.4
		%CV	50.9	35.9	33.5	31.2

Table 2 summarizes response and transplant outcomes.  One of two ALL patients achieved CR and was transplanted.  Among AML patients there were 7 CR and 2 CRi of which three went on to transplant.  An additional four patients became morphologically leukemia free (MLF) and were transplanted before full documentation of CR was achieved.  A large majority of patients given first-line treatment with CPX-351 responded or became suitable for transplant (10/13, 77%). 

Table 2: 206 Study Efficacy

Diagnosis	n	Response CR/CRi	Transplanted in CR/CRi	Induced MLF and Transplanted	No Response
ALL-Relapsed	2	1/0	1/0	0	1
AML-First Line de novo	8	5/0	0	1	2
AML-First Line sAML	5	1/2	1/1	1	1
AML-Salvage	11	1/0	1/0	2	8

                  

Conclusions:  Clinically relevant prolongation of QTcF is not a feature of CPX-351 treatment.   CPX-351 exposure was independent of renal function, indicating no need for dose adjustment when renal function is impaired.  The high rate of complete remission and referral for transplant corroborate the high level of efficacy observed in earlier studies with CPX-351.