Arthur C. Louie

First-In-Man Study of CPX-351: A Liposomal Carrier Containing Cytarabine and Daunorubicin in a Fixed 5:1 Molar Ratio for the Treatment of Relapsed and Refractory Acute Myeloid Leukemia

PURPOSE This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351. PATIENTS AND METHODS CPX-351 induction was administered on days 1, 3, and 5 by 90-minute infusion to 48 relapsed or refractory patients with acute myeloid leukemia (AML) or high-risk myelodysplasia. Doses started at 3 units/m(2) with dose doublings in single-patient cohorts until a pharmacodynamic effect (treatment-related adverse events or reduction in bone marrow cellularity or blast count) was observed, followed by 33% escalations in three patient cohorts until dose-limiting toxicity (DLT) occurred. RESULTS The maximum-tolerated dose was 101 units/m(2). DLTs consisted of hypertensive crisis, congestive heart failure, and prolonged cytopenias. Adverse events were consistent with cytarabine and daunorubicin treatment. Response occurred at doses as low as 32 units/m(2). Of 43 patients with AML, nine had complete response (CR) and one had CR with incomplete platelet recovery; of patients with acute lymphoblastic leukemia, one of three had CR. Eight CRs were achieved among the 31 patients with prior cytarabine and daunorubicin treatment. CR in AML occurred in five of 26 patients age ≥ 60 years and in five of 17 patients younger than age 60 years. Median half-life was 31.1 hours (cytarabine) and 21.9 hours (daunorubicin), with both drugs and their metabolites detectable > 7 days after the last dose. The targeted 5:1 molar ratio was maintained at all dose levels for up to 24 hours. CONCLUSION The recommended dose of CPX-351 for phase II study is 101 units/m(2). Further exploration of efficacy and safety is ongoing in phase II trials in newly diagnosed and first-relapse patients with AML.

Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML.

CPX-351 is a liposomal formulation of cytarabine:daunorubicin designed to deliver synergistic drug ratios to leukemia cells. In this phase 2 study, newly diagnosed older acute myeloid leukemia (AML) patients were randomized 2:1 to first-line CPX-351 or 7+3 treatment. The goal was to determine efficacy and identify patient subgroups that may benefit from CPX-351 treatment. Response rate (complete remission + incomplete remission) was the primary end point, with event-free survival (EFS) and overall survival (OS) as secondary end points. The 126 patients entered were balanced for disease and patient-specific risk factors. Overall, CPX-351 produced higher response rates (66.7% vs 51.2%, P = .07), meeting predefined criteria for success (P < .1). Differences in EFS and OS were not statistically significant. A planned analysis of the secondary AML subgroup demonstrated an improved response rate (57.6% vs 31.6%, P = .06), and prolongation of EFS (hazard ratio [HR] = 0.59, P = .08) and OS (HR = 0.46, P = .01). Recovery from cytopenias was slower after CPX-351 (median days to absolute neutrophil count ≥1000: 36 vs 32; platelets >100 000: 37 vs 28) with more grade 3-4 infections but without increase in infection-related deaths (3.5% vs 7.3%) or 60-day mortality (4.7% vs 14.6%), indicating acceptable safety. These results suggest a clinical benefit with CPX-351, particularly among patients with secondary AML, and provide the rationale for a phase 3 trial currently underway in newly diagnosed secondary AML patients. This study is registered at Clinicaltrials.gov as #NCT00788892.

Safety, Pharmacokinetics, and Efficacy of CPX-1 Liposome Injection in Patients with Advanced Solid Tumors

Purpose: CPX-1 is a novel, liposome-encapsulated formulation of irinotecan and floxuridine designed to prolong in vitro optimized synergistic molar ratios of both drugs postinfusion. This open-label, single-arm, dose-escalating phase I study was designed to determine the maximum tolerated dose and pharmacokinetics of CPX-1 in patients with advanced solid tumors. Experimental Design: Patients received CPX-1 at 30, 60, 100, 150, 210, or 270 units/m2 (1 unit = 1 mg irinotecan + 0.36 mg floxuridine) infused over 90 minutes every 14 days in 28-day cycles. Pharmacokinetic samples were collected on days 1 and 15 of cycle 1. Results: Thirty-three patients were enrolled, treated, and evaluated for safety; 30 patients were evaluated for response. A 1:1 plasma irinotecan to floxuridine molar ratio was maintained for 8 to 12 hours. Grade 3/4 toxicities included diarrhea (24.2%), neutropenia (12.1%), and hypokalemia (12.1%); 1 patient (270 units/m2) died of persistent diarrhea, which led to dehydration and renal failure (grade 5). Partial response occurred in 3 (12%) of the 25 subjects evaluated through Response Evaluation Criteria in Solid Tumors. Progression-free survival lasting >6 months occurred in 9 patients, 6 with colorectal cancer. Among 15 colorectal cancer patients (10 with prior irinotecan), the calculated median progression-free survival was 5.4 months; 11 patients (72.7%) achieved disease control and 2 patients (13%) had partial response. Conclusions: Outpatient CPX-1 was well tolerated and antitumor activity was shown in patients with advanced solid tumors. The recommended dose for future studies is 210 units/m2. This is the first clinical evaluation of fixed drug ratio dosing designed to maintain synergistic molar ratios for enhanced therapeutic benefit.

Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML.

CPX‐351 is a liposome‐encapsulated fixed‐molar‐ratio formulation of cytarabine and daunorubicin that exploits molar ratio–dependent drug‐drug synergy to enhance antileukemic efficacy.

Pharmacokinetics of CPX-351; a nano-scale liposomal fixed molar ratio formulation of cytarabine:daunorubicin, in patients with advanced leukemia

Forty-eight patients received CPX-351 (liposome-encapsulated cytarabine:daunorubicin at a 5:1 molar ratio) every other day for 3 doses at 10 dose levels. Pharmacokinetic parameters were dose-independent and exhibited low inter-patient variability. CPX-351 showed a negligible distribution phase and prolonged mono-exponential first-order plasma elimination (t(1/2)∼24 h). The plasma ratio of 5:1 was maintained at all dose levels. Nearly all of the detectable cytarabine and daunorubicin in circulation following CPX-351 administration was in the form of liposome encapsulated drug. Dose-dependent hematopoietic effects had early onset with cytopenias at 12 units/m(2), and a gradual increase in frequency and severity, until single induction complete response was achieved at 43 units/m(2). Non-hematologic effects had onset by 24 units/m(2) with shallow dose-response until maximum frequency and severity were observed at the 101-134 units/m(2) dose levels. Single induction response occurred over a 2.3-fold range of doses indicating that CPX-351 may be useful at high doses for patients suitable for intensive chemotherapy and at reduced doses for patients at increased risk of treatment-related mortality. The unique pharmacologic features of CPX-351 contribute to its promising antileukemic efficacy.

Skin rash following therapy with mitomycin C

A 39‐year‐old man developed a widespread pruritic vesicular rash 1 week following the second course of treatment with mitomycin C plus doxorubicin for carcinoma of unknown origin. Skin rash is an uncommon complication of treatment with mitomycin C, and the frequency of its occurrence may be increased when the drug is given in combination with other cytotoxic agents.

CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia

Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy.

Unsatisfactory efficacy in randomized study of reduced-dose CPX-351 for medically less fit adults with newly diagnosed acute myeloid leukemia or other high-grade myeloid neoplasm

The need for new therapies for medically less fit adults with acute myeloid leukemia (AML) is unquestioned.[1][1] CPX-351, a liposomal formulation of cytarabine and daunorubicin,[2][2] may be an attractive option. In patients with relapsed/refractory leukemia, in whom CPX-351 was administered on

Abstract 1292: Pharmacokinetics of CPX-351: A nano-scale liposomal fixed molar ratio of cytarabine-daunorubicin (Cyt:Daun) in patients with advanced leukemia

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: CPX-351 is a liposomal formulation that co-encapsulates Cyt and Daun enabling delivery of both drugs at a synergistic 5:1 molar ratio. A Phase I study in advanced AML patients demonstrated substantial efficacy with complete remissions (CRs) and acceptable safety. The MTD was 101 units/m2. One unit of CPX-351 contains 1 mg Cyt and 0.44mg of Daun. Here we examine the PK of CPX-351 as a function of dose, inter-patient variability and patient characteristics in order to identify potential PD relationships. Methods: 35 male and female patients with advanced hematologic malignancies were included in the PK portion of this Phase I trial and received 24, 32, 43, 57, 76, 101, or 134 units/m2 of CPX-351 by IV infusion over 90 minutes on Days 1, 3, and 5. Validated LC/MS/MS assays were used for determination of total plasma Cyt and Daun. PK parameters [Cmax, AUC, t1/2, Vss, CL, Cmax/Dose, AUC/Dose] were determined on Days 1 and 5. Results: Mean Cyt and Daun PK parameters are presented in the [table below][1]. No significant differences were observed in t1/2, Vss, CL, Cmax/Dose, or AUC/Dose among dose groups on either study day, although some drug accumulation was observed from day 1 to day 5. Cyt and Daun PK parameters were not correlated with patient gender, age or race. Incidence of non-hematologic toxicity increased with dose and systemic exposure. CRs were observed in patients receiving doses of 32-134 units/m2 of CPX-351. The responses at 101 units/m2 and above appear to be more durable. The Cyt:Daun molar ratio remained near 5:1 for up to 48 hours on both study days for all dose levels. Conclusions: Cyt and Daun delivered in CPX-351 exhibited linear single dose and multiple dose PK and low inter-patient variability in plasma concentrations within dose groups. CPX-351 provides predictable, extended systemic exposure of elevated Cyt:Daun concentrations near a 5:1 molar ratio. The 100 unit/m2 dose is undergoing testing in Phase II studies. ![Figure][2] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1292. doi:10.1158/1538-7445.AM2011-1292 [1]: #F1 [2]: pending:yes