|Jorge E. Cortes, MD
Deputy Chair and Chair
Chronic and Acute Myelogenous Leukemia Sections
Department of Leukemia
The University of Texas MD Anderson Cancer Center
|Farhad Ravandi, MD
Professor, Department of Leukemia
Division of Cancer Medicine
Chief, Section of Developmental Therapeutics
The University of Texas MD Anderson Cancer Center
|Elizabeth Paczolt, MD, FACNM
We interviewed acute myeloid leukemia (AML) thought-leaders Jorge E. Cortes, MD, and Farhad Ravandi, MD, of The University of Texas MD Anderson Cancer Center, to gain their insight on recent and ongoing clinical trials studying CPX-351 and vosaroxin.
CPX-351 (Vyxeos™) – Dr. Jorge Cortes
What is CPX-351 and what is its role in the treatment of AML?
Standard induction therapy for AML for the past three decades has consisted of daily administration of daunorubicin on days 1 to 3 along with cytarabine on days 1-7; this combination is commonly referred to as "7 + 3." However, this combination offers a very limited potential as an actual cure of leukemia. Differences in pharmacokinetics and pharmacodynamics between different cytotoxic agents can lead to changing drug ratios in vivo, preventing the actual maintenance of the desired or optimal drug ratio after administration of therapy.5
Nano-scale liposomal drug delivery vehicles are able to prolong and maintain drug ratios in vivo. CPX-351 (brand name Vyxeos™) fixes a 5:1 molar ratio of cytarabine and daunorubicin within a liposomal carrier, with each unit of CPX-351 containing 1 mg of cytarabine and 0.44 mg of daunorubicin, similar to standard induction therapy with these agents.5 In animal models, that 5:1 molar ratio, which is optimal for antileukemia effect, was maintained in both the plasma and the bone marrow in vivo for >24 hours, and treatment increased the survival of leukemia-affected mice when compared with conventional administration of daunorubicin and cytarabine. This suggested a markedly better therapeutic effect for CPX-351 compared to standard treatment.5,6
What are the clinical data demonstrating the effectiveness and safety of CPX-351 in treatment of patients with AML?
The first human study of CPX-351 was conducted by Feldman and colleagues, and was a phase 1 dose escalation trial designed to identify the maximum-tolerated dose of this agent, along with its pharmacokinetics and any associated dose-limiting toxicities. This study involved 48 patients with relapsed or refractory AML or high-risk myelodysplasia. The drug was administered as a first salvage treatment to 23 patients with AML, as second salvage to 10 patients, and as third or greater salvage to another 10 patients. Dosing was initiated at 3 units/m2 with dose doublings in single-patient cohorts until a pharmacodynamic effect was reached, identified through a reduction in bone marrow leukemic cellularity or blast count, or because of treatment-related adverse events (AEs). This led to cohorts of 3 patients with 33% dose escalations until dose-limiting toxicity occurred.5
Dose levels studied ranged from 3 units/m2 to 134 units/m2, and the maximum-tolerated dose was determined to be 101 units/m2, although responses were seen at doses as low as 32 units/m2. The most common dose-limiting toxicities included hypertensive crisis, congestive heart failure, and prolonged cytopenia. Overall, AEs were consistent with those seen with standard daunorubicin and cytarabine therapy. Among the 43 patients with AML, nine patients exhibited a complete response (CR) to CPX-351 and one had CR with incomplete platelet recovery. CR in patients with AML occurred in 5 of 26 patients 60 years of age or older, and in 5 of 17 patients younger than 60 years of age. The median half-life for daunorubicin was 21.9 hours and 31.1 hours for cytarabine, with both chemotherapies and their metabolites detectable in circulation >7 days after the last administered dose of CPX-351. Notably, the targeted 5:1 molar ratio was maintained at all dose levels for up to 24 hours post-administration.5
A phase 2 study was performed comparing CPX-351 with standard 7 + 3 induction. Patients in this trial included adults with AML between 60 and 75 years of age who were newly-diagnosed and treatment-naive for AML. The goal of the study was to determine efficacy of CPX-351 and delineate patient subgroups who would benefit from therapy, with a primary endpoint of response rate (RR) comprising complete and incomplete remission. Secondary endpoints included event-free survival (EFS) and overall survival (OS). Participants included 126 patients balanced for disease- and patient-specific risk factors who were randomized 2:1 to CPX-351 vs 7 + 3 chemotherapy. CPX-351 induction therapy was administered at 100 U/m2 on days 1, 3, and 5, delivering 100 mg/m2 of cytarabine and 44 mg/m2 of daunorubicin. In the control arm, patients received 100 mg/m2 of cytarabine administered by 7-day continuous infusion and 60 of daunorubicin on days 1 to 3.7
Results demonstrated that CPX-351 produced a higher RR of 66.7% vs 51.2% for those who received conventional 7 + 3 therapy. The difference in EFS and OS between the two cohorts was in favor of CPX-351 but not statistically significant. In a secondary pre-specified analysis of patients with secondary leukemia evolving from previous chemotherapy, another tumor, or progression of myelodysplastic syndrome (MDS) to AML, the RR to CPX-351 was 57.6% vs 31.6% to standard therapy. In addition, EFS was prolonged in this subgroup and there was also a statistically significant improvement in OS. A higher rate of grade 3 to 4 infections was associated with CPX-351 therapy but without an increase in infection-related deaths, although recovery from cytopenias was slower in this patient group. Overall results suggested strong clinical benefit from administration of CPX-351, especially in patients with secondary AML.7
[Update 01/15/18: At the 2015 ASH meeting, results from a phase 2 study of CPX-351 in patients with newly diagnosed AML at high risk for induction mortality were reported. In this study, a reduced dose of CPX-351 ((50 or 75 U/m2) was investigated. Based on the safety of these two doses, additional patients were added to a third cohort of 12 patients who received CPX-352 at a dose of 100 U/m2. The overall response rates (CR/CRp/CRi) were 20% in patients (n=15) receiving 50 U/m2, 40% in patients (n=25) receiving 75 U/m2, and 47% in patients receiving 100 U/m2.8]
A second phase 2 study was performed simultaneously on patients with AML who had received induction therapy in the past but lost response to treatment, with patients up to 85 years of age included in this trial. Patients were stratified by the European Prognostic Index into favorable-, intermediate-, and poor-risk groups based upon duration of first CR, cytogenetics, age, and transplant history. Patients were then randomized 2:1 to CPX-351 vs a standard chemotherapy regimen of the investigator's choice, including mitoxantrone, VP-16 and cytarabine (MEC), or other salvage ratio. Results demonstrated that patients again had an improved RR with CPX, and with stratification by the European Prognostic Index, it was very clear that the subgroup categorized as having unfavorable disease with the worst prognosis had higher RRs (39.3%) for EFS and OS. In the patients with a favorable or intermediate prognosis, there was no difference in the survival and lower RRs (27.6%). In addition, 60-day mortality was lower in the CPX-351 study arm for poor-risk patients vs those with lesser risk (16.1% vs. 24.1%, respectively).9
What are the clinical data that led to the recent approval of this agent by the United States Food and Drug Administration for use in adults with newly-diagnosed therapy-related AML or AML with myelodysplasia-related changes?
A phase 3 trial studied CPX-315 vs 7 + 3 in 309 patients 60 to 75 years of age with newly-diagnosed, secondary AML. Patients had a history of prior cytotoxic therapy, or antecedent MDS, or chronic myelomonocytic leukemia (CMML). Patients were randomized 1:1 to either CPX-351 or 7 + 3, with endpoints including OS and EFS with final analysis beginning after a minimum follow-up of 13.7 months. Treatment with CPX-351 resulted in a statistically significant superior overall survival vs 7 + 3 (median OS 9.56 months vs 5.95 months), paralleled with an improved EFS. In terms of CR or complete remission with incomplete blood count recovery (CRi), the CR/CRi response also favored CPX-351 (47.7%) vs standard therapy (33.3%). Grade 3 to 5 AEs were equal and similar in intensity between the two treatment arms.10 Based on these results, CPX-351 was approved in August 2017 for treatment of adults with newly-diagnosed therapy-related AML or AML with myelodysplasia-related changes.11
Vosaroxin – Dr. Farhad Ravandi
What is vosaroxin and what is its role in the treatment of AML?
Vosaroxin is a quinolone-derived anti-cancer drug that is effective against AML myeloid blasts, and it has topoisomerase II inhibitory action. It is an interesting agent because it does abate two mechanisms of resistance, one being P-glycoprotein-driven drug exclusion and the other being p53-mediated resistance. In contrast with other traditional topoisomerase inhibitors, vosaroxin is only minimally metabolized and is not associated with free radical formation or formation of reactive oxygen species or toxic metabolites.12
What are the clinical data demonstrating the effectiveness and safety of vosaroxin in treatment of patients with AML?
In an early phase 1b/2 study, vosaroxin plus cytarabine showed clinical activity and was well-tolerated in patients with relapsed or refractory AML. Following therapy with this combination, 25% of patients in this study had a CR, and 30-day all-cause mortality was low at only 2.5%.13
The main phase 3 study for vosaroxin was the VALOR trial, a double-blind, placebo-controlled trial at 101 international sites; 711 patients ≥18 years with refractory AML or who were in first relapse after 1 or 2 cycles of previous induction chemotherapy (at least one cycle of anthracycline or anthracenedione plus cytarabine) were included. Patients were assigned 1:1 to vosaroxin plus cytarabine or placebo plus cytarabine and were stratified by age and location. The primary efficacy endpoint was OS with secondary endpoints of EFS, relapse, toxicity, or early mortality. The study had a primary safety endpoint of 30-day and 60-day all cause mortality.12
Results demonstrated a median OS of 7.5 months in the vosaroxin arm vs 6.1 months in the placebo group. A higher proportion of patients achieved CR in the treatment cohort (30%) compared to those who received placebo (16%). Early mortality was similar between the two groups (8% vs 7%, respectively). Treatment-related AEs occurred in 33% of those who received vosaroxin vs 17% of patients who received placebo. The most frequently seen grade 3 or higher AEs included febrile neutropenia, neutropenia, stomatitis, hypokalemia, bacteremia, sepsis, and pneumonia.12
It should be noted that the improvement in response was most compelling in patients 60 years of age or older who achieved a 35% RR, so the greatest benefit was seen in elderly patients. Overall, although there was no significant difference in the primary endpoint between the groups, the stratified analysis suggested that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients, especially as a treatment option for those patients ≥60 years of age.12 Unfortunately, this data was not accepted by drug approval bodies in either the United States or Europe initially, so the drug remains unapproved for clinical use in both regions.
A British group, the Medical Research Council of the United Kingdom (MRC) did a small study to assess vosaroxin added to low-dose cytarabine in a randomized phase 2 study, but this demonstrated increased toxicity and increased early mortality for the combination therapy arm. As a result, they decided not to take this research further.14
More recently, I was involved in a study combining vosaroxin with decitabine in patients with newly-diagnosed AML or high-risk MDS. In this phase 2 randomized trial, we initially administered a dosage of vosaroxin 90 mg/m2 with decitabine 20 mg/m2 to 22 patients, but due to a high incidence of mucositis, the dosage of vosaroxin was lowered to 70 mg/m2 for the subsequent 43 patients. A total of 65 secondary AML/MDS patients were considered evaluable for study purposes, with a median age of 69 years of age (range of 60 to 78 years of age).15
Results demonstrated that the overall response rate (ORR) was 74%, including CR in 48% of patients treated, with a CRi of 9%. The median duration of response to this combination was 9.9 months. The lower 70 mg/m2 dose was associated with similar ORR to the initial 90 mg/m2 dose (74% vs 73%, respectively). Grade 3/4 mucositis was noted in 17% of those treated, but there was reduced incidence of mucositis in those treated with lower dose vosaroxin (30% vs 59% respectively). We concluded that the combination of lower-dose vosaroxin and decitabine warrants further investigation.15
- Kumar CC. Genetic abnormalities and challenges in the treatment of acute myeloid leukemia. Genes Cancer. 2011;2(2):95-107.
- Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002. Cancer Causes Control. 2008;19(4):379-390.
- Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30.
- National Cancer Institute. Adult Acute Myeloid Leukemia Treatment–for health professionals (PDQ®). (January 20, 2017). Available at: https://www.cancer.gov/types/leukemia/hp/adult-aml-treatment-pdq#section/_46.
- Feldman EJ, Lancet JE, Kolitz JE, et al. 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. J Clin Oncol. 2011;29(8)979-985.
- Tardi P, Johnstone S, Harasym N, et al. In vivo maintenance of synergistic cytarabine: daunorubicinratios greatly enhances therapeutic efficacy. Leuk Res. 2009;33(1):129-139.
- Lancet JE, Cortes JE, Hogge DE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014;123(21):3239-3246.
- Borthakur G, Kantarjian HM, DiNardo CD, et al. Phase II study of CPX-351 (cytarabine:daunorubicin) liposome injection in patients (pts) with newly diagnosed acute myeloid leukemia (AML) at high risk for induction mortality. Presented at: 59th Annual Meeting and Exposition of the American Society of Hematology; Atlanta, GA; December 9-12, 2017. Abstract 892.
- Cortes JE, Goldberg SL, Feldman EJ, et al. Phase II, Multicenter, Randomized Trial of CPX-351 (cytarabine:daunorubicin) Liposome Injection versus Intensive Salvage Therapy in Adults with First Relapse AML. Cancer. 2015;121(2)234-242.
- Lancet JE, Uy GL, Cortes JE, et al. Final results of a phase II randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol. DOI: 10.1200/JCO.2016.34.15_suppl 7000 (May 2016).
- United States Food and Drug Administration. FDA approves first treatment for certain types of poor-prognosis acute myeloid leukemia. (August 3, 2017). Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm569883.htm.
- Ravandi F, Ritchie EK, Sayar H, et al. Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2015;16(9):1025-1036.
- Lancet JE, Roboz GJ, Cripe LD, et al. A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia. Haematologica. 2015;100(2):231-237.
- Dennis M, Russell N, Hills RK, et al. Vosaroxin and vosaroxin plus low-dose Ara-C (LDAC) vs low-dose Ara-C alone in older patients with acute myeloid leukemia. Blood. 2015;125(19):2923-2932.
- Daver N, Kantarjian H, Garcia-Manero G, et al. Vosaroxin in combination with decitabine in newly diagnosed older patients with acute myeloid leukemia or high-risk MDS. Haematologica. 2017 Jul 20. pii: haematol.2017.168732. doi: 10.3324/haematol.2017.168732. [Epub ahead of print].