CPX-351 Versus Immediate Stem Cell Transplantation for the Treatment of High-Grade Myeloid Cancers With Measurable Residual Disease

A Randomized Trial for Patients With High-Grade Myeloid Neoplasms With Measurable Residual Disease (MRD): CPX-351 vs. Immediate Allogeneic Hematopoietic Cell Transplantation

This phase II trial studies the effect of CPX-351 followed by donor stem cell transplantation versus immediate donor stem cell transplantation in treating patients with high-grade myeloid cancers with measurable residual disease. Chemotherapy drugs, such as CPX-351, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before donor stem cell transplantation may help kill cancer cells in the body and make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow.

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome With Excess Blasts-2; Myeloid Neoplasm
• Intervention / Treatment: Drug: Liposome-encapsulated Daunorubicin-Cytarabine; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Detailed Description

OUTLINE:

Patients are randomized to 1 of 2 arms.

ARM A: Patients undergo alloHCT.

ARM B: Patients receive CPX-351 intravenously (IV) over 90 minutes on days 1, 3, and 5. Treatment may repeat for an additional cycle for a total of 2 cycles (on days 1 and 3 only of cycle 2) in the absence of disease progression or unacceptable toxicity. Within 60 days after completion of CPX-351, patients undergo alloHCT.

After completion of study enrollment, patients are followed up for up to 5 years.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Acute myeloid leukemia (AML) other than acute promyelocytic leukemia (APL), myelodysplastic syndrome with excess blasts-2 (MDS-EB2), or another high-risk myeloid neoplasm (>= 10% blasts in the blood or marrow), having completed at least one cycle of chemotherapy intended to induce remission

• Subjects must have MRD, defined as the presence of original disease detected by multi-parameter flow cytometry and cytogenetic/molecular assessment within 90 days of chemotherapy intended to induce remission:

  • Abnormal cells identified by multiparameter flow cytometry, present at a frequency of between 0% and 5% of total nucleated cells, judged in the opinion of the hematopathologist to represent continued presence of malignant cells
  • Abnormal karyotype; present in any number of metaphase cells
  • Abnormal fluorescence in-situ hybridization; judged in the opinion of the hematopathologist to represent continued presence of malignant cells
  • The presence of any leukemia associated mutation as detected by DNA sequencing, except mutations in DNMT3A, TET2, or ASXL1. This includes (but is not limited to) the following genes: CBL (CDS), CSF3R (exons 14, 15, 17), EZH2 (exons 15-20), FBXW7 (CDS), FGFR1 (exons 4, 11-17, partial 18), FLT3 (p.D835H), GATA1 (exons 2-3), GATA2 (exons 3-5), HRAS (exon 1-2), IDH1(p.R132), IDH2 (exon 4), JAK2 (exon 12, 14, 16), KIT (8-18), KMT2A (CDS), KRAS (CDS), MAP2K1 (exons 2, 3, 6), MPL (exon 10), MYD88 (exon 3-5), NOTCH1 (exons 20, 26, 27), NPM1 (exon 12), NRAS (CDS), PDGFRA (exons 12-18), PHF6 (CDS), PTEN (CDS), RB1 (CDS), RUNX1 (exon 4-8), SF3B1 (exon 14-16), SRSF2 (exon 1), STAG2 (CDS), STAT3 (exons 20-21), TP53 (CDS), U2AF1 (exons 2, 6), WT1 (CDS), and ZRSR2 (CDS)

• Allowable prior therapy:

  • For the purposes of this study intensive chemotherapy will include regimens listed below. Additional regimens may be included at the discretion of the study principal investigator (PI)

    • Any regimen including cytarabine at a dose of 100 mg/m^2/day for at least 7 days and an anthracycline at any dose +/- gemtuzumab ozogamicin (GO)
    • Any regimen including cytarabine at a dose of at least 100 mg/m^2/day for at least 5 days and a purine analog at any dose (e.g. clofarabine, fludarabine, cladribine) +/- GO
• Ability to understand and voluntarily sign a written informed consent document (ICF)
• Absence of a concomitant illness with a likely survival of < 1 year
• Medically fit, defined as a treatment related mortality score (TRM) of =< 13.1 calculated according to Walter et al, Journal of Clinical Oncology (JCO) 2011
• Additionally, subjects should be eligible in the opinion of their treating physician for allogeneic transplantation
• Bilirubin =< 2.5 x institutional upper limit of normal, unless elevation is thought to be due to Gilberts syndrome or hemolysis (within 14 days of study start [unless otherwise noted] to be enrolled in the study)
• Left ventricular ejection fraction >= 40% assessed by multiple gated acquisition scan (MUGA), echocardiography or other appropriate diagnostic modality within 12 months of enrollment with no clinical evidence of decompensated congestive heart failure
• Creatinine clearance of >= 30 mL/min as measured by Cockcroft Gault equation (within 14 days of study start [unless otherwise noted] to be enrolled in the study)
• Consent of female patients with a negative serum or urine pregnancy test to use a medically acceptable method of contraception throughout the entire study period and for 6 months following the last dose of CPX-351
• Male patients must be willing to refrain from sperm donation for 6 months following the last dose of CPX-351 and must use adequate contraception throughout the entire study period and for 6 months following the last dose of CPX-351
• Patients enrolling in this trial should intend to complete the treatments described and should be eligible in the opinion of the treating physician for allogeneic transplantation
• Patients must have a caregiver capable of providing post-HCT care, who will be present once conditioning therapy begins
• The informed consent document (ICF) must be signed and dated by the subject or by the subject's legally authorized representative if the subject is unable to sign

Exclusion Criteria:

• Allogeneic myeloablative hematopoietic cell transplant within 6 months
• Autologous hematopoietic cell transplant within 6 months

• Known Hypersensitivity to CPX-351

  • Patients may not have known hypersensitivity to CPX-351, daunorubicin, cytarabine, or liposomal products
• Prior treatment with two or more cycles of CPX-351
• Treatment within the last 30 days of other investigational antineoplastic agents

• Evidence of organ dysfunction likely to preclude safe transplantation including the following:

  • Symptomatic coronary artery disease or uncontrolled arrhythmia within the prior 3 months and since most recent anthracycline exposure
  • Myocardial impairment of any cause resulting in heart failure as determined by New York (NY) Heart Association Criteria (class III or IV)
  • Corrected diffusion capacity of the lung for carbon monoxide (DLCOc) < 40% or forced expiratory volume in 1 second (FEV1) < 50%
  • Need for supplemental oxygen
• Active systemic fungal, bacterial, viral or other infection, unless under treatment with anti-microbials and/or controlled or stable (e.g. if specific, effective therapy is not available/feasible or desired [e.g. chronic viral hepatitis, human immunodeficiency virus (HIV)])
• Female patients who are pregnant, nursing, or lactating
• Patients with an inability to accept blood transfusions
• Inability to give informed consent, or unable to comply with the treatment protocol including appropriate supportive care, follow-up and tests
• Any other condition that would cause a risk to patients if they participate in the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A (alloHCT); Patients undergo alloHCT.	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo alloHCT; Other Names: Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT; Stem Cell Transplantation, Allogeneic
Experimental: Arm B (CPX-351, alloHCT); Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5. Treatment may repeat for an additional cycle for a total of 2 cycles (on days 1 and 3 only of cycle 2) in the absence of disease progression or unacceptable toxicity. Within 60 days after completion of CPX-351, patients undergo alloHCT.	Drug: Liposome-encapsulated Daunorubicin-Cytarabine; Given IV; Other Names: CPX-351; Cytarabine-Daunorubicin Liposome for Injection; Daunorubicin and Cytarabine (Liposomal); Liposomal AraC-Daunorubicin CPX-351; Liposomal Cytarabine-Daunorubicin; Liposome-encapsulated Combination of Daunorubicin and Cytarabine; Vyxeos; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo alloHCT; Other Names: Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT; Stem Cell Transplantation, Allogeneic

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	The survival (in days) of subjects in the two arms will be compared using the log-rank test.	Up to 5 years post-randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse-free survival	The following comparisons will be made: (1) number of days elapsing between the date of MRD identification and the date of death or relapse, (2) among transplanted patients, the number of days elapsing between the date of transplantation and the date of death or relapse.	From the time of randomization and (among patients transplanted) from the time of transplantation up to 5 years post-randomization
Rate of transplantation	The proportion of patients having begun transplantation conditioning 60 days and 180 days following enrollment will be compared using the chi-squared test. The time to transplantation among the two arms will be compared by comparing the number of days elapsed between enrollment and the initiation of transplantation conditions by the log-rank test.	Up to 5 years post-randomization
Frequencies of the types of transplantation received	Among the patients receiving transplantation, the proportion of patients in each arm receiving myeloablative transplantation conditioning will be compared using the chi-squared or Fisher's exact test. Among patients receiving transplantation, the proportion of patients in each arm receiving donor stem cells from a haploidentical donor, an unrelated donor, or from cord blood unit will each be compared using the chi-squared or Fisher's exact test.	Up to 5 years post-randomization

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: Jazz Pharmaceuticals
• Investigators: Principal Investigator: Filippo Milano, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): August 9, 2021
• Primary Completion (Actual): August 27, 2023
• Study Completion (Actual): August 27, 2023

Study Registration Dates

• First Submitted: August 21, 2020
• First Submitted That Met QC Criteria: August 21, 2020
• First Posted (Actual): August 25, 2020

Study Record Updates

• Last Update Posted (Actual): September 6, 2023
• Last Update Submitted That Met QC Criteria: August 31, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Myeloid and Monocytic Leukemia
• Additional Relevant MeSH Terms: Pathologic Processes; Bone Marrow Diseases; Hematologic Diseases; Anemia; Neoplastic Processes; Anemia, Refractory; Neoplasms; Myelodysplastic Syndromes; Neoplasm, Residual; Anemia, Refractory, with Excess of Blasts; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cytarabine; Daunorubicin
• Other Study ID Numbers: RG1007476; NCI-2020-05619 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 10545 (Fred Hutch/University of Washington Cancer Consortium)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No