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

Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04526288
• Other study ID #: RG1007476
• Secondary ID: NCI-2020-0561910
• Status: Terminated
• Phase: Phase 2
• Start date: August 9, 2021
• Est. completion date: August 27, 2023

Study information

• Verified date: April 2024
• Source: Fred Hutchinson Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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 will be followed for up to 2 years.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1
• Est. completion date: August 27, 2023
• Est. primary completion date: August 27, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 (tet methylcytosine dioxygenase 2), or ASXL1. This includes (but is not limited to) the following genes: CBL (CDS), CSF3R (colony stimulation factor 3 receptor; exons 14, 15, 17), EZH2 (exons 15-20), FBXW7 (CDS), FGFR1 (exons 4, 11-17, partial 18), FLT3 (FMS-like tyrosine kinase 3; p.D835H), GATA1 (exons 2-3), GATA2 (exons 3-5), HRAS (exon 1-2), IDH1 (isocitrate dehydrogenase NADP+ 1; p.R132), IDH2 (exon 4), JAK2 (Janus kinase 2; 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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Anemia, Refractory, with Excess of Blasts
• Myelodysplastic Syndrome With Excess Blasts-2
• Myelodysplastic Syndromes
• Myeloid Neoplasm
• Neoplasm, Residual
• Neoplasms

Intervention

Procedure:
• Allogeneic Hematopoietic Stem Cell Transplantation
Undergo alloHCT

Drug:
• Liposome-encapsulated Daunorubicin-Cytarabine
Given IV

Locations

Country	Name	City	State
United States	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Center	Jazz Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival	The survival (in days) of subjects in the two arms will be compared using the log-rank test.	Up to 730 days post-randomization.
Secondary	Relapse-free Survival	The following comparisons will be made: (1) number of days elapsing between the date of minimal residual disease (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 up to 2 years post-randomization. For descriptive purposes, we shall also report survival and relapse-free survival from time of transplant up to 2 years post-transplant among patients who receive a transplant.
Secondary	Rate of Transplantation	This outcome will be assessed among patients who have 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 2 years post-randomization
Secondary	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 2 years post-randomization