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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Acute Myeloid Leukemia, Myelodysplastic Syndrome With Excess Blasts-2, Myeloid Neoplasm

Intervention / Treatment
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* Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
* Drug: Liposome-encapsulated Daunorubicin-Cytarabine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (alloHCT)<br>Patients undergo alloHCT. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo alloHCT<br>* Other names: Stem Cell Transplantation, Allogeneic;|
| Experimental: Arm B (CPX-351, alloHCT)<br>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. | Procedure: Allogeneic Hematopoietic Stem Cell Transplantation<br>* Undergo alloHCT<br>* Other names: Stem Cell Transplantation, Allogeneic;Drug: Liposome-encapsulated Daunorubicin-Cytarabine<br>* Given IV<br>* Other names: Daunorubicin and Cytarabine (Liposomal);|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myeloid and Monocytic Leukemia