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

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring Myeloid and Monocytic Leukemia Read More

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