| Eligibility |
Inclusion Criteria:
- Patients must have acute myeloid leukemia (AML) of Intermediate or High risk (IR or HR
per National Comprehensive Cancer [NCCN] Criteria) in first CR/CRi achieved with 1 or
2 cycles of cytarabine based induction therapy. Zero to 1 cycle of cytarabine based
consolidation will be allowed post CR1. OR Nucleophosmin 1(NPM 1) positive AML ((in
the absence of FMS like tyrosine kinase 3 (FLT3) mutation)) at diagnosis with positive
NPM1 PCR (measurable residual disease [MRD]) after at least 1 cycle of
cytarabine-based consolidation chemotherapy OR Secondary AML(s-AML) based on prior MDS
or CMML in first CR/CRi. OR Therapy-related AML (t-AML) with IR or HR criteria
- Vyxeos induction (up to 2 cycles to reach CR1) and 0-1 cycle of vyxeos consolidation
will be allowed.
- Eligible to receive RIC or Non myeloablative (NMA) transplant preparative regimen with
post-transplant cyclophosphamide (PTCY) based GVHD prophylaxis, at the discretion of
study investigator.
- Patients must have a calculated creatinine clearance (Cockcroft-Gault equation) > 50
mL/min.
- Patients must have a related or unrelated donor. Sibling donor must be a 6/6 match for
human leukocyte antigen A (HLA-A) and HLA-B at intermediate or higher resolution, and
DRB1 at high resolution using DNA-based typing; must be willing to donate peripheral
blood stem cells; and meet institutional criteria for donation. Unrelated donor must
be a 7/8 or 8/8 match at HLA-A, -B, -C, and -DRB1 at high resolution using DNA-based
typing; must be willing to donate peripheral blood mononuclear cells (PBSCs); and be
medically eligible to donate stem cells according to National Marrow Donor Program
(NMDP) criteria.
- Patients must be willing to have peripheral blood stem cells as the graft source.
- Patients must have adequate hepatic function (i.e., serum bilirubin level =1.5 times
the upper limit of normal [ULN], aspartate aminotransferase (AST), and alanine
aminotransferase (ALT), defined as =2.5 × ULN). Higher levels of bilirubin are
acceptable in the setting of Gilbert's disease with no other provable etiologies for
altered liver function.
- Patients must have a Karnofsky performance score (KPS) =70 and/or ECOG score of =2.
- Patients must have recovered from the toxicities of the most recent
induction/consolidation chemotherapy. Recovery is defined by the absence of persistent
treatment-related AE of grade 2 or above. Persistent cytopenia meeting the criteria
for a CRi and controlled infections on antimicrobials is acceptable.
- Women of childbearing potential must be surgically sterile or agree to practice
abstinence or utilize acceptable contraception (intrauterine, injectable, transdermal,
or combination oral contraceptive) during the period while receiving study medication
and for at least 6 months after the last dose of CC-486. Males who are sexually active
with women of childbearing potential must be surgically sterile or using an acceptable
method of contraception (defined as barrier methods in conjunction with spermicides)
from time of screening through at least 3 months after the last dose of CC-486.
- Patients must be able to understand the study procedures, agree to participate in the
study program, and voluntarily provide written Informed Consent
- Patients must have no active COVID-19 infection symptoms at the time of enrollment.
Those who tested positive in the past or made recovery post infection must be symptom
free for at least 2 weeks prior to enrollment.
- Patients must be able to start transplant preparative regimens no later than 35 days
from Day 1 of the most recent CC-486 cycle administration.
Exclusion Criteria:
- Patients may not have Acute Promyelocytic leukemia
- Patients may not have favorable risk AML per National Comprehensive Cancer Network
(NCCN) guidelines ((Core binding factor leukemias, CCAAT/enhancer-binding
protein-alpha (CEBPA) double mutant, AML with concomitant mutations in Nucleophosmin 1
(NPM1) and FLT3))
- Patients must not have received more than two rounds of chemotherapy to achieve first
CR or CRi
- Patients may not have had exposure to hypomethylating agent (HMA) to treat the
leukemia or prior hematologic malignancy ((i.e., myelodysplastic syndrome (MDS),
Chronic Myelomonocytic Leukemia (CMML)) in the 6 months prior to study enrollment.
- Patients may not be, per investigator evaluation, currently in need of other
leukemia-directed therapy such as FLT3- or Isocitrate dehydrogenase (IDH)-directed
therapy.
- Patients may not have myeloproliferative neoplasm progressing to AML (except for CMML)
- With related and unrelated donors, patients may not have high pre-transplant
donor-specific HLA antibodies warranting need for desensitization or other maneuvers
per discretion of the treating physician.
- Patients may not have previously received radiation to maximum tolerable limits to any
critical normal organ.
- Patients with prior Central Nervous System (CNS) involvement or extramedullary disease
will be excluded.
- Patients may not have previously received allogeneic Hematopoietic Cell
Transplantation (HCT).
- Patients may not have clinically significant cardiac disease ((New York Heart
Association (NYHA) Class III or IV)); clinically significant arrhythmia i.e.,
ventricular tachycardia, ventricular fibrillation, or "Torsade de Pointes."
Significant active cardiac disease within the previous 6 months including NYHA class 4
Congestive Heart Failure (CHF), Unstable angina, and Myocardial Infarction
- Patients may not have abnormal QTcF (>480 msec) after electrolytes have been corrected
(at least two different ECG readings and at least 15 minutes between readings).
Subjects with paced rhythm or prolonged QTcF may be exempt from this exclusion if
considered eligible for transplant per treating physician clinical judgement with
optional cardiology consultation.
- Patients may not have positive test results for human immunodeficiency virus (HIV) or
hepatitis B (HBV) or C (HCV). Subjects with a past positive HBV test results due to
previous exposure but who have cleared the virus or are vaccinated against hepatitis
B, as evidenced by negative hepatitis B surface antigen (HbsAg), negative HBV viral
load, and positive antibody to the HbsAg (anti-HBs) are not excluded. Subjects who
have positive hepatitis test results with adequate organ function as defined in the
protocol are not excluded.
- Patients may not have uncontrolled systemic fungal, bacterial, or viral infection
(defined as ongoing signs/symptoms related the infection without improvement despite
appropriate antibiotics, antiviral therapy, and/or other treatment)
- Patients may not have had an active malignancy within 1 year of entry. Active
malignancy is defined as those malignancies requiring treatment with anti-cancer
therapy or with a survival prognosis of less than 2 years at the time of inclusion.
Exceptions to this exclusion include myelodysplastic syndrome/CMML, treated
non-melanoma skin cancer, completely resected Stage 0 or 1 melanoma no less than 1
year from resection, cervical carcinoma in situ or cervical intraepithelial neoplasia,
Breast cancers on long term hormonal therapy (1 year or more), and successfully
treated organ-confined prostate cancer with no evidence of progressive disease based
on prostate specific antigen (PSA) levels and not on active therapy.
- Patients may not be currently receiving any other investigational agents for relapse
reduction.
- Patients seeking umbilical cord blood transplants, or bone marrow graft, or mismatched
unrelated donor (MMUD) with <9/10 HLA match are ineligible.
- Ex-vivo T cell depletion or use of campath, antithymocyte globulin (ATG), or other
anti-T cell antibodies as GVHD prophylaxis are not allowed. Patients are allowed to
receive abatacept as approved by FDA.
- Patients may not have known uncontrolled and active alcohol or substance abuse
- Patients may not have any ongoing medical and non-medical condition that may render
the patient ineligible for ASCT
- Pregnant or breast-feeding females are not eligible. (Lactating females must agree not
to breast feed while taking CC-486).
- Patients may not have a history of inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis), celiac disease (i.e., sprue), prior gastrectomy or upper bowel
removal, or any other gastrointestinal disorder or defect that would interfere with
the absorption, distribution, metabolism, or excretion of the study drug and/or
predispose the subject to an increased risk of gastrointestinal toxicity
- Patients may not have abnormal coagulation parameters (PT >15 seconds, PTT>40 seconds,
and/or INR >1.5). Patients with chronic anticoagulation can be considered for
inclusion after discussion with the PI
- Patients may not have known or suspected hypersensitivity to azacitidine or mannitol
- Patients may not have any significant medical, surgical, or mental health problem that
would prevent appropriate patient participation in the study
- Patients may not have any conditions including, but not limited to, laboratory
abnormalities which put patients at unacceptable risk as per evaluation of treating
physician
- Patients may not have a history of idiopathic thrombocytopenic purpura, disseminated
intravascular coagulation, thrombotic thrombocytopenic purpura (TTP) or hemolytic
uremic syndrome (HUS)
|
