This will be a single arm, open label pilot study of 5AZA-alt-DEC. Participants will be
treated for a minimum of 24 weeks in the absence of clear evidence of progressive disease.
Participants who have any response will be permitted to continue treatment until relapse or
progression of disease that is not sensitive to protocol defined dose escalation.
The primary objective of this study is to determine Overall Response Rate (ORR) of
5AZA-alt-DEC. The combined response endpoint will include complete response (CR), partial
response (PR), and hematologic improvement (HI), with HI criteria specifically as defined by
The secondary endpoints of this study include:
- Cumulative incidence of response for both CR and overall response
- Duration of response (DOR)
- Safety evaluation by tabulation of adverse events of grade 3 and higher
Correlative endpoints include:
- Correlation of DNMT1 depletion with clinical response criteria
- Correlation of clinical response with disease biological phenotype measured by
morphology and cytogenetics
- Exploratory measurements of pyrimidine metabolism pre-treatment and on-therapy
- Patient must have myelodysplastic syndrome (MDS) or MDS/myeloproliferative overlap
disorder with potential sensitivity to Hypomethylating agents (HMA) therapy
- Myelodysplastic Syndromes:
- As classified by hematopathology review of WHO categories,
myelodysplastic/myeloproliferative neoplasm unclassifiable, refractory
anemia with ring sideroblasts and thrombocytosis, refractory cytopenia with
unilineage dysplasia (RCUD), refractory anemia with ring sideroblasts
(RARS), refractory cytopenia with multi-lineage dysplasia (RCMD), refractory
anemia with excess blasts (RAEB), myelodysplastic syndrome with isolated
del(5q), myelodysplastic syndrome unclassifiable (MDS-U).
- Patient with MDS who are IPSS-R high and very high risk should only be
considered if their primary clinician feels that they will not tolerate
azacitidine 75mg/m^2 given proven overall survival benefit in higher risk
MDS from AZA-001 with this treatment.
- Myelodysplastic/myeloproliferative neoplasm overlap disorders ---MDS/MPN
crossover syndromes with limited evidence of extramedullary hematopoiesis (may
not have palpable splenomegaly) and reticulin fibrosis of grade 1 or less without
evidence of progression to accelerated phase. These may include but may not be
limited to Refractory anemia with ringed sideroblasts and essential
thrombocytosis (RARS-T), Chronic myelomonocytic leukemia (CMML), Atypical Chronic
myeloid leukemia (Atypical CML) (BCR-ABL negative), and myelodysplastic and
myeloproliferative overlap syndrome not otherwise specified (MDS/MPN NOS)
- Indication for HMA therapy: Symptomatic anemia OR thrombocytopenia with a platelet
count of <100 x 109/L OR transfusion dependence for red-cells OR transfusion
dependence for platelets OR absolute neutrophil count < 1.5 x 109/L
- Patients must have performance status of 60% or greater by Karnofsky Performance
- Subjects must have the ability to understand and the willingness to sign a written
informed consent document and complete study related procedures.
- Prior Treatment with azacitidine, decitabine or investigational HMA therapy with
overlapping mechanism of action (e.g. guadecitibine)
- No other disease directed therapy, save for hydroxyurea, including experimental or
investigational drug therapy for 14 days prior to study entry.
- Currently pregnant or breast-feeding. Females of child bearing potential (FOCBP) must
have negative serum pregnancy test within 72 hours from treatment start. (NOTE: FOCBP
is any biologic female, regardless of sexual or gender orientation, having undergone
tubal ligation, or remaining celibate by choice, who has not undergone a documented
hysterectomy or bilateral oophorectomy or has had a menses any time in the preceding
12 months (therefore not naturally post-menopausal for > 12 months)
- Uncontrolled intercurrent illness that could limit life expectancy or ability to
complete study correlates. This includes, but is not limited to:
- Ongoing or active infection. As patients with MDS and MDS/MPNs are prone to
infections, if patients are actively being treated with appropriate antibiotics
or antifungal therapy with clinical evidence of infection control, then they will
be considered eligible for study.
- Uncontrolled concurrent malignancy
- Congestive heart failure of NYHA class III/IV. Patients with compensated heart
failure are permitted.
- Unstable angina pectoris
- New or unstable cardiac arrhythmia. Stable or controlled arrhythmias are
- Decompensated liver cirrhosis (Child-Pugh score ≥12 or a MELD score ≥21)
- Psychiatric illness/social situations that would limit compliance with study
- Any other prior or ongoing condition, in the opinion of the investigator, that
could adversely affect the safety of the patient or impair the assessment of
- FOCBP and males that are unwilling to agree to use dual contraceptive measures (i.e.,
hormonal or barrier method of birth control; abstinence, condom) prior to study entry
and for the duration of study participation. Should a female subject become pregnant
or suspect she is pregnant while participating in this study, she should inform the
treating physician immediately
- Sexually active male who is unwilling to use a condom when engaging in any sexual
contact with a female with child-bearing potential, beginning at the screening visit
and continuing until 4 weeks after taking the last dose of 5AZA-alt-DEC.
- Patients with known active HIV infection, as this will further increase the risk for
opportunistic infections. However, patients with chronic HIV with undetectable viral
load by PCR, without opportunistic infection, and on a stable regimen of
antiretroviral therapy would be eligible.
- Known allergy or hypersensitivity to any component of azacitidine or decitabine