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
IWG criteria
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
Inclusion Criteria:
- Participants must have MDS or MDS/myeloproliferative overlap disorder with potential
sensitivity to HMA therapy, defined as prior published evidence of response to HMA
- 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).
- Participant with MDS who are IPSS-R high and very high risk or IPSS
intermediate 2 risk and higher are excluded 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 RARS-T, CMML, Atypical CML (BCR-ABL negative), and 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 < 1.0 x 109/L
--Participants with lower risk MDS must have must have failed or have
contraindications to available therapies (e.g. lenalidomide, epoetin if indicated for
symptomatic anemia and/or transfusion dependence of red cells) known to be effective
for treatment of their disease
- Participants must have performance status of 60% or greater by Karnofsky Performance
Status (KPS)
- Must have adequate end organ function defined as:
- AST and ALT < 3× the upper limit of normal (ULN)
- Bilirubin ≤ 1.5× the ULN. If elevated bilirubin is due to impaired conjugation
(e.g Gilbert's disease or concomitant medication) or disease related hemolysis,
then direct bilirubin ≤ 1.5× the ULN
- As azacitidine and decitabine have little renal metabolism, and have proven
safety even in dialysis participants, renal function is not an inclusion or
exclusion criteria
- Subjects must have the ability to understand and the willingness to sign a written
informed consent document and complete study related procedures.
Exclusion Criteria:
- MDS with IPSS-R high or very high risk, or IPSS intermediate-2 or high risk disease
- 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.
- Toxicity (grade 2 or higher) from prior therapies including chemotherapy, targeted
therapy, immunotherapy, experimental therapy, radiation or surgery must be resolved to
grade 1 or less.
- Currently pregnant or breast-feeding. Females of child bearing (FOCBP) potential 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 participants with MDS and MDS/MPNs are prone to
infections, if participants 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. Participants with compensated
heart failure are permitted.
- Unstable angina pectoris
- New or unstable cardiac arrhythmia. Stable or controlled arrhythmias are
permitted
- Decompensated liver cirrhosis (Child-Pugh score ≥12 or a MELD score ≥21)
- Psychiatric illness/social situations that would limit compliance with study
requirements.
- Any other prior or ongoing condition, in the opinion of the investigator, that
could adversely affect the safety of the participant or impair the assessment of
study results.
- WOCBP 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.
- Participants with known active HIV infection, as this will further increase the risk
for opportunistic infections. However, participants 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
formulations
