Inclusion Criteria:
- Must be ≥ 18 years of age at the time of signing the Informed Consent Form (ICF); must
voluntarily sign an ICF; and must be willing and able to meet all study requirements.
- Must have morphologically confirmed diagnosis of MDS/MPN, excluding JMML, in
accordancewith WHO (2016) diagnostic criteria.
- Treatment-naïve patients (patients who have had no prior disease-modifying therapy)
may enroll in any AM-001 Arm that is open to accrual in phase 1 or phase 2.
Treatment-naïve patients may have received recombinant erythropoietin, danazol,
hydroxyurea or anagrelide, which are not considered to be disease-modifying therapy
for the purpose of this study.
- After an appropriate wash-out period, patients who have failed (or were intolerant to)
prior therapy with a regimen(s) containing a DNMTi may enroll in any Arm in phase 1b
or any Arm which has met the criterion of the first Simon's Stage and are open to
accrual in the second Simon's Stage in phase 2. Except in the first stage of the phase
2, there are no limits on number of prior therapies if the patient meets all other
eligibility criteria. Previously treated patients include:
- Patients treated with DNMTi therapy prior to enrollment in AM-001 who failed to
achieve a complete remission, per the MDS/MPN IWG response criteria, after at
least 4 cycles of DNMTi therapy
- ;Patients enrolled in AM-001, or patients treated off-study with a regimen
containing a DNMTi, who have definitive disease progression as defined in the
protocol after at least 2 cycles of the prior therapy-this includes patients who
fail to achieve a response with clearly progressive disease and patients who
achieve an initial response who then lose that response;
- Patients enrolled in AM-001 who have stable disease as best response at the
second response evaluation after 6 cycles of the prior AM-001 therapy;
- Patients treated on AM-001 who had and recovered from an adverse event that
precludes further therapy on that Arm; after recovery from a toxicity that is
likely to be related to ASTX727, enrollment in another AM-001 may occur provided
that dose modifications are made as appropriate.
- Must be willing to undergo bone marrow biopsy with aspiration during screening and
bone marrow aspiration with tissue collection for disease assessment and correlative
studies periodically throughout the trial.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
- Life expectancy of at least 3 months, as assessed by the treating physician.
- For previously treated patients, recovery to ≤ Grade 1 or baseline of any toxicities
due to prior systemic treatments, excluding alopecia.
- Must have adequate hepatic and renal function during screening as demonstrated by:
- ALT (SGPT) and AST (SGOT) ≤ 3x the institutional upper limit of normal (ULN);
- Total bilirubin ≤ 1.5x ULN or ≤ 2x ULN, if upon judgment of the treating
investigator the elevated bilirubin is due to extramedullary hematopoiesis
related to the underlying MDS/MPN or to Gilbert's disease;
- Creatinine < 1.5x ULN or estimated creatinine clearance (eCCR) >/=40
ml/min/1.73m2 Patients must have eCCR >/= 60ml/min/1.73m2 to enter into the
INCB59872 arm. eCCR may be calculated using the standard institutional formula.
The estimation tool/formula employed and result must be declared in the case
report form (CRF).
Exclusion Criteria:
- Patients should be excluded from any treatment Arm that includes a novel targeted
agent to which they have had previous exposure. Novel targeted agents in this study
include itacitinib (INCB039110) only, currently. Patients who have had prior exposure
to ASTX727 therapy are not excluded, provided they meet all other eligibility
criteria.
- Prior receipt of any investigational study drug, including treatment on any prior
AM-001 Arm, within 30 days or 5 half-lives (whichever is longer) before receiving the
first dose of study drug in an Arm of AM-001, except if approved by the medical
monitor.
- Prior receipt of any systemic antineoplastic therapy, including but not limited to
prior DNMTi therapy, standard induction or cytotoxic chemotherapy (excluding
hydroxyurea), or approved targeted agent within 21 days or 5 half-lives (whichever is
longer) before receiving the first dose of study drug in an Arm of AM-001.
- Known hypersensitivity to decitabine.
- Transformation to acute myeloid leukemia (e.g. >20% myeloid blasts in bone marrow or
>20% circulating blasts in peripheral blood).
- Organ transplant recipients including allogeneic hematopoietic stem cell transplant
(HSCT).
- History of clinically significant or uncontrolled cardiac disease, including recent
history (within 6 months) of unstable angina, acute myocardial infarction, New York
Heart Association Class III or IV congestive heart failure, or clinically significant
arrhythmia. Patients with history of atrial tachycardia and/or bradycardia that is
well-controlled with medical management and/or pacemaker for at least 1 month before
the first dose of study drug will be allowed.
- History of abnormal EKG or presence of abnormal screening EKG that, in the
investigator's opinion, is clinically significant and contraindicated for clinical
study. Corrected QT interval (QTc), as corrected by Fredericia, on screening EKG >500
milliseconds is excluded, unless there is concomitant right bundle branch block (RBBB)
or concomitant left bundle branch block (LBBB) with a pacemaker.
- Any known contraindications to the use of ASTX727.
- Any sign of active and clinically significant bleeding.
- Other active malignancy, not including localized non-melanoma skin cancer, cervical
carcinoma in situ, breast ductal carcinoma in situ of the breast, or localized
prostate cancer controlled with hormone therapy. Patients with history of other
cancers should be free of disease without ongoing anti-neoplastic therapy for at least
2 years.
- Receipt of wide-field radiotherapy (including therapeutic radioisotopes) ≤ 28 days or
limited field radiation for palliation ≤ 14 days prior to starting study medications;
or has not recovered from side effects of such therapy.
- Patients who require continuation of a prohibited concomitant medication for which no
alternative therapy or allowable substitute is available.
- Active, uncontrolled infection. Patients with infection that is under control with
active treatment are eligible.
- Major surgery requiring general anesthesia within 4 weeks prior to starting study
treatment.(Placement of a central line or port-a-catheter is acceptable within this
time frame and does not exclude the patient.)
- Women who are pregnant or lactating.
- Subjects who expect to conceive or father children within the projected duration of
the study and/or who are unwilling to use highly effective methods of contraception
throughout the duration of the study, starting with the screening visit through the
end of treatment visit. For women of child-bearing potential (WOCBP), a negative urine
pregnancy test at screening and immediately prior to initiating treatment on any
AM-001 treatment Arm (Cycle 1 Day 1) is required.
- Any concurrent serious or unstable medical or psychiatric condition that in the
investigator's opinion would jeopardize the patient's ability to provide informed
consent or to comply with the protocol.
- Any psychological, familial, geographical or sociological condition that in the
investigator's opinion would jeopardize the patient's ability to comply with the
protocol.
