A Phase 1b/2 Study of Alvocidib Plus Decitabine or Azacitidine in Patients With MDS

Inclusion Criteria:

1. Aged ≥18 years
2. Phase 1b Dose Escalation: Patients with previously untreated MDS and patients with MDS who received fewer than six (6) cycles of previous HMAs. Phase 1b Expansion: Untreated patients with de novo or secondary MDS. Phase 2: Untreated patients with de novo or secondary MDS
3. Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score ≤2 at enrollment
4. Provide written informed consent prior to any study-related procedure. (In the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed.)
5. Patients with a life expectancy of ≥3 months (90 days)
6. Patients with adequate major organ functions meeting the following criteria on the basis of laboratory data within 4 weeks (28 days) before enrollment (if multiple data are available, most recent data during the period):

   1. Serum creatinine: ≤1.8× the upper limit of the normal (ULN) range
   2. Total bilirubin: ≤2× the ULN
   3. Aspartate transaminase (AST) and alanine transaminase (ALT): ≤3× the ULN
   4. Left ventricular ejection fraction (LVEF) \>45% by echocardiogram or multigated acquisition (MUGA) scan
7. Be able to comply with the requirements of the entire study.
8. Patients with Revised International Prognostic Scoring System (IPSS-R) intermediate-, high-, and very high-risk MDS

Exclusion Criteria:

1. Presence of concomitant severe cardiovascular disease:

   1. Patients who had myocardial infarction within 6 months (180 days) before enrollment
   2. Patients with significant diseases at enrollment that may affect study treatment, such as New York Heart Association (NYHA) Functional Class III or IV heart disease, National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade ≥3 arrhythmia, angina pectoris, abnormal electrocardiogram findings, interstitial pneumonia or pulmonary fibrosis
2. Presence of concomitant malignancy requiring chemotherapy or any malignancy (except basal and squamous cell carcinoma of the skin) for which the patient received chemotherapy within 6 months prior to enrollment. NOTE: Diagnosis of any previous or concomitant malignancy is thus not an exclusion criterion.
3. Presence of uncontrolled or uncontrollable infection(s); or ≥Grade 3 infection according to NCI CTCAE v5.0
4. Presence of any psychological, familial, sociological or geographical condition that, in the opinion of the investigator, could potentially hinder compliance with the study protocol and follow-up schedule
5. Patients with a dry tap on bone marrow aspiration before enrollment
6. Patients with concurrent autoimmune disease or a history of chronic or recurrent autoimmune disease, or patients who require long-term systemic steroid therapy greater than the equivalent of 20 mg of prednisone daily (excluding therapy given on an 'as needed' \[PRN\] basis)
7. Patients with other documented malignancies within past year aside from synchronous or metachronous multiple cancers with a disease-free period of ≤5 years (excluding carcinoma in situ, mucosal carcinoma, or other such carcinomas curatively treated with local therapy)
8. Patients with ≥Grade 2 hemorrhage according to NCI CTCAE v5.0
9. Patients who have previously received alvocidib or another cyclin-dependent kinase 9 (CDK9) inhibitor
10. Patients who are pregnant or breastfeeding
11. Female patients of childbearing potential who are sexually active and unwilling to use a medically acceptable method of contraception associated with a low failure rate prior to study entry, for the duration of study participation and for at least 6 months after the last dose of study drug. (Patients will be considered to be of childbearing potential unless surgically sterilized by hysterectomy, or bilateral tubal ligation / salphingectomy, or postmenopausal for at least 2 years.)
12. Male patients with partners of childbearing potential who are unwilling to use condoms in combination with a second effective method of contraception during the trial and for at least 3 months after the last administration of study treatment.
13. Patients who are inappropriate for participation in the study for other reasons in the opinion of the investigator or sub-investigator(s)
14. Patients with a known hypersensitivity to decitabine (those patients enrolled in escalation) or azacitidine or mannitol
15. Patients who have received erythropoietin-stimulating agents (ESAs) within 2 weeks (14 days) prior to Cycle 1/Day 1