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

A Phase 1b/2, Open-label Clinical Study to Determine Preliminary Safety and Efficacy of Alvocidib When Administered in Sequence After Decitabine or Azacitidine in Patients With MDS

Alvocidib, a cyclin-dependent kinase 9 (CDK 9) inhibitor, in time-sequential therapy demonstrated significant clinical activity in secondary AML patients with prior MDS. Patients with IPSS-R intermediate and above MDS have an increased risk of developing AML and may be treated with the same chemotherapy regimens used in patients with AML. Eight Phase I or II clinical trials have been completed in patients with AML, totaling more than 400 patients with both relapsed/refractory or newly diagnosed AML.

Preclinical studies have demonstrated that decitabine exposure increased the expression of NOXA, which is a specific antagonist of the survival factor MCL 1. Pharmacologic downregulation of MCL-1 via CDK 9 inhibition, as well as upregulation of the MCL-1 antagonist, NOXA, following decitabine exposure may result in enhanced antileukemic activity in MCL-1-dependent malignancies.

PHASE 1b:

Patients will be enrolled in cohorts of 3-6 patients. Escalation of the alvocidib dose will follow a standard 3+3 design with sequential cohorts of 3 patients treated with incrementally higher doses of alvocidib administered in sequence after decitabine (during dose escalation) or azacitidine until a dose-limiting toxicity (DLT) is observed and the MTD is established.

Once the MTD or preliminary RP2D of alvocidib administered via hybrid dosing is identified, 2 cohorts of at least 3 patients each will receive azacitadine followed by alvocidib administered as a 30-60 minute IV infusion.

Expansion at MTD Once the MTD or preliminary RP2D of alvocidib administered as a 30-to-60 minute IV infusion is determined, up to 25 patients will be enrolled in an Expansion cohort to receive alvocidib following azacitadine to confirm safety, explore potential biomarkers, and evaluate potential signals of alvocidib activity. Once this Expansion cohort is completed, the study will progress to Phase 2

PHASE 2:

Phase 2 design is based on the Simon 2-stage minimax design (Simon 1989).

• Stage 1: Up to 15 evaluable patients will be enrolled and treated at the RP2D identified in the Phase 1b study.
• Stage 2: Ten patients will be enrolled to bring the total enrollment in Phase 2 (including Stage-1 patients) to 25 evaluable patients. Stage-2 patients will also receive the RP2D dose of alvocidib administered by 30-to-60 minute IV infusion identified in the Phase 1b study. If 6 or more responses are observed in 25 patients, the conclusion will be that the combination regimen is worthy of further investigation.

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