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.
• Aged ≥18 years
• 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
• Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score ≤2 at enrollment
• 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.)
• Patients with a life expectancy of ≥3 months (90 days)
• 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):
‣ Serum creatinine: ≤1.8× the upper limit of the normal (ULN) range
⁃ Total bilirubin: ≤2× the ULN
⁃ Aspartate transaminase (AST) and alanine transaminase (ALT): ≤3× the ULN
⁃ Left ventricular ejection fraction (LVEF) \>45% by echocardiogram or multigated acquisition (MUGA) scan
• Be able to comply with the requirements of the entire study.
• Patients with Revised International Prognostic Scoring System (IPSS-R) intermediate-, high-, and very high-risk MDS