PF285 ZELLA‐101: PHASE 1 STUDY OF ALVOCIDIB FOLLOWED BY 7+3 INDUCTION IN NEWLY DIAGNOSED AML PATIENTS

Abstract

Background:Alvocidib, a potent cyclin‐dependent kinase‐9 (CDK‐9) inhibitor, has been studied extensively in newly diagnosed and relapsed/refractory AML in a timed sequential combination with cytarabine and mitoxantrone (ACM) with promising activity. Inhibition of CDK‐9 leads to downregulation of BCL‐2 family member, MCL‐1, which in turn inhibits tumor growth. We hypothesized that alvocidib followed by 7+3 induction therapy would be safe and effective in newly diagnosed non‐favorable risk AML.Aims:To evaluate the safety and clinical activity of alvocidib, in combination with cytarabine and daunorubicin (7+3), in previously untreated AMLMethods:We are conducting a multicenter, open‐label, dose‐escalation, safety and biomarker prediction study (Zella 101) of alvocidib given as timed sequential therapy prior to cytarabine and daunorubicin for adults with previously untreated AML. The key eligibility criteria are: ages 18–65 years; previously untreated AML; ECOG PS 0–2; and no major organ dysfunction. Treatment consisted of increasing dose levels of alvocidib starting at 20 mg/m2as a 30‐minute IV bolus followed by 30 mg/m2over 4 hours on days 1–3, cytarabine 100 mg/m2/day by continuous IV infusion on days 5–11, and daunorubicin 60 mg/m2IV on days 5–7. Dose escalation was assessed by standard 3+3 design. Reinduction therapy with alvocidib (same dose as induction) days 1–3, followed by cytarabine 100 mg/m2/day continuous IV days 5–9 and daunorubicin 45 mg/m2IV days 5–6 was recommended in patients with >10% and >5% cellularity and blasts, respectively.Results:A total of 13 patients have been enrolled to date with the median age of 59 years (Range: 31–65 years) (See Table 1). The maximum dose of alvocidib administered was 30 mg/m2as a 30‐minute IV bolus followed by 60 mg/m2over 4 hours on days 1–3 as previously given in prior studies. Overall, alvocidib was well tolerated. The most common NCI CTCAE ≥Grade 3 treatment emergent nonhematologic AEs noted in ≥3 patients in the safety population were device related infection (30.8%), diarrhea (30.8%) and lung infection (23.1%). Cytogenetics were reported on 7 patients, 5 were intermediate to high risk. Ten patients were evaluable with post baseline response assessments, two patients were too early for disease assessment, and one patient died prior to disease assessment due to septic shock. Nine of the 10 evaluable patients achieved CR (9/10, 90%).Summary/Conclusion:Alvocidib given as timed sequential therapy prior to cytarabine and daunorubicin (7+3) induction in newly diagnosed AML demonstrated an acceptable safety profile with an MTD (30 mg/m2IV bolus followed by 60 mg/m2infusion over 4 hours) similar to previously investigated timed sequential regimens of alvocidib. Future directions include a randomized phase 2 expansion comparing cytarabine and daunorubicin with or without preceding timed sequential alvocidib, and prospective BH3 profiling of AML patients.image