Phase 1 Study of Alvocidib (DSP-2033) in Combination with Cytarabine/Mitoxantrone (ACM) or Cytarabine/Daunorubicin (A+7+3) in Japanese Patients (Pts) with Acute Myeloid Leukemia (AML)
Authors: Morita Yasuyoshi , Ikezoe Takayuki , Ando Kiyoshi , Onozawa Masahiro , Yamane Takahisa , Hosono Naoko , Kiguchi Toru , Iwasaki Hiromi , Miyamoto Toshihiro , Kasai Miho , Sugimoto Saori , Miyazaki Yasushi , Kizaki Masahiro , Akashi Koichi 
Published: November 2020

Background: Alvocidib is a potent cyclin-dependent kinase 9 inhibitor, which has previously been shown to downregulate the B-cell lymphoma-2 family member MCL-1 (myeloid cell leukemia-1) which, in turn, sensitizes tumor cells to apoptotic signals. Alvocidib has been studied globally in relapsed/refractory (R/R) AML in combination with cytarabine/mitoxantrone, as well as in newly diagnosed AML in combination with cytarabine/daunorubicin, and has demonstrated acceptable clinical activity. However, safety and tolerability in Japanese AML pts are unknown.
Aims: To evaluate the safety and tolerability of alvocidib administered as ACM or A+7+3.
Methods: This multicenter, open-label, uncontrolled phase 1 study (NCT03563560) included 2 regimens: ACM (in pts R/R to cytarabine/anthracycline based intensive chemotherapy and without a cumulative total exposure of anthracycline [daunorubicin-equivalent dose] exceeding 360 mg/m2 at entry) and A+7+3 (in newly diagnosed, treatment naive pts). Key eligibility criteria for both regimens were age 20-64 years, Eastern Cooperative Oncology Group performance status ≤ 2, a left ventricular ejection fraction ≥ 50%, and no major organ dysfunction. The ACM regimen (cohorts R1 and R2) comprised a fixed dose hybrid regimen of alvocidib (30 mg/m2/day as a 30-minute intravenous [IV] bolus followed by 60 mg/m2/day over 4 hours as a continuous IV infusion on days 1-3), and escalating doses of cytarabine (300 or 667 mg/m2/day by continuous IV infusion on days 6-8) and mitoxantrone (14 or 40 mg/m2/day IV infusion on day 9 or 10 starting 12 hours after completing cytarabine) in a standard 3+3 design. In the A+7+3 regimen (cohort F1) the dose of each component was fixed according to the recommended dose from the ongoing phase 1 study in the US (NCT03298984). Treatment consisted of the alvocidib hybrid regimen on days 1-3, cytarabine 100 mg/m2/day by continuous IV infusion on days 5-11, and daunorubicin 60 mg/m2/day IV on days 5-7. The primary study objective was to determine the safety and tolerability of alvocidib in combination with each type of chemotherapy, via the assessment of dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs; graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03). Secondary objectives were to evaluate the pharmacokinetics (including maximum plasma concentration [Cmax] and area under the concentration-time curve up to the last measurable concentration [AUC0-last]) and clinical activities of these regimens.
Results: Between April 2018 to October 2019, 10 pts were enrolled, with a median (range) age of 45.0 (25-64) years. Of these, 6 pts (2 with relapsed disease and 4 with refractory disease) received ACM and 4 pts received A+7+3 (Table). Alvocidib was tolerated and DLTs were not observed in either of the two regimens. The most common TEAEs were hematologic events. The most common Grade ≥ 3 non-hematologic TEAEs occurring in ≥ 2 pts in the ACM regimen were diarrhea (50%), hepatic function abnormal (33%), sepsis (33%), cardiac failure (33%) and hypokalemia (33%). The most common Grade ≥ 3 non-hematologic TEAEs noted in ≥ 2 pts in the A+7+3 regimen were diarrhea (100%), tumor lysis syndrome (50%), and vomiting (50%). In the ACM regimen in R/R AML, all 6 pts were evaluable, of whom 5 (83%) achieved an objective response, including 4 complete remissions (CRs) and 1 morphologic leukemia-free state. The mean duration of CR was 13.6 months. In the A+7+3 regimen in newly diagnosed AML, 3 out of 4 pts were evaluable. All 3 evaluable pts achieved CR. One pt did not complete the A+7+3 regimen due to tumor lysis syndrome and was discontinued from the study prior to disease assessment. Overall, the mean Cmax of alvocidib in plasma was 1241 ng/mL on day 1 and 1217 ng/mL on day 3. The mean AUC0-last was 6555 h*ng/mL on day 1 and 7998 h*ng/mL on day 3.
WSummary: Alvocidib in combination with cytarabine 667 mg/m2/day and mitoxantrone 40 mg/m2/day IV infusion in Japanese pts with R/R AML or cytarabine/daunorubicin (7+3) induction in Japanese pts with newly diagnosed AML showed an acceptable safety profile similar to previously investigated regimens in other studies. These data suggest that future studies of alvocidib in hematological malignancies are warranted, and planned directions for alvocidib development include phase 1/2 efficacy and safety studies in combination with other agents.

Disclosures
Ando: Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Kiguchi:SymBio Pharmaceuticals., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Research Funding; Daiichi Sankyo Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Honoraria; Mochida Pharmaceutical Co., Ltd.: Honoraria; Taiho Pharmaceutical Co., Ltd.: Research Funding; Teijin Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Pfizer Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Novartis Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Sumitomo Dainippon Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Janssen Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Celgene Co., Ltd.: Honoraria, Research Funding; Celltrion, Inc.: Research Funding; Bristol-Myers Squibb Co., Ltd.: Honoraria, Research Funding; MSD Co., Ltd.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria; Sanofi K.K., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Honoraria, Research Funding; Astellas Pharmaceutical Co., Ltd.: Honoraria, Research Funding. Kasai:Sumitomo Dainippon Pharma Co., Ltd.: Current Employment. Sugimoto:Sumitomo Dainippon Pharma Co., Ltd.: Current Employment. Miyazaki:NIPPON SHINYAKU CO.,LTD.: Honoraria; Otsuka Pharmaceutical: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma KK: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Celgene: Honoraria.