Phase I study of alvocidib plus cytarabine/mitoxantrone or cytarabine/daunorubicin for acute myeloid leukemia in Japan. Issue 12 (10th October 2022)

• Record Type: Journal Article
• Authors: Ikezoe, Takayuki; Ando, Kiyoshi; Onozawa, Masahiro; Yamane, Takahisa; Hosono, Naoko; Morita, Yasuyoshi; Kiguchi, Toru; Iwasaki, Hiromi; Miyamoto, Toshihiro; Matsubara, Keisuke; Sugimoto, Saori; Miyazaki, Yasushi; Kizaki, Masahiro; Akashi, Koichi
• Is Part Of: Cancer science. Volume 113:Issue 12(2022)
• Page Start: 4258
• Page End: 4266
• Publication Date: 2022-10-10
• Subjects: alvocidib -- clinical trial -- Japan -- leukemia, myeloid -- safety; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.15458
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Therapeutic improvements are needed for patients with acute myeloid leukemia (AML), particularly those who have relapsed or who have treatment‐refractory (R/R) AML or newly diagnosed patients with poor prognostic factors. Alvocidib (DSP‐2033), a potent cyclin‐dependent kinase 9 inhibitor, has previously demonstrated promising clinical activity for the treatment of AML. In this multicenter, open‐label, uncontrolled, 3 + 3 phase I study, we investigated the safety and tolerability of alvocidib administered in combination with either cytarabine and mitoxantrone (ACM) for R/R AML or cytarabine/daunorubicin (A + 7 + 3) for newly diagnosed AML. Alvocidib was administered to all patients as a 30‐min intravenous (i.v.) bolus (30 mg/m 2 /d), followed by a continuous i.v. infusion over 4 h on days 1–3 (60 mg/m 2 /d). A total of 10 patients were enrolled: six received ACM (at two dose levels of cytarabine and mitoxantrone) and four received A + 7 + 3. Alvocidib was tolerated and no dose‐limiting toxicities were observed. All patients experienced adverse events, of which diarrhea was the most frequent (100%); hematologic events were also common. Alvocidib concentration peaked at the end of dosing (4.5 h after start of administration), plasma accumulation after repeated dosing was minimal and urinary excretion was negligible. The rate of complete remission/complete remission with incomplete hematologic recovery was 66.7% with the ACM regimen in R/R AML, including four complete remission (median duration 13.6 months), and 75% (three complete remission) with the A + 7 + 3 regimen. Further development of alvocidib in hematologic malignancies is warranted. The trial is registered with Clinicaltrials.gov, NCT03563560. Abstract : The data demonstrated that both alvocidib regimens had an acceptable safety profile in Japanese patients with AML. The clinical activity was also promising, although this was a very small group of patients.