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. 2022 May 21;22(1):569.
doi: 10.1186/s12885-022-09622-0.

Volasertib as a monotherapy or in combination with azacitidine in patients with myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia: summary of three phase I studies

Uwe Platzbecker  1 , Joerg Chromik  2 , Jan Krönke  3 , Hiroshi Handa  4 , Stephen Strickland  5 , Yasushi Miyazaki  6 , Martin Wermke  7 , Wataru Sakamoto  8 , Yoshifumi Tachibana  9 , Tillmann Taube  10 , Ulrich Germing  11
Affiliations

Volasertib as a monotherapy or in combination with azacitidine in patients with myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia: summary of three phase I studies

Uwe Platzbecker et al. BMC Cancer. .

Abstract

Background: This report summarizes three phase I studies evaluating volasertib, a polo-like kinase inhibitor, plus azacitidine in adults with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia, or acute myeloid leukemia.

Methods: Patients received intravenous volasertib in 28-day cycles (dose-escalation schedules). In Part 1 of 1230.33 (Study 1; NCT01957644), patients received 250-350 mg volasertib on day (D)1 and D15; in Part 2, patients received different schedules [A, D1: 170 mg/m2; B, D7: 170 mg/m2; C, D1 and D7: 110 mg/m2]. In 1230.35 (Study 2; NCT02201329), patients received 200-300 mg volasertib on D1 and D15. In 1230.43 (Study 3; NCT02721875), patients received 110 mg/m2 volasertib on D1 and D8. All patients in Studies 1 and 2, and approximately half of the patients in Study 3, were scheduled to receive subcutaneous azacitidine 75 mg/m2 on D1-7.

Results: Overall, 22 patients were treated (17 with MDS; 12 previously untreated). Across Studies 1 and 2 (n = 21), the most common drug-related adverse events were hematological (thrombocytopenia [n = 11]; neutropenia [n = 8]). All dose-limiting toxicities were grade 4 thrombocytopenia. The only treated patient in Study 3 experienced 18 adverse events following volasertib monotherapy. Studies 1 and 2 showed preliminary activity (objective response rates: 25 and 40%).

Conclusions: The safety of volasertib with azacitidine in patients with MDS was consistent with other volasertib studies. All studies were terminated prematurely following the discontinuation of volasertib for non-clinical reasons by Boehringer Ingelheim; however, safety information on volasertib plus azacitidine are of interest for future studies in other diseases.

Keywords: Acute myeloid leukemia; Chronic myelomonocytic leukemia; Myelodysplastic syndrome; Phase I; Volasertib.

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Conflict of interest statement

Uwe Platzbecker received grant support, paid to GWT-TUD, from Amgen; lecture fees, grant support, paid to the University of Leipzig; fees for serving on a steering committee, consulting fees, and travel support from Celgene; grant support, paid to GWT-TUD, from Janssen Biotech; grant support, paid to University Dresden, from Merck and Novartis; and lecture fees from Novartis. Joerg Chromik declares no potential conflict of interest. Jan Krönke reports being part of an advisory council or committee for Janssen, Takeda, and Celgene/Bristol-Myers Squibb; received honoraria from Sanofi. Hiroshi Handa received honoraria from Janssen, Takeda, Celgene, Novartis, Ono, AbbVie, and Kyowa-Kirin; consulting fees from Janssen, Takeda, Celgene, and AbbVie; grants or funds from Takeda, Celgene, Novartis, Ono, AbbVie, Kyowa-Kirin, and Chugai. Stephen Strickland received consulting fees (in the past two years) from AbbVie, ArcherDx, Genentech, Incyte, Kura Oncology, Novartis, Pfizer, and Syros. Yasushi Miyazaki received honoraria from AbbVie, Novartis, Astellas, Synbio, Sumitomo-Dainippon, Chugai, Celgene, Nippon-shinyaku, Ohtsuka, and Kyouwa-Kirin; and grants or funds from Sumitomo-Dainippon, and Chugai. Martin Wermke received honoraria from Bristol-Myers Squibb, Merck, Roche, Novartis, Kite, Boehringer Ingelheim, and AstraZeneca; consulting or advisory role fees from Bristol-Myers Squibb, Novartis, Kite, Heidelberg Pharma, Roche, and Boehringer Ingelheim; travel, accommodation, expenses from Glenmark, Bristol-Myers Squibb, and AstraZeneca. Wataru Sakamoto is an employee of Nippon Boehringer Ingelheim Co., Ltd. Yoshifumi Tachibana is an employee of Nippon Boehringer Ingelheim. Tillmann Taube is an employee of Boehringer Ingelheim International. Ulrich Germing received speaker’s honorarium from Celgene, Novartis, and Jazz; consulting fees from Celgene; and institutional research support from Celgene, and Novartis.

Figures

Fig. 1
Fig. 1
Overview of study design and treatment schedule in Studies 1, 2, and 3. Azacitidine was given at 75 mg/m2 to all patients in Studies 1 and 2, and approximately half of patients in Study 3. All planned cycles were 28 days. Aza, azacitidine; D, day; EOT, end of treatment; FU, follow-up
Fig. 2
Fig. 2
a Drug related adverse events (%) reported in ≥ 2 patients and b response in Study 1 (Part 1; n = 13) and Study 2 (n = 5). *One patient was not included in the efficacy evaluation in Study 1.  ISR, injection site reaction; WBC, white blood cell
See this image and copyright information in PMC

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