Top

Published in:

Open Access 01-12-2022 | Myelodysplastic Syndrome | Research article

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

Authors: Uwe Platzbecker, Joerg Chromik, Jan Krönke, Hiroshi Handa, Stephen Strickland, Yasushi Miyazaki, Martin Wermke, Wataru Sakamoto, Yoshifumi Tachibana, Tillmann Taube, Ulrich Germing

Published in: BMC Cancer | Issue 1/2022

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.

Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47. https://doi.org/10.1182/blood-2016-08-733196.CrossRefPubMedPubMedCentral

Itzykson R, Fenaux P, Bowen D, Cross NCP, Cortes J, De Witte T, et al. Diagnosis and treatment of chronic myelomonocytic leukemias in adults: recommendations from the European Hematology Association and the European LeukemiaNet. Hemasphere. 2018;2:e150. https://doi.org/10.1097/HS9.0000000000000150.CrossRefPubMedPubMedCentral

Platzbecker U. Treatment of MDS. Blood. 2019;133:1096–107. https://doi.org/10.1182/blood-2018-10-844696.CrossRefPubMed

Rudolph D, Steegmaier M, Hoffmann M, Grauert M, Baum A, Quant J, et al. BI 6727, a polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res. 2009;15:3094–102. https://doi.org/10.1158/1078-0432.CCR-08-2445.CrossRefPubMed

Diesch J, Zwick A, Garz A-K, Palau A, Buschbeck M, Götze KS. A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers. Clin Epigenet. 2016;8:71. https://doi.org/10.1186/s13148-016-0237-y.CrossRef

Fenaux P, Haase D, Sanz GF, Santini V, Buske C, Group EGW. Myelodysplastic syndromes: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii57–69. https://doi.org/10.1093/annonc/mdu180.CrossRefPubMed

Wang H, Li Y, Lv N, Li Y, Wang L, Yu L. Predictors of clinical responses to hypomethylating agents in acute myeloid leukemia or myelodysplastic syndromes. Ann Hematol. 2018;97:2025–38. https://doi.org/10.1007/s00277-018-3464-9.CrossRefPubMed

Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126:291–9. https://doi.org/10.1182/blood-2015-01-621664.CrossRefPubMedPubMedCentral

Gil-Perez A, Montalban-Bravo G. Management of myelodysplastic syndromes after failure of response to hypomethylating agents. Ther Adv Hematol. 2019;10:2040620719847059. https://doi.org/10.1177/2040620719847059.CrossRefPubMedPubMedCentral

10.

Rudolph D, Impagnatiello MA, Blaukopf C, Sommer C, Gerlich DW, Roth M, et al. Efficacy and mechanism of action of volasertib, a potent and selective inhibitor of polo-like kinases, in preclinical models of acute myeloid leukemia. J Pharmacol Exp Ther. 2015;352:579–89. https://doi.org/10.1124/jpet.114.221150.CrossRefPubMed

11.

Ottmann OG, Muller-Tidow C, Kramer A, Schlenk RF, Lubbert M, Bug G, et al. Phase I dose-escalation trial investigating volasertib as monotherapy or in combination with cytarabine in patients with relapsed/refractory acute myeloid leukaemia. Br J Haematol. 2019;184:1018–21. https://doi.org/10.1111/bjh.15204.CrossRefPubMed

12.

Dohner H, Lubbert M, Fiedler W, Fouillard L, Haaland A, Brandwein JM, et al. Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy. Blood. 2014;124:1426–33. https://doi.org/10.1182/blood-2014-03-560557.CrossRefPubMedPubMedCentral

13.

Dohner H, Symeonidis A, Sanz MA, Deeren D, Demeter J, Anagnostopoulos A, et al. Phase III randomized trial of volasertib plus low-dose cytarabine (LDAC) versus placebo plus LDAC in patients aged ≥65 years with previously untreated AML, ineligible for intensive therapy. Haematologica. 2016;101(Suppl 1):185–6.

14.

Oncoheroes Biosciences Inc. Onchoheroes Biosciences Inc. and Boehringer Ingelheim International GmbH sign exclusive licensing agreements for volasertib. 2019. https://oncoheroes.com/press-releases-content/2019/9/11/oncoheroes-biosciences-inc-and-boehringer-ingelheim-international-gmbh-sign-exclusive-licensing-agreement-for-volasertib. Accessed 18 June 2021.

15.

Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and proposal for modification of the international working group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–25. https://doi.org/10.1182/blood-2005-10-4149.CrossRefPubMed

16.

Kobayashi Y, Yamauchi T, Kiyoi H, Sakura T, Hata T, Ando K, et al. Phase I trial of volasertib, a polo-like kinase inhibitor, in Japanese patients with acute myeloid leukemia. Cancer Sci. 2015;106:1590–5. https://doi.org/10.1111/cas.12814.CrossRefPubMedPubMedCentral

17.

Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20:2429–40. https://doi.org/10.1200/jco.2002.04.117.CrossRefPubMed

18.

Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and leukemia group B. J Clin Oncol. 2006;24:3895–903. https://doi.org/10.1200/jco.2005.05.4346.CrossRefPubMed

19.

Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223–32. https://doi.org/10.1016/s1470-2045(09)70003-8.CrossRefPubMedPubMedCentral

Title: 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
Authors: Uwe Platzbecker
Joerg Chromik
Jan Krönke
Hiroshi Handa
Stephen Strickland
Yasushi Miyazaki
Martin Wermke
Wataru Sakamoto
Yoshifumi Tachibana
Tillmann Taube
Ulrich Germing
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Myelodysplastic Syndrome
Acute Myeloid Leukemia
Neutropenia
Thrombocytopenia
Leukemia
Published in: BMC Cancer / Issue 1/2022
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-022-09622-0

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2022

Thymoquinone upregulates IL17RD in controlling the growth and metastasis of triple negative breast cancer cells in vitro

A risk scoring system to predict the individual incidence of early-onset colorectal cancer

Clinical significance and oncogenic function of NR1H4 in clear cell renal cell carcinoma

The short-term and oncologic outcomes of younger VS older colorectal cancer patients undergoing primary surgery: a propensity score matching analysis

Retraction Note: Comparison of minimally invasive Ivor Lewis esophagectomy and left transthoracic esophagectomy in esophageal squamous cell carcinoma patients: a propensity score-matched analysis

The experiences and perceptions of female breast cancer patients regarding weight management during and after treatment for oestrogen-receptor positive disease: a qualitative study

Keynote webinar | Spotlight on antibody–drug conjugates in cancer