A randomized phase 2 trial of nintedanib and low-dose cytarabine in elderly patients with acute myeloid leukemia ineligible for intensive chemotherapy

Abstract

We investigated the safety and efficacy of nintedanib added to low-dose cytarabine (LDAC) in a phase 1/2 study in patients 60 years or older with newly diagnosed or relapsed/refractory (r/r) AML ineligible for intensive chemotherapy. The results of the dose-finding phase 1 part have been previously published. Patients were randomized 1:1 to LDAC plus nintedanib or LDAC plus placebo stratified by AML status (newly diagnosed vs r/r). LDAC was applied subcutaneously at 20 mg twice daily on days 1 to 10. Nintedanib/placebo was orally administered twice daily on days 1 to 28 in 28-day cycles. The primary endpoint was overall survival (OS). Between 05/2017 and 09/2019, 31 patients were randomized and 30 were treated, before the study was terminated prematurely due to slow recruitment. Median (range) age of patients was 76 (60-84) years. Twenty-two patients (73%) had r/r AML. Median OS in patients treated with LDAC and nintedanib was 3.4 months, compared with 3.6 months in those treated in the placebo arm, with a HR adjusted for AML status of 1.19 (corresponding confirmatory adjusted 95% CI, 0.55-2.56; univariate log-rank P = 0.96). In the 22 patients with r/r AML, median OS was 3.0 months in the nintedanib and 3.6 months in the placebo arm (P = 0.36). One patient in the nintedanib and two patients in the placebo arm achieved a CR and entered maintenance treatment. Nintedanib showed no superior therapeutic activity over placebo when added to LDAC in elderly AML patients considered unfit for intensive chemotherapy. The trial was registered at clinicaltrials.gov NCT01488344.

Keywords: Acute myeloid leukemia; Angiogenesis; Low-dose cytarabine; Nintedanib.

Conflict of interest statement

This was an independent, investigator-initiated study supported by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany. BI had no role in the design, analysis or interpretation of the results in this study. BI was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to BI substance, as well as intellectual property considerations. J.G. received honoraria from TESARO, QUIRIS Healthcare, Ecker + Ecker, Dr. August Wolff, Roche, University Clinics Schleswig–Holstein, and RWTH Aachen University. J.-H.M. received honoraria from Astellas, Pfizer, Daiichi Sankyo, BMS, Celgene, Novartis, Jazz, and BeiGene. G.L. received research grants not related to this manuscript from AGIOS, AQUINOX, AstraZeneca, Bayer, Celgene, Gilead, Janssen, Morphosys, Novartis, Roche, and Verastem. G.L. received honoraria from ADC Therapeutics, Abbvie, Amgen, AstraZeneca, Bayer, BMS, Celgene, Constellation, Genmab, Gilead, Incyte, Janssen, Karyopharm, Miltenyi, Morphosys, NanoString, Novartis, and Roche. C.S. received honoraria from AbbVie, AstraZeneca, Astellas, BMS, Celgene, Jazz, Novartis, Pfizer and Roche. The remaining authors declare no competing financial interests.

© 2022. The Author(s).

Figures

Fig. 1

CONSORT flowchart. ITT, intention to treat

Fig. 2

Patient outcome and overall survival. (A) Swimmer plot of individual treatment courses and outcome in all 30 patients. Treatment allocation is color-coded. (B) Kaplan–Meier estimates of OS of all 30 patients treated in the study. Dashed lines mark the median survival time. The transparent areas represent the pointwise 95% CI (log-transformed) of the Kaplan–Meier estimates. Abbreviations: HR, hazard ratio; NE, not estimable; adj, adjusted; unadj, unadjusted; OS, overall survival

Fig. 3

Adverse events. Butterfly plot displaying the percentage of patients with at least one AE or with at least one AE of CTCAE grade ≥ 3 by system organ class