1. Cusatuzumab plus azacitidine in newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy (CULMINATE): part one of a randomised, phase 2, dose optimisation study.
- Author
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Pabst T, Papayannidis C, Demirkan F, Doronin V, Fogliatto LM, Guttke C, Gyan E, Hamad N, Herrera P, Hultberg A, Jacobs J, Johnson AJ, Langlois A, Ma X, Martinelli G, Arnan M, Müller R, Nottage K, Ofran Y, Özcan M, Samoilova O, Tolbert JA, Trudel GC, Xiu L, Vey N, and Wei AH
- Subjects
- Adult, Humans, Male, Female, Azacitidine adverse effects, Remission Induction, Drug Administration Schedule, Antibodies, Monoclonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute diagnosis
- Abstract
Background: Cusatuzumab, a high-affinity anti-CD70 antibody, has shown preliminary activity as a treatment for acute myeloid leukaemia when combined with azacitidine. We aimed to determine the optimum dose for future trials of cusatuzumab in combination with azacitidine in patients with previously untreated acute myeloid leukaemia who are not eligible for intensive chemotherapy., Methods: In this randomised, phase 2, open-label, dose-optimisation study we enrolled adult patients aged 18 years or older with newly diagnosed acute myeloid leukaemia not eligible for intensive chemotherapy, and with Eastern Cooperative Oncology Group scores of 0-2, from 40 hospitals and centres across seven countries. In part one of the trial, participants were randomly allocated 1:1 to 10 mg/kg or 20 mg/kg intravenous cusatuzumab on days 3 and 17, combined with subcutaneous or intravenous azacitidine 75 mg/m
2 on days 1-7 in 28-day cycles. The primary efficacy outcome was the rate of complete remission in the intention-to-treat group. The two dose cohorts were evaluated independently without between-cohort statistical comparison. Safety analyses were performed in all patients who received one dose of study drug. Part two of the trial was planned to be a single-arm expansion to evaluate cusatuzumab plus azacitidine at the cusatuzumab dose level selected in part one (primary hypothesis ≥35% rate of complete remission vs null hypothesis of 20%); however, changes in the acute myeloid leukaemia treatment landscape during this trial made it unlikely that enrolment to part two of the study would be clinically feasible, so the study stopped at the end of part one. The trial was registered at ClinicalTrials.gov, NCT04023526., Findings: 103 patients were enrolled between Aug 30, 2019, and Feb 25, 2020, and randomly assigned to either cusatuzumab 10 mg/kg (n=51) or 20 mg/kg (n=52). Median follow-up was 7·2 months (IQR 10·7 months). 57 of 103 (55%) patients were male and 46 (45%) patients were female, 78 (76%) were White, one (1%) was Asian, and 24 (23%) did not report their race. In the 10 mg/kg group, complete remission rate was 12% (six of 51 patients; 95% CI 6-23) and in the 20 mg/kg group was 27% (14 of 52; 17-40). Grade 3 or worse treatment-emergent adverse events (TEAEs) were similar between the cusatuzumab 10 mg/kg (n=51) and 20 mg/kg (n=51) cohorts and included thrombocytopenia (24 patients [47%] vs 29 [57%]), anaemia (24 [47%] vs 17 [33%]), and neutropenia (20 [39%] in both cohorts). Serious TEAEs were also similar in the two cohorts (44 [86%] vs 40 [78%]). Treatment-related TEAEs leading to death were reported in both groups (three patients [6%] in the 10 mg/kg group vs one patient [2%] in the 20 mg/kg group); the reported causes of death were pneumonia (n=2) and septic shock (n=2)., Interpretation: Although part one of this study was not designed to formally compare the two dose cohorts for efficacy, the totality of clinical data for cusatuzumab studies performed to date indicate that cusatuzumab 20 mg/kg plus azacitidine represents the optimal dose for further studies. A phase 1b study investigating the triple combination of cusatuzumab with venetoclax and azacitidine is underway (NCT04150887)., Funding: Janssen Research & Development and argenx., Competing Interests: Declaration of interests CG is an employee of Johnson & Johnson and has stock options. EG has received consulting fees and research funding from Novartis. AH is an employee of argenx which includes stock options and patents. AJJ is an employee and has stock options in Janssen. AL is an employee of Janssen R&D and has stock options in Johnson & Johnson. MA has received consulting fees from BMS-Celgene, Novartis, Astellas, Jazz Pharmaceuticals, and Pfizer; and is an advisory board member for BMS-Celgene and Novartis. KN is an employee of Janssen R&D; and has stock options in Johnson & Johnson. MÖ has received a research grant from Janssen; received grant funding or contracts from AbbVie, Bayer, Janssen, Acerta, Beddy's, Merck Sharp & Dohme, Roche, and Takeda; and has received meeting support from AbbVie, Jazz Pharmaceuticals, and Roche. GCT has stock options in Johnson & Johnson. NV has received honoraria payment from Amgen, argenx, BMS, Janssen, and Roche; and received meeting support from Novartis, Amgen, and BMS. AHW has received research funding from Novartis, AbbVie, Servier, BMS, Syndax, Astex, AstraZeneca, and Amgen; is an employee of Walter and Eliza Hall Institute of medical research which receives milestone and royalty payments related to venetoclax and is eligible for financial benefits associated with these payments; has received consulting fees from Shoreline, Servier, Novartis, and AbbVie; has served on speaker's bureaus for AbbVie, Novartis, BMS, and Astellas; and has served on advisory boards for Novartis, Astellas, Janssen, Amgen, Roche, Pfizer, AbbVie, Servier, Gilead, BMS, Macrogenics, and Agios. XM was an employee of Janssen at the time the study was completed. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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