Trial in progress: A Phase IIb randomized clinical trial combining oral azacitidine and vididencel, a novel immunotherapy, for post-remission / maintenance therapy for adult patients with cytogenetically intermediate and high-risk Acute Myeloid Leukemia (ALLG AMLM22/D4 CADENCE)

Abstract

Abstract Despite achieving remission, patients with AML have a substantial risk of relapse, particularly if adverse molecular risk, elderly or if measurable residual disease (MRD) is present after therapy. A phase 3 study has demonstrated that maintenance therapy in first complete remission (CR1) with oral-azacitidine (oral-Aza) improves overall survival in patients not proceeding to allogeneic stem cell transplant (alloSCT) (Wei, et al. 2020, NEJM). Vididencel is a human-derived allogeneic cell product that activates a systemic anti-leukemia immune response by presenting leukemia-associated antigens to the patient's dendritic cells. In phase 1/2 studies, post-remission therapy with vididencel enhanced clearance of MRD and produced durable remissions in patients with MRD-positive AML not proceeding to alloSCT (van de Loosdrecht et al. ASH 2021, 2024). It is hypothesized that combined oral-Aza and vididencel will improve anti-leukemic efficacy and based on non-overlapping toxicities, be well-tolerated. The CADENCE trial aims to determine the preliminary efficacy of oral-Aza and vididencel, compared to oral-Aza alone, in preventing relapse via sustaining or inducing MRD negativity in patients with AML in CR1. The research is a cooperative trial group study led by Australasian Leukaemia and Lymphoma Group (ALLG), as a domain (D) of ALLG AMLM22 (D4) (ANZCTR number: 12624000738527). Study Design and Methods Study population: AML patients (≥18 years) with intermediate or adverse risk cytogenetics in CR1 (including CRh / CRi) following intensive chemotherapy induction (± consolidation) and not intended for CR1 alloSCT are included, irrespective of MRD status. Major exclusions include favourable cytogenetics, non-intensive induction, prior hypomethylating agents for AML, active malignancy, infection or immune condition requiring significant immunosuppression. The trial is open at multiple centres in Australia. Treatment and allocation: Patients are randomized 1:1 into 1 of 2 treatment groups: control arm of oral-Aza (300 mg, Day 1-14 of 28 day cycles, until disease progression or intolerance) or experimental arm (oral-Aza, plus vididencel (7 intradermal doses (priming and booster courses) during the first 6 cycles). Study design and endpoints: The trial will be conducted in 2 stages. Stage 1 (pilot) (n=40) has a primary endpoint of safety, with monitoring of preliminary efficacy (rate of MRD-negative CR). Seamless expansion to Stage 2 (expansion) based on safety and preliminary efficacy in Stage 1 will aim to further enrol 100 patients. The combined primary endpoint is leukemia event free survival (LFS) with ‘event’ defined as MRD relapse / progression prompting change in treatment (acknowledging emerging practice), morphological relapse or death. Secondary endpoints include MRD responses, relapse free and overall survival, time to next treatment, safety and quality of life. Biomarkers: Morphological assessment of response and centralised MRD flow cytometry will be performed on bone marrow regularly for 24 months. Molecular MRD will be performed as per ELN guidelines in accredited diagnostic laboratories. Exploratory biomarkers include blood immune profiling using 40-colour flow cytometry, specific antigen T cell responses and TCR sequencing to determine immune predictors and correlates of response. Statistical analysis: Superiority of the experimental arm will be claimed when 2 proof-of-concept (PoC) criteria are met: 1) The observed hazard ratio (HR) (investigational vs control arm) is ≤0.8; and 2) The posterior probability that the true HR is ≤1.0 is, given the data, ≥0.8. A target of 140 patients (71 events) is required to achieve an 85% chance that PoC is declared when the true HR is 0.62. Futility thresholds are also defined. The conclusion from Stage 1-2 will be a recommendation for a Phase 3 study. Conclusions The CADENCE trial incorporates a novel immunotherapeutic approach in AML, contemporary and robust endpoint definitions and assessments and aims to improve standard of care in AML maintenance in preventing relapse. Acknowledgments This trial is funded by Mendus AB. We gratefully acknowledge the patients and families. Contact: www.allg.org.au