Trial in progress: Phase II Study of (early) combination salvage therapy with venetoclax and intensified decitabine in relapsed/refractory AML (VenSwitch) Free

Background and Significance Acute Myeloid Leukemia (AML) in the refractory or relapsed setting (r/r) has an unfavorable prognosis. This largely ows to an adverse genetic profile with aberrations conferring resistance to conventional cytostatic chemotherapy (e.g. TP53 or myelodysplasia-related aberrations), especially in patients with refractory disease. Allogeneic hematopoietic stem cell transplantation (alloHSCT) still remains the only curative treatment for these patients. Different paths to alloHSCT all aim at remission induction and comprise different salvage therapies such as HAM, MEC or FLAG-IDA. However, Composite Complete Remssion Rates (CRc) are unsatisfactory (about 35 to 60%; Wattad et al., Leukemia, 2017). Taking into account the toxicity of these regimens with early mortality rates of about 10% (Westhus et al., Leuk Lymphoma, 2019), repeated exposure of chemoresistant disease to cytostatic chemotherapy alone can be questioned. Our study tests the alternative approach of a switch from intensive to less intensive treatment modality with an alternative mechanism of action. We hypothesize that this switch may enhance efficacy while at the same time sparing toxicity, thus enabeling subsequent alloHSCT in a better condition. Preclinical data suggest that prior cytostatic chemotherapy and the elicited cellular stress enhance susceptibilty to Bcl-2-inhibition (Niu et al., Clin Cancer Res, 2016). Thus, we hypothesized that Venetoclax treatment might be especially effective in patients shortly after cytostatic chemotherapy, which guided our design of the study treatment. We proposed to treat patients with poor response to induction chemotherapy with a regimen composed of 10 days of Decitabine (Lübbert et al., Lancet Haematol, 2023) and 28 days of Venetoclax. Retrospective data on 15 patients from our center showing a response rate ~85% and a CRc rate ~70% further support this approach.

Study Design and Methods The trial VenSwitch is registered with clinicaltrials.gov (NCT06156579) and has the EU Trial Number (2022-502665-15-00). It is conducted as mononcentric, single-arrm phase II trial. General study design and analysis of the primary endpoint, (response to therapy on day 28 of therapy), follows a Simon Optimal Design. This design includes 27 patients and tests the alternative hypothesis of a response rate of 60% against a null hypothesis of a response rate of 35% (5% one-sided probability of type I error, 80% power). Stage 1 enrolls 9 patients (≥4 responses required) and stage 2 further 18 patients. DSMB-Meetings are held after 3 and 9 patients. 14 responses are required to meet the primary endpoint. Enrolled are transplant-eligible patients with AML or MDS IB2 (WHO 2022), who are either refractory to induction chemotherapy or have relapsed after prior remission. Of note, this trial refractory disease more broadly and also includes patients with poor response (≥20% bone marrow blasts at day 15 or ≥5% at day 28 of the first cycle of induction chemotherapy). Excluded are patients, who have already recieved an allogeneic stem cell transplantation and relapsed FLT3-mutated patients in case a complete remission with FLT3-inhibitor has been achieved in the past. Patients who are enrolled receive a 3 day Venetoclax Ramp Up, followed by 10 days of Decitabine (20 mg/m²i.v. ) accompanied by 28 days of Venetoclax (400 mg p.o.). Patients who achieve a morphologic leukemia free state (MLFS) at day 15 receive a shortened Venetoclax course of 21 days. Depending on the response, patients receive 1-2 cycles of therapy. Patient should proceed to alloHSCT (post protocol treatment). Patients are followed up until day 100 after end of treatment. As mentioned above, the primary endpoint is response (at least MLFS) at day 28. Important secondary endpoints include safety endpoints such as the incidence of AEs CTCAE Grade ≥3 until day 30 after end of treatment and the time to hematopoietic recovery. Further endpoints include patient-reported outcomes, MRD (qpCR-based for validated markers and exploratory NGS-tracking for all other markers), time-to-transplant and overall survival. A scientific companion program includes spatial assessment of the bone marrow microenvironment under therapy and sequential transcriptomic analyses by single-cell RNA-sequencing of bone marrow samples. The trial started enrollment in November 2023 an has enrolled 18 patients to date.