A phase I study of the myeloid cell leukemia 1 (MCL1) inhibitor tapotoclax (AMG 176) in patients with myelodysplastic syndromes after hypomethylating agent failure.
Year: 2024
Type: conference-abstract
Abstract: 6570 Background: Though hypomethylating agent (HMA) therapy is standard for patients (pts) with myelodysplastic syndromes (MDS), once pts are refractory to or no longer respond to HMA therapy (i.e. HMA failure), survival remains dismal and treatment options non-existent. Tapotoclax directly induces apoptosis in cells dependent on MCL1 for survival. Given preclinical data establishing MCL1 as a promising target in MDS, we hypothesized that tapotoclax may be safe and clinically active in pts with HMA failure MDS. Methods: We designed a phase I study evaluating the safety and tolerability of tapotoclax (NCT05209152). Adult pts with HMA failure MDS (no response after ≥4 HMA cycles or progression/relapse at any time on HMAs) were eligible. Using a standard modified Toxicity Probability Interval design, all pts received intravenous tapotoclax every 7 days with each cycle lasting 28 days in the exploratory dose-finding portion. Results: Between 10/2022-12/2023, 4 pts received tapotoclax 120 mg/m2 and 3 pts 240 mg/m2. Pts were overall very high risk and heavily pre-treated with a median of 4 lines of therapy. The median number of cycles of tapotoclax received was 3. No dose-limiting toxicities (DLTs) were observed. The most common treatment-related adverse events (AEs) were nausea (85%), fatigue (43%), diarrhea (29%), and palpitations (14%). Regarding cardiac AEs, 1 pt experienced arrhythmias that were possibly related to tapotoclax but self-resolved. One pt had prolonged QTc intervals but had similar prolongation prior to tapotoclax exposure. No clinically-significant troponin elevations were observed. No pts responded, and this trial was terminated due to lack of clinical activity. Three pts (43%) were taken off study due to no response, 1 (14%) to proceed to stem cell transplantation, 1 (14%) from recurrent peritoneal cancer, 1 (14%) due to transformation to acute myeloid leukemia, and 1 (14%) from an unrelated death due to infection. However, 2 of 3 pts (67%) who started the clinical trial with BM blasts ≥ 5% underwent transient but unsustained blast reduction after cycle 3. All pts were transfusion-dependent with red blood cells (RBCs) at the time of clinical trial enrollment, but 5 pts (71%) decreased RBC transfusions by ≥2 units between cycle 1-2 and 1 individual (14%) attained transfusion independence for 7 weeks. Conclusions: This phase 1 study demonstrated that tapotoclax was safe and tolerated in a high-risk cohort of pts with MDS after HMA failure. No DLTs were observed, and cardiac AEs self-resolved without dose reductions. Though no pts responded, some pts experienced transient blast reduction and decreased RBC transfusion burden. Given its manageable toxicity profile and transitory anti-leukemic and transfusion-independent effects, the use of tapotoclax in combination with HMA or other therapies may warrant further consideration. Clinical trial information: NCT05209152 .
Source: Journal of Clinical Oncology
Authors: Kelly Sharon Chien, Juan Jose Rodriguez-Sevilla, Yesid Alvarado Valero, Guillermo Montalban Bravo, Danielle Hammond, Mahesh Swaminathan, Alexandre Bazinet, Jacqueline Kimberley, Kristy Bodden, Heather Schneider, Xiao Qin Dong, Sherry Pierce, Xuelin Huang, Elias Jabbour, Hagop M. Kantarjian, Guillermo Garcia-Manero
Institution: The University of Texas MD Anderson Cancer Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: Amgen
OpenAlex ID: W4400108964