Tapotoclax Demonstrates Safety, Yields Anti-Leukemic Effects but No Responses in MDS Following HMAs

Treatment with tapotoclax (AMG 176) was tolerable and led to reductions in bone marrow blasts and transfusion dependence in patients with high-risk myelodysplastic syndromes (MDS) after hypomethylating agents (HMAs), according to data from a phase 1 study (NCT05209152).

Results presented at the 2024 EHA Congress demonstrated that no responses were observed among evaluable patients (n = 7). However, 2 of 3 patients who had a bone marrow blast of at least 5% experienced unsustained blast reduction after at least 1 cycle of treatment. All patients were transfusion dependent at baseline, and 71% of patients experienced a reduction of at least 2 packed red blood cell units between cycles 1 and 2. Additionally, 1 patient (14%) achieved transfusion independence for approximately 7 weeks.

The trial was ultimately terminated due to lack of clinical activity during the dose-exploring phase of the study.

Regarding safety, no dose-limiting toxicities (DLTs) were reported. One patient died due to an infection during cycle 2 of treatment; however, this was deemed unrelated to tapotoclax.

“Given [the] manageable toxicity profile and transitory anti-leukemic and transfusion-independent effect, the use of tapotoclax in combination with [an] HMA or other types of therapies may warrant further consideration,” lead study author Kelly Chien, MD, an assistant professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, and colleagues wrote in a poster presentation of the data.

Current frontline therapies for patients with MDS often include HMAs such as azacitidine and decitabine. However, many patients have disease that ultimately becomes refractory to or relapses after HMAs, leaving a need for novel therapeutic approaches.

Tapotoclax is a first-in-class small molecule that selectively inhibits MCL1, disrupting its protein-to-protein interactions within the BCL2 family and inducing apoptosis in MCL1-dependent cancer cells. This phase 1 trial sought to explore the safety and potential efficacy of tapotoclax in patients with MDS following prior HMA therapy.

Trial Design

The primary end point of the study was safety, including the incidence of DLTs and adverse effects (AEs). Secondary end points included overall response rate (ORR) according to 2006 International Working Group (IWG) criteria.

The study commenced in October 2022 and enrolled 7 patients by December 2023. Participants were treated with varying doses of tapotoclax once per week: 3 patients received 120 mg/m², and 4 patients received 240 mg/m².

Bone marrow aspirations and biopsies were performed at baseline and after cycles 1 and 2, then every other cycle thereafter, to monitor response.

Patient Characteristics

The trial enrolled adult patients with high-risk MDS who had undergone prior HMA therapy and either did not respond after 4 cycles of therapy or experienced disease progression or relapsed during HMA treatment.

Patients in the study had a median age of 77 years (range, 61-83), and 57% were male. A majority (71%) had high- or very high–risk MDS per IPSS-R or IPSS-M. Additionally, 43% had therapy-related MDS, 29% had complex cytogenetics, and 29% harbored TP53 mutations.

Patients received a median of 4 prior lines of therapy (range, 1-8). The median number of cycles of a prior HMA was 10 (range, 2-24), and 29% of patients responded to a prior HMA. Notably, 1 patient (14%) received prior venetoclax (Venclexta).

Additional Safety Data

During the study, patients received a median of 3 cycles of tapotoclax (range, 2-4). One patient developed arrhythmias with premature atrial and ventricular contractions that were possibly related to tapotoclax; however, these resolved without dose interruptions or reductions.

Other common AEs included nausea (grade 1/2, 71%; grade 3, 14%), fatigue (57%; 0% ), and diarrhea (29%; 0%). One patient had QTc prolongation, but this patient also had similar prolongation prior to treatment. There were no signs of clinically significant cardiac enzyme elevation.

Reasons for treatment discontinuation included progressive disease or lack of response (57%); allogeneic stem cell transplant (14%); recurrent peritoneal cancer with the need for therapy (14%); and patient request for hospice and subsequent unrelated death (14%).

Reference

Chien KS, Rodriguez-Sevilla JJ, Alvarado Y, et al. A phase I study of the myeloid cell leukemia 1 (MCL1) inhibitor tapotoclax (AMG 176) in patients with myelodysplastic syndrome after hypomethylating agent failure. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract P1897.