Abstract CT063: First in human phase 1 study of DT2216, a selective BCL-xL degrader, in patients with relapsed/refractory solid malignancies (NCT04886622)
Authors: Daruka Mahadevan, Minal Barve, Devalingam Mahalingam, Jay Parekh, Michael Kurman, James Strauss, Larry Tremaine, Robert Hromas, Joshua Sills, John McCulloch, John Harkey, Stacy Suberg, Lisa Zimmerman, Guangrong Zheng, Daohong Zhou
Journal: Cancer Research (2025)

Abstract Background: Upregulation of B-cell lymphoma extra-large (BCL-xL) has been implicated in cancer drug resistance and relapse. Small molecule inhibition of BCL-xL with navitoclax resulted in on-target, dose-limiting thrombocytopenia. DT2216 is the first BCL-xL PROTAC degrader that is more effective than navitoclax and has reduced platelet toxicity in preclinical models by selectively degrading BCL-xL via the VHL E3 ligase, which is minimally expressed in platelets. Methods: A dose escalation study using a 3 + 3 design. Doses ranged from 0.04 to 0.4 mg/kg IV twice weekly (BIW) in a 28-day cycle. Eligible subjects had solid tumors of any histology that had progressed on standard treatment and had measurable tumor by RECIST 1.1. Tumor assessment was at 8-week intervals. BCL-xL levels were measured in peripheral leukocytes by Western blotting. Results: 20 patients were enrolled with a median age of 60.5 yr; 60% female, 45% Hispanic, 15% African American and 55% had colorectal or pancreatic cancer. One dose limiting toxicity (DLT) was observed, a grade 4 thrombocytopenia at dose level 5 (0.32mg/kg), that resolved in 48 hours and patient remained on study. Patients remained on study for a median of 57 days (range 7 - 253). No patient discontinued due to treatment-related adverse events (TRAEs). The best response was stable disease (SD), observed in 20% of patients. The median duration of SD was 107 days. 19 of 20 patients completed the DLT period with one choosing to discontinue early to enter hospice. Reversible thrombocytopenia occurred in cycle 1 (C1) but not in C2, with most events noted at doses over 0.32mg/kg. The lowest platelet counts in C1 ranged from 24,000 to 297,000 with a median of 84,000. In all cases platelets recovered to &amp;gt;50,000 within 4 days and &amp;gt;75,000 in 1 week. There were no episodes of bleeding or TRAEs leading to death. Two patients required dose reduction due to repeated thrombocytopenia in C1, but both continued on study. Median overall survival was 7.9 months (95% CI 4.0 - NE). Plasma AUC of DT2216 was dose proportional, and all PK parameters were independent of dose, with the mean plasma t1/2 7.1 to 12.8 hrs, CL 4.1 to 7.9 mL/min/kg and Vdss &amp;lt;100 mL/kg. Patients receiving 0.4 mg/kg of DT2216 demonstrated rapid and sustained degradation of BCL-xL protein in peripheral leukocytes over the 72-96 hr dosing intervals with degradation fraction of &amp;gt;95%. Conclusions: Based on the rapid recovery of the transient thrombocytopenia that occurred only in the first cycle and the degradation of BCL-xL in peripheral leukocytes, the recommended phase 2 dose of DT2216 is 0.4 mg/kg IV BIW. Phase 2 clinical trials are being initiated for DT2216 in CTCL as monotherapy and in combination with chemotherapy in ovarian cancer and fibrolamellar HCC. Citation Format: Daruka Mahadevan, Minal Barve, Devalingam Mahalingam, Jay Parekh, Michael Kurman, James Strauss, Larry Tremaine, Robert Hromas, Joshua Sills, John McCulloch, John Harkey, Stacy Suberg, Lisa Zimmerman, Guangrong Zheng, Daohong Zhou. First in human phase 1 study of DT2216, a selective BCL-xL degrader, in patients with relapsed/refractory solid malignancies (NCT04886622) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT063.