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Updated: Jun 30, 2026
A Human Peripheral Blood Mononuclear Cell PBMC Engrafted Humanized Xenograft Model for Translational Immuno-oncology I-O Research
Published on: August 15, 2019
First in human phase 1 study of DT2216, a selective BCL-xL degrader, in patients with relapsed/refractory solid
Daruka Mahadevan1, Minal Barve2, Devalingam Mahalingam3
1Mays Cancer Center, San Antonio, TX, USA. mahadevand@uthscsa.edu.
Background:
Small molecule inhibition of BCL-XL with navitoclax resulted in on-target dose-limiting thrombocytopenia. DT2216 was more effective than navitoclax and 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 with doses ranging from 0.04 to 0.4 mg/kg IV twice weekly (BIW) was performed. Eligible subjects had solid tumors of any histology that had progressed on standard treatment and had measurable tumor by RECIST v1.1. Tumor assessment was performed at 8-week intervals. BCL-XL levels were measured in peripheral leukocytes by western blotting.
Results:
Twenty patients were enrolled, with a median age of 60.5 year; 60% were female. Only one dose-limiting toxicity was observed, grade 4 thrombocytopenia that resolved within 48 h. Stable disease, observed in 20% of the patients. The lowest platelet count in the first cycle ranged from 24,000 to 297,000. In all cases, the platelet count recovered to > 50,000 within 4 days and > 75,000 within 1 week. There were no episodes of bleeding or treatment emergent adverse events leading to death. The median overall survival was 7.9 months. The plasma AUC of DT2216 was dose proportional with no dose accumulation. Patients receiving 0.4 mg/kg DT2216 demonstrated rapid and sustained degradation of BCL-XL.
Conclusions:
Based on the rapid recovery of transient thrombocytopenia that occurred only in the first cycle and the degradation of BCL-XL in peripheral leukocytes, the RP2D of DT2216 is 0.4 mg/kg IV BIW. (NCT04886622).
Insights
DT2216, a novel BCL-XL degrader, shows promise in treating solid tumors by effectively reducing platelet toxicity. The recommended dose of 0.4 mg/kg IV BIW was established in a phase 1 trial.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Navitoclax, a BCL-XL inhibitor, caused dose-limiting thrombocytopenia.
- DT2216 selectively degrades BCL-XL via VHL E3 ligase, minimizing platelet toxicity.
- VHL E3 ligase expression is low in platelets, contributing to DT2216's reduced toxicity.
Purpose of the Study:
- To evaluate the safety and tolerability of DT2216 in patients with solid tumors.
- To determine the recommended phase 2 dose (RP2D) of DT2216.
- To assess the preliminary efficacy and pharmacokinetic profile of DT2216.
Main Methods:
- A dose escalation study (3+3 design) with DT2216 administered intravenously twice weekly (BIW).
- Doses ranged from 0.04 to 0.4 mg/kg.
- Patients with advanced solid tumors progressing on standard therapy were enrolled. Tumor assessments were performed every 8 weeks.
Main Results:
- Twenty patients were enrolled; one dose-limiting toxicity (Grade 4 thrombocytopenia) was observed and resolved within 48 hours.
- Stable disease was observed in 20% of patients, with rapid platelet count recovery in all cases.
- DT2216 demonstrated dose-proportional pharmacokinetics without accumulation, and 0.4 mg/kg led to rapid BCL-XL degradation.
Conclusions:
- The recommended phase 2 dose (RP2D) of DT2216 is 0.4 mg/kg IV BIW.
- DT2216 shows a favorable safety profile with manageable and transient thrombocytopenia.
- The drug effectively degrades BCL-XL in peripheral leukocytes, supporting its therapeutic potential.
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