Related Experiment Video
Updated: May 5, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
A phase 1 study of the BCL2-targeted deoxyribonucleic acid inhibitor (DNAi) PNT2258 in patients with advanced solid
Anthony W Tolcher1, Wendi V Rodrigueza, Drew W Rasco
1South Texas Accelerated Research Therapeutics (START), LLC, San Antonio, TX, USA.
Purpose:
Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were assessed in this phase 1 study of PNT2258, a BCL-2-targeted liposomal formulation of a 24-base DNA oligonucleotide called PNT100.
Methods:
Patients with malignant solid tumors were assigned sequentially to one of ten dose-escalation cohorts of PNT2258 at 1, 2, 4, 8, 16, 32, 64, 85, 113, and 150 mg/m(2) administered intravenously on days 1 through 5 of each 21-day cycle. Pharmacokinetics were determined on days 1 and 5 of the first cycle. Lymphocyte and platelets concentrations were measured for evidence of BCL2-targeted effect. CT scans were used to identify radiologic evidence of anti-tumor effect.
Results:
Twenty-two subjects received PNT2258, and the maximum tolerated dose for PNT2258 was not reached. Doses at or above 32 mg/m(2) resulted in exposure to PNT2258 above the exposure level required for anti-tumor activity in preclinical xenograft testing of 22,377 ng h/ml (PK analysis 2012). Fatigue was the most commonly reported adverse event. Dose-limiting toxicity, manifesting as a transient increase in aspartate aminotransferase, occurred at 150 mg/m(2), the highest dose tested. Four subjects, two each with diagnosis of non-small-cell lung cancer and sarcoma, treated at doses of 64 mg/m(2) or higher, remained on study for 5-8 cycles.
Conclusions:
PNT2258 was safe and well tolerated at the doses tested up to 150 mg/m(2). Exposure to PNT2258 resulted in clinically manageable decreases in lymphocyte and platelet concentrations.
Insights
This Phase 1 study evaluated PNT2258, a BCL-2-targeted therapy, in patients with solid tumors. PNT2258 demonstrated safety and tolerability up to 150 mg/m², with manageable side effects and evidence of anti-tumor activity.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Malignant solid tumors represent a significant unmet medical need.
- Targeting BCL-2 offers a potential therapeutic strategy in oncology.
- PNT2258 is a novel liposomal formulation of a DNA oligonucleotide targeting BCL-2.
Purpose of the Study:
- To assess the maximum tolerated dose (MTD) of PNT2258.
- To evaluate the safety and tolerability of PNT2258 in patients with solid tumors.
- To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of PNT2258.
Main Methods:
- Phase 1, dose-escalation study of PNT2258 in patients with malignant solid tumors.
- Intravenous administration of PNT2258 in ten dose cohorts (1-150 mg/m²) over 5 days every 21 days.
- PK analysis, assessment of lymphocyte and platelet counts, and CT scans for anti-tumor effect.
Main Results:
- Twenty-two subjects received PNT2258; the MTD was not reached.
- Doses ≥ 32 mg/m² achieved preclinical anti-tumor exposure levels.
- Fatigue was the most common adverse event; transient AST elevation at 150 mg/m² was dose-limiting.
Conclusions:
- PNT2258 was safe and well-tolerated up to 150 mg/m².
- Clinically manageable decreases in lymphocyte and platelet counts were observed.
- Four patients with NSCLC and sarcoma showed prolonged treatment duration at higher doses.
