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A Phase 2 Study of PNT2258 for Treatment of Relapsed or Refractory B-Cell Malignancies

Wael Harb, Nehal J. Lakhani, Richard Messmann, , Ayad M. Al-Katib
Published: 22 July 2021

Abstract: Background PNT2258 consists of a native, chemically unmodified, 24-base DNA oligonucleotide designed to target the regulatory region upstream of the BCL2 gene, delivered in a protective liposome. Derangement of BCL2-regulated control mechanisms is a defining characteristic of certain malignancies, and it was hypothesized that the oligonucleotide would promote anticancer activity via suppression of BCL2 transcription. Methods PNT2258 was evaluated in this, multicenter, non-randomized, open-label Phase 2 study in 13 subjects with relapsed/refractory B-cell malignancies to investigate potential antitumor activity and safety. Subjects with follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, or chronic lymphocytic leukemia received intravenous PNT2258 120 mg/m2 on Days 1–5 of a 21-day cycle for up to 8 cycles, followed by 100 mg/m2 on Days 1–2 of a 28-day cycle until study withdrawal. Results All 13 subjects were treated with PNT2258 monotherapy and evaluable for response and safety and tolerability. The overall response rate was 53.8% [7/13; 95% confidence interval (CI): 25.1%–80.8%]. Median duration of response was 23.4 months (range: 3, 31.5). The disease control rate of subjects with stable disease or better was 84.6% [95% CI: 54.6%–98.1%]. The most frequently (≥ 50%) observed adverse events (AEs) were nausea, chills, diarrhea, fatigue, headache, vomiting, and back pain. Hypertension (30.8%) and diarrhea (23.1%) were the most frequent grade ≥ 3 AEs. No deaths were observed. Conclusions Clinically meaningful and durable activity with an acceptable safety profile was observed in subjects with relapsed/refractory B-cell malignancies who received single-agent PNT2258. Trial registration NCT01733238, first posted 26-Nov-2012. https://clinicaltrials.gov/ct2/show/NCT01733238
Keywords: BCL2 / B-cell lymphoma / DLBCL / oligonucleotide therapy / adverse event / AUC / area under the curve / B-cell lymphoma 2 / CAR-T / chimeric antigen receptor T-cell / confidence interval / CLL / chronic lymphocytic leukemia / complete response / computed tomography / diffuse large B-cell lymphoma / DNAi / DNA interference / DOR

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