A phase 1 study of the BCL2-targeted deoxyribonucleic acid inhibitor DNAi PNT2258 in patients with advanced solid tumorsReport as inadecuate




A phase 1 study of the BCL2-targeted deoxyribonucleic acid inhibitor DNAi PNT2258 in patients with advanced solid tumors - Download this document for free, or read online. Document in PDF available to download.

Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 2, pp 363–371

First Online: 03 December 2013Received: 18 July 2013Accepted: 13 November 2013DOI: 10.1007-s00280-013-2361-0

Cite this article as: Tolcher, A.W., Rodrigueza, W.V., Rasco, D.W. et al. Cancer Chemother Pharmacol 2014 73: 363. doi:10.1007-s00280-013-2361-0

Abstract

PurposeMaximum 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.

MethodsPatients 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 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.

ResultsTwenty-two subjects received PNT2258, and the maximum tolerated dose for PNT2258 was not reached. Doses at or above 32 mg-m 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, 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 or higher, remained on study for 5–8 cycles.

ConclusionsPNT2258 was safe and well tolerated at the doses tested up to 150 mg-m. Exposure to PNT2258 resulted in clinically manageable decreases in lymphocyte and platelet concentrations.

KeywordsPNT2258 Phase I DNAi Deoxyribonucleic acid inhibitor BCL2 Liposome  Download fulltext PDF



Author: Anthony W. Tolcher - Wendi V. Rodrigueza - Drew W. Rasco - Amita Patnaik - Kyriakos P. Papadopoulos - Alex Amaya - Timot

Source: https://link.springer.com/







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