A phase 1 study of the BCL2-targeted deoxyribonucleic acid inhibitor (DNAi) PNT2258 in patients with advanced solid tumors

• Published in: Cancer chemotherapy and pharmacology Vol. 73; no. 2; pp. 363 - 371
• Main Authors: Tolcher, Anthony W., Rodrigueza, Wendi V., Rasco, Drew W., Patnaik, Amita, Papadopoulos, Kyriakos P., Amaya, Alex, Moore, Timothy D., Gaylor, Shari K., Bisgaier, Charles L., Sooch, Mina P., Woolliscroft, Michael J., Messmann, Richard A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2014; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Biological and medical sciences; Cancer Research; DNA - antagonists & inhibitors; Female; Humans; Liposomes - administration & dosage; Male; Maximum Tolerated Dose; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Molecular Targeted Therapy; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Oligodeoxyribonucleotides - administration & dosage; Oligonucleotides - administration & dosage; Oligonucleotides - adverse effects; Oligonucleotides - pharmacokinetics; Oncology; Original; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Proto-Oncogene Proteins c-bcl-2 - genetics; Treatment Outcome; Tumors; BCL2; Liposome; DNAi; PNT2258; Phase I; Deoxyribonucleic acid inhibitor; Human; Solid tumor; Targeting; Drug carrier; Malignant tumor; Target; DNA; C-Onc gene; Phase I trial; Advanced stage; Inhibitor; Protooncogene; Cancer
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-013-2361-0

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.