Oblimersen (OBL; Genasense®), a Phosphorothioate (PS) Bcl-2 Antisense Oliogonucleotide (ASO), Can Be Safely Administered by Bolus Subcutaneous (SC) Injection and Brief IV Infusion.
Authors: Tolcher Anthony , Julian Thomas , Qureshi Anila 
Published: November 2019

Abstract
Background: Oblimersen (OBL) is an 18-mer PS-ASO that down-regulates Bcl-2 and amplifies the activity of cytotoxic drugs in patients (pts) with chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphoma (NHL), and melanoma. PS-ASOs like OBL are commonly administered by continuous intravenous infusion (CIV) in order to avoid high peak plasma concentrations that have been associated with cardiovascular collapse, complement activation, and death in primates. However, we consistently observed no such reactions in patients who received inadvertent overdoses of OBL. Furthermore, preclinical studies in xenograft tumors in mice indicated that intratumoral uptake and retention of OBL was enhanced with short IV infusion. Given the inconvenience of CIV and based on recent preclinical data, we evaluated the safety and pharmacokinetics (PK) of OBL administered as weekly subcutaneous (SC) injection, a brief 2-hr IV infusion for 5 days, and a weekly 2-hr infusion.
Methods: Eligible pts had: advanced solid tumors; no available standard therapy; adequate organ function; and ECOG performance status of 0 to 2. In the SC study, single doses of 75, 150, and 225 mg were given to 8 pts, followed by a multiple dose study at 150 mg, 225 mg, and 300 mg. Pts received OBL by 2-hr IV infusion once weekly for 3 weeks (Days 1, 8, 15) starting at a dose of 300 mg and increasing in increments of 100 mg to the maximum tolerated dose (MTD). Blood samples were obtained for complement, Bcl-2, and PK analyses. Dose escalation utilized an accelerated dose escalation schedule.
Results: Single pt cohorts were treated at each 2-hr dose level ranging from 300 to 800 mg. Syncope occurred in 1 pt treated with 900 mg, but treatment of 2 additional pts at this dose was uneventful. At the 1000 mg dose level, all pts experienced fever, chills, and moderate decreases in blood pressure, generally limited to the first infusion, which were not felt to be dose-limiting. The PK were dose-proportional over the 300 to 900 mg dose range. AUC and Cmax levels nearly were dose-proportional, and dose-normalized AUC and Cmax values were constant. Cmax values at 900 mg were > 50 μg/mL, and exceeded by >10-fold the Css of CIV schedules in solid tumor pts. There was no change in metabolism or plasma clearance with increasing doses. Large inter-patient variability was observed; however, intra-patient variability was low, as indicated by a coefficient of variation of < 20% for Cmax values obtained on Days 1, 8, and 15. No consistent pattern in complement activation was observed. One patient with metastatic NSCLC remains on study at 14 weeks with a 10% reduction in tumor size. OBL given by SC injection was associated with a Grade 1 erythematous rash at the injection site in all pts, which resolved within 7 days. AUC0–24 exposure at the 225-mg SC dose was similar to previously established 24-h steady-state AUCs after 3 mg/kg by CIV infusion.
Conclusions: OBL AUC exposure from a single SC injection is similar to that observed using the 3mg/kg daily dose level administered by CIV to pts with CLL. OBL can also be administered safely by 2-hr IV infusion at weekly doses up to 1,000 mg. Corticosteroids are being tested to evaluate whether constitutional reactions can be ameliorated, and then a twice-per-week schedule will be designed to examine OBL-induced down-regulation of Bcl-2 alone and in combination with cytotoxic drugs in specific diseases.