Abstract A065: Completion of Acclaim-1 dose escalation: Recommended Phase 2 dose of quaratusugene ozeplasmid gene therapy and Osimertinib
Authors: Spira Alexander I , Berz David , Jotte Robert M , Pachipala Krishna K , Berger Mark S 
Published: December 2023

Abstract
Introduction: Expression of TUSC2, a tumor suppressor gene, is decreased in 82% of patients with NSCLC. Quaratusugene ozeplasmid gene therapy, which restores TUSC2 expression, consists of a plasmid containing the TUSC2 gene encapsulated in lipid nanoparticles. Partial Phase 1 data evaluating escalating doses of quaratusugene ozeplasmid with standard osimertinib dosing were previously published (ASCO 2023) but were incomplete and did not establish a RP2D.
Methods: Eligible patients had NSCLC with EGFR mutations and progression on osimertinib. Quaratusugene ozeplasmid was administered IV every 21 days in escalating doses and osimertinib 80 mg was administered PO daily. Dexamethasone, acetaminophen, and diphenhydramine were given prior to each treatment to prevent post-infusion symptoms. Efficacy was evaluated after every even cycle of treatment using RECIST 1.1 criteria. Safety was evaluated using CTCAE v5, with dose limiting toxicities (DLTs) generally defined as ≥Gr 3 adverse events (AEs). Three dose levels (0.06, 0.09, and 0.12 mg/kg) of quaratusugene ozeplasmid were planned. A standard dose escalation with 3-6 patients/dose level was used.
Results: Twelve patients were enrolled (3M/9F), median age 59.5, with 3 at 0.06 mg/kg, 4 at 0.09 mg/kg, and 5 at 0.12 mg/kg. There were no DLTs. The most common AEs in ≥ 20% in preliminary data, regardless of relationship, were, in order of frequency, myalgia, pyrexia, chills, diarrhea, influenza-like illness, nausea, cytokine release syndrome and headache. The only Grade 3/4 AEs considered to be related were lymphopenia in 2 patients, and neutropenia in 1 patient. There was a post-infusion syndrome of myalgia, pyrexia, and chills that started 3-4 hours after quaratusugene ozeplasmid infusion and resolved over several hours with acetaminophen and diphenhydramine therapy. One patient at the 0.06 mg/kg dose level, previously treated with carboplatin, pemetrexed, and osimertinib, had a partial remission (PR) by investigator evaluation and treatment is ongoing 1 year later after 18 cycles with PR. Another patient at the 0.09 mg/kg dose level, previously treated with osimertinib, had stable disease for 14 cycles before progression.
Conclusions: Among the 12 patients treated with escalating doses of quaratusugene ozeplasmid and standard doses of osimertinib, all of whom had progressed on osimertinib containing regimens, there were two patients with prolonged time to progression, including one with continuing PR. Quaratusugene ozeplasmid was generally well tolerated with no DLTs. Quaratusugene ozeplasmid administration was associated with a post-infusion syndrome of fever and chills managed with prophylactic steroids, acetaminophen and diphenhydramine. The study’s Safety Review Committee met and determined that the RP2D of quaratusugene ozeplasmid in combination with osimertinib in patients with NSCLC progressing after osimertinib treatment is 0.12 mg/kg.
Citation Format: Alexander I Spira, David Berz, Robert M Jotte, Krishna K Pachipala, Mark S Berger. Completion of Acclaim-1 dose escalation: Recommended Phase 2 dose of quaratusugene ozeplasmid gene therapy and Osimertinib [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A065.