ACCLAIM-1 dose escalation: Determination of quaratusugene ozeplasmid and osimertinib recommended phase 2 dose (RP2D).
Authors: Berz David , Jotte Robert M. , Pachipala Krishna Kishore , Spira Alexander I. , Berger Mark S. 
Published: June 2023

e15081 Background: Expression of TUSC2, a tumor suppressor gene, is decreased in 82% of patients with NSCLC. Quaratusugene ozeplasmid, which restores TUSC2 expression, consists of a plasmid containing the TUSC2 gene encapsulated in lipid nanoparticles. Preclinical work in mouse xenografts demonstrated markedly improved control of EGFR mutant tumors when quaratusugene ozeplasmid was combined with osimertinib. A previous monotherapy study led to a RP2D of 0.06 mg/kg which was also used in a study in combination with erlotinib. The present study evaluated escalating doses of quaratusugene ozeplasmid with standard osimertinib dosing. Methods: Eligible patients were NSCLC patients 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 a post-infusion inflammatory syndrome. Efficacy was evaluated at baseline and 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: Eight patients were enrolled (2M/6F), median age 59.5 years, with 3 at 0.06 mg/kg, 4 at 0.09 mg/kg, and 1 at 0.12 mg/kg. There were no DLTs. The most common AEs in preliminary data, regardless of relationship, in ≥ 20% were, in order of frequency, myalgia, pyrexia, chills, diarrhea, headache, influenza-like illness and pain. The only Grade 3/4 AEs were lymphopenia and neutropenia in 1 patient each. 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 after 11 cycles with PR. Another patient at the 0.09 mg/kg dose level, previously treated with osimertinib, has stable disease and is continuing treatment after 9 cycles. Conclusions: There was 1 PR with quaratusugene ozeplasmid and osimertinib combination therapy in the 8 patients enrolled in the Phase 1 dose escalation, all of whom had progressed on osimertinib. Quaratusugene ozeplasmid was generally well tolerated, and was associated with a post-infusion syndrome of fever and chills managed with steroids, acetaminophen and diphenhydramine. Based on these data, the RP2D of quaratusugene ozeplasmid in combination with osimertinib in patients with NSCLC progressing after osimertinib treatment is expected to be 0.12 mg/kg. Clinical trial information: NCT04486833 .