Khanh T Do

First-in-human phase I/II, open-label study of mRNA-2416 alone or combined with durvalumab in patients with advanced solid tumors and ovarian cancer

Abstract Background mRNA-2416 is a novel lipid nanoparticle-encapsulated messenger RNA (mRNA) encoding human OX40 ligand (OX40L) for intratumoral (Itu) injection. OX40L plus immune checkpoint inhibitor (ICI) increased preclinical antitumor activity, thus mRNA-2416 plus ICI may potentiate antitumor activity. Methods This first-in-human, phase I/II, open-label, multicenter study examined the safety, tolerability, and efficacy of mRNA-2416 alone (arm A) or with durvalumab (arm B) in patients with advanced solid tumors or lymphoma (NCT03323398). Phase I primary objectives included assessment of safety/tolerability and maximum tolerated dose (MTD)/recommended dose for expansion; phase II arm B dose expansion assessed objective response rate in ovarian cancers. Secondary objectives included pharmacokinetics, disease control rate, duration of response, and progression-free survival (PFS). Assessments of immunologic response to treatment were exploratory. Results From August 2017 to August 2021, 79 patients were enrolled; 61 received treatment (arm A: 39, arm B: 22), including 16 in the expansion cohort. MTD was not reached. Treatment-related emergent adverse events were primarily grade 1/2, with 8 grade 3 and no grade 4/5 events. On-treatment tumor biopsies demonstrated increased OX40L protein expression, elevated PD-L1, and proinflammatory responses. Tumor shrinkage occurred in injected and surrounding non-injected tumors. Median (95% CI) PFS was 60.0 (50.0 to 108.0) and 50.0 (38.0 to 55.0) days for arms A and B, respectively. Conclusions mRNA-2416 alone or with durvalumab was well tolerated. Pharmacodynamic analyses support Itu mRNA proof-of-concept. Predefined primary efficacy endpoints were not met in an exploratory cohort of ovarian cancer. Additional research is warranted to further inform this therapeutic approach.

Immune modulating activity of the CHK1 inhibitor prexasertib and anti-PD-L1 antibody LY3300054 in patients with high-grade serous ovarian cancer and other solid tumors

Checkpoint kinase 1 (CHK1) has dual roles in both the DNA damage response and in the innate immune response to genotoxic stress. The combination of CHK1 inhibition and immune checkpoint blockade has the potential to enhance anti-tumoral T-cell activation. This was an open-label phase 1 study evaluating the CHK1 inhibitor prexasertib and the anti-PD-L1 antibody LY3300054. After a lead-in of LY3300054 (Arm A), prexasertib (Arm B) or the combination (Arm C), both agents were administered intravenously at their respective recommended phase 2 doses (RP2Ds) on days 1 and 15 of a 28-day cycle. Flow cytometry of peripheral blood was performed before and during treatment to analyze effects on immune cell populations, with a focus on T cell subsets and activation. Plasma cytokines and chemokines were analyzed using the Luminex platform. Among seventeen patients enrolled, the combination was tolerable at the monotherapy RP2Ds, 105 mg/m Prexasertib in combination with PD-L1 blockade was tolerable and demonstrated preliminary activity in CCNE1-amplified HGSOC with evidence of cytotoxic T-cell activation in patient blood samples. ClinicalTrials.gov identifier: NCT03495323. Registered April 12, 2018.