RT Journal Article
SR Electronic
T1 First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e005813
DO 10.1136/jitc-2022-005813
VO 11
IS 5
A1 Julius Strauss
A1 Jean-Laurent Deville
A1 Mario Sznol
A1 Alain Ravaud
A1 Marco Maruzzo
A1 Russell K Pachynski
A1 Theodore S Gourdin
A1 Michele Maio
A1 Luc Dirix
A1 Jeffrey Schlom
A1 Renee N Donahue
A1 Yo-Ting Tsai
A1 XiaoZhe Wang
A1 Yulia Vugmeyster
A1 Frank Beier
A1 Joerg Seebeck
A1 Andreas Schroeder
A1 Sarah Chennoufi
A1 James L Gulley
YR 2023
UL http://jitc.bmj.com/content/11/5/e005813.abstract
AB Background In preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and dose-expansion results from the phase Ib JAVELIN IL-12 trial investigating M9241 plus avelumab.Methods In the dose-escalation part of JAVELIN IL-12 (NCT02994953), eligible patients had locally advanced or metastatic solid tumors; in the dose-expansion part, eligible patients had locally advanced or metastatic urothelial carcinoma (UC) that had progressed with first-line therapy. Patients received M9241 at 4, 8, 12, or 16.8 µg/kg every 4 weeks (Q4W) plus avelumab 10 mg/kg every 2 weeks (Q2W, dose levels (DLs) 1–4) or M9241 16.8 µg/kg Q4W plus avelumab 800 mg once a week for 12 weeks followed by Q2W (DL5/dose expansion). Primary endpoints for the dose-escalation part were adverse events (AEs) and dose-limiting toxicities (DLTs), and those for the dose-expansion part were confirmed best overall response (BOR) per investigator (Response Evaluation Criteria in Solid Tumors V.1.1) and safety. The dose-expansion part followed a two-stage design; 16 patients were enrolled and treated in stage 1 (single-arm part). A futility analysis based on BOR was planned to determine whether stage 2 (randomized controlled part) would be initiated.Results At data cut-off, 36 patients had received M9241 plus avelumab in the dose-escalation part. All DLs were well tolerated; one DLT occurred at DL3 (grade 3 autoimmune hepatitis). The maximum-tolerated dose was not reached, and DL5 was declared the recommended phase II dose, considering an observed drug–drug interaction at DL4. Two patients with advanced bladder cancer (DL2 and DL4) had prolonged complete responses. In the dose-expansion part, no objective responses were recorded in the 16 patients with advanced UC; the study failed to meet the criterion (≥3 confirmed objective responses) to initiate stage 2. Any-grade treatment-related AEs occurred in 15 patients (93.8%), including grade ≥3 in 8 (50.0%); no treatment-related deaths occurred. Exposures for avelumab and M9241 concentrations were within expected ranges.Conclusions M9241 plus avelumab was well tolerated at all DLs, including the dose-expansion part, with no new safety signals. However, the dose-expansion part did not meet the predefined efficacy criterion to proceed to stage 2.Data are available upon reasonable request. Any requests for data by qualified scientific and medical researchers for legitimate research purposes will be subject to Merck’s (CrossRef Funder ID: 10.13039/100009945) Data Sharing Policy. All requests should be submitted in writing to Merck’s data sharing portal (https://www.merckgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html). When Merck has a coresearch, codevelopment, comarketing or copromotion agreement, or when the product has been out-licensed, the responsibility for disclosure might be dependent on the agreement between parties. Under these circumstances, Merck will endeavor to gain agreement to share data in response to requests.