{"doi":"10.1136/jitc-2022-005813","title":"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","abstract":"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.","journal":"Journal for ImmunoTherapy of Cancer","year":2023,"id":332354,"datarank":0.8098237779204918,"base_score":3.258096538021482,"endowment":3.258096538021482,"self_citation_contribution":0.4887144807032224,"citation_network_contribution":0.32110929721726944,"self_endowment_contribution":0.4887144807032224,"citer_contribution":0.32110929721726944,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":21,"citers_with_citation_signal":18,"citers_with_endowment":18,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9504,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT02994953"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1058503,"name":"Jean‐Laurent Deville","orcid":"0000-0001-9727-5710","position":1,"is_corresponding":false},{"id":819153,"name":"Mario Sznol","orcid":"0000-0003-4137-9662","position":2,"is_corresponding":false},{"id":240465,"name":"Alain Ravaud","orcid":"0000-0001-9455-6744","position":3,"is_corresponding":false},{"id":1028179,"name":"Marco Maruzzo","orcid":"0000-0002-6256-9249","position":4,"is_corresponding":false},{"id":230230,"name":"Russell K. Pachynski","orcid":"0000-0002-8966-7631","position":5,"is_corresponding":false},{"id":582835,"name":"Theodore Stewart Gourdin","orcid":null,"position":6,"is_corresponding":false},{"id":68926,"name":"Michele Maio","orcid":"0000-0002-0323-6321","position":7,"is_corresponding":false},{"id":13410,"name":"Luc Dirix","orcid":null,"position":8,"is_corresponding":false},{"id":239943,"name":"Jeffrey Schlom","orcid":"0000-0001-7932-4072","position":9,"is_corresponding":false},{"id":239940,"name":"Renee N. Donahue","orcid":"0000-0002-6828-3073","position":10,"is_corresponding":false},{"id":762303,"name":"Yo-Ting Tsai","orcid":"0000-0002-7556-1633","position":11,"is_corresponding":false},{"id":1059070,"name":"XiaoZhe Wang","orcid":null,"position":12,"is_corresponding":false},{"id":1058504,"name":"Yulia Vugmeyster","orcid":"0000-0002-6289-2521","position":13,"is_corresponding":false},{"id":342358,"name":"Frank Beier","orcid":"0000-0002-8505-7537","position":14,"is_corresponding":false},{"id":1059071,"name":"Joerg Seebeck","orcid":null,"position":15,"is_corresponding":false},{"id":1059072,"name":"Andreas Schröeder","orcid":null,"position":16,"is_corresponding":false},{"id":1059073,"name":"Sarah Chennoufi","orcid":null,"position":17,"is_corresponding":false},{"id":239942,"name":"James L. Gulley","orcid":"0000-0002-6569-2912","position":18,"is_corresponding":false},{"id":239941,"name":"Julius Strauss","orcid":"0000-0002-7550-4938","position":0,"is_corresponding":true}],"reference_count":19,"raw_metadata":null,"created_at":"2026-07-19T01:09:30.139849Z","pmid":"37236636","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}