943TiP - PEMDA-HN, an open-label, phase II, randomized controlled study of danvatirsen plus pembrolizumab compared to pembrolizumab alone in recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC)

Background

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in survival of tumor cells, as well as promotion of an immune-suppressive tumor microenvironment. Danvatirsen (DAN) is a 16-nucleotide, generation 2.5 antisense oligonucleotide designed to down-regulate the expression of human STAT3 messenger RNA. Over 500 patients with hematologic malignancies or solid tumors have been exposed to DAN monotherapy or in combination. A tolerable safety profile has been demonstrated and toxicities are manageable. The SCORES Study (ESMO 2018) in RM HNSCC patients naïve to programmed cell death (ligand)1 (PD-(L)1) therapy demonstrated that DAN in combination with the PD-L1 inhibitory antibody durvalumab approximately doubled the objective response rate (ORR) seen with durvalumab alone in previous studies. Several patients had complete responses (CR). The response was enhanced in patients with a PD-L1 tumor proportion score ≥20. The current study aims at evaluating the combination of DAN with pembrolizumab, an anti-PD-1 agent approved as first line monotherapy for RM HNSCC.

Trial design

PEMDA-HN is a multicenter, open-label, randomized phase 2 study. Approximatively 81 RM HNSCC patients with a PD-L1 combined positive score (CPS) ≥20 will be randomized in a 2:1 ratio to receive either DAN (3 mg/kg intravenously [IV] weekly) and pembrolizumab (200 mg IV every 3 weeks) or pembrolizumab alone (200 mg IV every 3 weeks) as a first line therapy for recurrent or metastatic disease. After the screening period, eligible patients will receive study treatment until disease progression or discontinuation. The primary endpoint of the study is to determine the ORR by response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) as assessed by the investigator. Key secondary objectives are safety, additional antitumor activity evaluation (CR rate, duration of response, disease control rate, progression free survival, and overall survival) and pharmacokinetics. Exploratory endpoints include but are not limited to target engagement and biomarker evaluation. The study is being conducted at US study centers.

Clinical trial identification

NCT05814666.

Editorial acknowledgement

Legal entity responsible for the study

Flamingo Therapeutics NV.

Funding

Flamingo Therapeutics.

Disclosure

N. Saba: Financial Interests, Personal, Other, Honoraria: American Journal of Managed Care; AstraZeneca; Eisai; EMD Serono; Exelixis; GSK; Inovio Pharmaceuticals; Merck; Novartis; Vaccinex Aveo, Tosk, Aduro; Financial Interests, Institutional, Funding: Exilexis, Bristol-Myers Squibb; Financial Interests, Institutional, Principal Investigator: Flamingo Therapeutics; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Merck; Financial Interests, Personal, Patents, Royalties, Other Intellectual Property: Springer textbook Royalty; Uptodate chapter writing and editing. H. Youssoufian: Financial Interests, Personal, Advisory Role: Flamingo Therapeutics, Verastem Oncology, Treos Bio; Financial Interests, Personal, Advisory Board: C4 Therapeutics; Financial Interests, Personal, Leadership Role: Solid Therapeutics . E. Cohen: Financial Interests, Personal, Other, Consulting: Eisai, Merck, MSD, Nectin Tx, Pangea Therapeutics, Roche, Adagene, Astellas, Cidara, Genmab, Gilboa, iTeos, Eli Lilly, Novartis, Nykode, PCI Biotech, Replimune, Soteria, Viracta; Financial Interests, Personal, Other, DSMB: Kura; Financial Interests, Personal, Other, BOD: Akamis Bio; Financial Interests, Personal, Stocks/Shares: Kinnate Biophama, Primmune Therapeutics. J. Singh: Financial Interests, Institutional, Principal Investigator: Flamingo Therapeutics. L. MAKRIS: Financial Interests, Personal and Institutional, Leadership Role, Consulting company for multiple biotechnology companies: Stathmi, Inc; Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Flamingo Therapeutics. M. Perdomini: Financial Interests, Personal, Full or part-time Employment: Flamingo Therapeutics; Financial Interests, Personal, Stocks/Shares: Flamingo Therapeutics. S. MacIntyre: Financial Interests, Personal, Full or part-time Employment: Flamingo Therapeutics; Financial Interests, Personal, Stocks/Shares: Flamingo Therapeutics. A. Denker: Financial Interests, Personal, Full or part-time Employment: Flamingo Therapeutics; Financial Interests, Personal, Stocks/Shares: Flamingo Therapeutics, AstraZeneca, ElevateBio LLC, Merck Sharp and Dohme Corp.