A phase 1 dose-escalation study to investigate the safety, efficacy, pharmacokinetics, and pharmacodynamic activity of cln-619 (Anti-MICA/B antibody) alone and in combination with pembrolizumab in patients with advanced solid tumors.
Authors: Wang Judy S. , Gutierrez Martin , Rasco Drew W. , Melero Bermejo Ignacio , Powderly John D. , Hamilton Erika P. , Millward Michael , Arance Ana Maria , Stec Rafal , Moreno Victor , Sharma Manish , Lugowska Iwona A. , Shackleton Mark J. , Frentzas Sophia , Janik John Edward , Liu Tracy , Shapiro Irina , Whalen Kerry , Jones Jeffrey Alan , Spira Alexander I. 
Published: June 2023

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Background: MICA and MICB are stress-induced ligands upregulated on the majority of human tumors. Engagement of MICA/B by the activating receptor NKG2D on NK cells and several subsets of T cells results in immune-mediated target cell lysis. However, proteases in the tumor microenvironment cleave cell surface MICA/B, enabling immune evasion. CLN-619 is a humanized MICA/B-specific IgG1 monoclonal antibody designed to prevent the proteolytic release of MICA/B, restoring immune-mediated tumor cell lysis. CLN-619 is expected to have broad anti-tumor activity. Methods: This phase 1, multicenter, open-label, first-in-human dose-escalation study (NCT05117476) enrolls patients (pts) with advanced solid tumors who progressed on available therapies, were intolerant to treatment, or refused noncurative standard treatment. CLN-619 alone (dose levels (DL) of 0.1, 0.3, 1, 3, 6, 10mg/kg) were administered intravenously every three weeks. Corticosteroid pre-medication for infusion related reaction (IRR) prophylaxis were required starting at the 3 mg/kg DL. A parallel dose-escalation is exploring CLN-619 (DL 1.0 mg/kg and higher) in combination with pembrolizumab. Response (RECIST 1.1) is assessed every 9 weeks. Data from the monotherapy dose escalation are described. Results: As of Dec 2, 2022, 23 pts (median age, 63 y, range 47-83) were enrolled, 48% were male and 61% had ECOG PS 1. Major tumor types included colon (4), cervical (3), lung (3) and prostate (3). All pts received prior systemic therapy (median 3, range 1-7); 12 patients had prior checkpoint inhibitor. The median number of CLN-619 cycles received was 2 (range, 0–8). Treatment-emergent adverse events (TEAEs) in ≥20% of pts were abdominal pain (26%), nausea (22%), pyrexia (22%), and infusion related reaction (IRR) (22%). IRRs occurred at dose levels of 0.3 mg/kg and higher. All IRR occurred in Cycle 1 and resolved within 3 hours of onset. One case of Gr3 laryngeal edema occurred at the 10 mg/kg DL in the absence of required steroid premedication and led to dose discontinuation. No fatal TEAEs were reported. A nearly dose-proportional increase in CLN-619 exposure was observed between the 0.1 mg/kg and 10 mg/kg dose levels. CLN-619 half-life ranged from 87.6 to 307 hours for DL ranging from 0.1 mg/kg to 6 mg/kg. There was one confirmed complete response in a patient with recurrent salivary gland tumor who progressed following a complete response on a PD-1 blocking agent. Another patient with cervical cancer maintained SD for 9 cycles before progressing. Conclusions: CLN-619 therapy was well tolerated at doses ranging from 0.1 to 10 mg/kg and demonstrated monotherapy clinical activity, including objective response in a patient progressing after PD-1. Updated data from the dose-escalation portion of the trial will be presented. Clinical trial information: NCT05117476 .