A phase 1 dose-escalation study to investigate the safety, efficacy, pharmacokinetics, and pharmacodynamic activity of CLN-619 (anti-MICA/MICB antibody) alone and in combination with pembrolizumab in patients with advanced solid tumors.

Authors

John Powderly, II

John D. Powderly

Carolina BioOncology Institute, Huntersville, NC

John D. Powderly , Martin Gutierrez , Judy S. Wang , Erika P. Hamilton , Manish Sharma , Alexander I. Spira , Michael Millward , Mark J. Shackleton , Sophia Frentzas , Marianna Koczywas , Naveen Mehta , Ann Marie Christensen , Irina Shapiro , Kerry Whalen , Jennifer Michaelson , Patrick Baeuerle , John Edward Janik , Drew W. Rasco

Organizations

Carolina BioOncology Institute, Huntersville, NC, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, Florida Cancer Specialists, Sarasota, FL, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, START Midwest, Grand Rapids, MI, Virginia Health Specialists, Fairfax, VA, School of Medicine and Pharmacology, The University of Western Australia, Western Australia, Australia, Department of Oncology, Alfred Health and Monash University, Melbourne, Australia, Monash Hospital, Victoria, Australia, City of Hope, Duarte, CA, Cullinan Oncology, LLC, Cambridge, MA, START, San Antonio, TX

Research Funding

Pharmaceutical/Biotech Company

Background: The major histocompatibility complex (MHC) class I-related proteins MICA and MICB are stress-inducible, surface glycoproteins that are up-regulated on human tumors. MICA/MICB are ligands for the activating receptor, Natural Killer Group 2 member D (NKG2D) expressed on Natural Killer (NK) cells, CD8+ T cells, γδ T cells and iNKT cells. Proteases in the tumor microenvironment cleave MICA/MICB from the cell surface which enables tumor cells to evade immune cell recognition and destruction by NKG2D-expressing cells. Increased concentrations of shed MICA have been observed in serum from patients across multiple tumor types and correlate with poor survival. CLN-619 is a humanized, clinical-stage, MICA/MICB-specific IgG1 monoclonal antibody that prevents the proteolytic release of MICA/MICB thereby exposing tumor cells for immune destruction through both NKG2D-mediated and antibody-dependent cell-mediated cytotoxicity (ADCC). The antibody has been shown to restore the MICA/MICB-NKG2D axis to promote NK-mediated tumor cell lysis (AACR Annual Meeting abstract 3506, April 2022). In mice bearing MICA/MICB-expressing human tumor xenografts, CLN-619 treatment yielded robust anti-tumor activity at low doses. MICA/MICB is expressed in a wide range of solid tumors. Therefore, CLN-619 is expected to have broad anti-tumor activity. Methods: CLN-619 is being evaluated in an open-label, non-randomized, dose-escalation (phase 1) study as monotherapy, and in combination with pembrolizumab, in patients with advanced solid tumors. Cohort expansion in patients with specific indications as monotherapy and in combination with pembrolizumab will be conducted. The phase 1 study explores ascending intravenous doses of CLN-619 as monotherapy (0.1, 0.3, 1.0, 3.0, 6.0 and 10.0 mg/kg) and in combination with pembrolizumab (200 mg) in 21-day cycles to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Key eligibility criteria include 1) histological or cytological diagnosis of cancer and 2) refractory metastatic disease, or locally advanced disease not amenable to local therapy. At the RP2D, CLN-619 monotherapy will be evaluated in non-small cell lung and cervical cancer. In parallel, a cohort of patients will be administered CLN-619 in combination with pembrolizumab. Serum levels of soluble MICA/MICB, identity of MICA/MICB alleles, phenotypes of peripheral blood mononuclear cells, cytokines and tumor biopsies will be investigated for correlative pharmacodynamic and predictive biomarkers. This clinical trial is in progress (NCT05117476) and has completed accrual of three participants at the first dose level. Clinical trial information: NCT05117476.

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Abstract Details

Meeting

2022 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Developmental Therapeutics—Immunotherapy

Track

Developmental Therapeutics—Immunotherapy

Sub Track

New Targets and New Technologies (IO)

Clinical Trial Registration Number

NCT05117476

Citation

J Clin Oncol 40, 2022 (suppl 16; abstr TPS2688)

DOI

10.1200/JCO.2022.40.16_suppl.TPS2688

Abstract #

TPS2688

Poster Bd #

332a

Abstract Disclosures