IRB Study Number 25-791
Status Recruiting
Phases Phase 1, Phase 2
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Primary Objectives:
Dose Escalation
•To assess the safety and tolerability of ADG126 at escalating dose levels, in combination with pembrolizumab in adults with advanced/metastatic solid tumors
•To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) ofADG126 + pembrolizumab
•To assess the safety and tolerability of ADG126 + pembrolizumab in combination with the following standard of care (SOC) therapies in subjects with microsatellite stable colorectal cancer(MSS CRC)
oTrifluridine/tipiracil-bevacizumab
oFruquintinib
•To determine the MTD and/or RP2D of ADG126 + pembrolizumab in combination with the following SOC therapies:
oTrifluridine/tipiracil-bevacizumab
oFruquintinib
Dose Expansion
•To assess the preliminary antitumor activity of ADG126 + pembrolizumab
•To assess the preliminary antitumor of ADG126 + pembrolizumab in combination with thefollowing SOC therapies in MSS CRC
oTrifluridine/tipiracil-bevacizumab
oFruquintinib
Dose Optimization
•To characterize the optimal dose based on safety and efficacy parameters
Secondary Objectives:
Dose Escalation
•To assess the pharmacokinetic (PK) profile of ADG126 and pembrolizumab
•To assess dose proportionality of key PK parameters (area under the time concentration curve[AUC], maximum concentration [Cmax])
•To assess the immunogenicity of ADG126 and pembrolizumab
•To characterize the relationship between immunogenicity (anti-drug antibody [ADA] positivity) andPK, safety, and efficacy parameters
•To evaluate the preliminary antitumor activity of the ADG126 + pembrolizumab
To assess the preliminary antitumor of the ADG126 + pembrolizumab in combination with the following SOC therapies in MSS CRC
o Trifluridine/tipiracil-bevacizumab
o Fruquintinib
Dose Expansion
• To assess the safety and tolerability of ADG126 + pembrolizumab in adults with advanced/metastatic solid tumors
• To assess the safety and tolerability of ADG126 + pembrolizumab in combination with the following SOC therapies in MSS CRC:
o Trifluridine-tipiracil-bevacizumab
o Fruquintinib
• To assess the PK profile of ADG126 and pembrolizumab
• To assess the immunogenicity of ADG126 and pembrolizumab
Dose Optimization
• To assess the efficacy outcomes in the defined patient population
Exploratory Objectives:
• To assess pharmacodynamic and potential predictive biomarkers, including serum cytokines such as IL-2, IL-4, IL-6, IL-8, TNF-α, IL-1β, IFN-γ, IL-10 and plasma soluble proteins (MMP9/uPA), circulating tumor DNA (ctDNA), regulatory T cells (Tregs), tumor infiltrated lymphocytes (TILs), microsatellite instability (MSI), programmed cell death ligand 1 (PD-L1), tumor mutational burden (TMB), and/or pharmacogenomic biomarkers.
Inclusion Criteria
≥18 years of age at the time of informed consent.
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 with no deterioration over the previous 2 weeks.
For Dose Escalation Phase Only: Patients with histologically or cytologically confirmed, locally advanced or metastatic solid tumors, who have progressed after all standard therapies, or for whom no further standard therapy exists, including CRC, NSCLC, HCC, esophageal squamous cell carcinoma (SCC), HNSCC, cutaneous SCC, penile/anal SCC and cervical cancer (additional tumor types may be eligible after discussion with Sponsor).
Dose Expansion Phase Only: Tumor tissues (archived or fresh biopsy) before treatment are required for all patients. Biopsies and tumor tissues after treatment are optional. Patients must have one of the following tumor types including the corresponding criteria.
MSS CRC – ADG126 + pembrolizumab
• Advanced/metastatic CRC not amenable to curative surgery, with MSS status defined per local or central laboratory assessment
• Has received at least 2 and no more than 3 prior systemic treatments regimens, including 5-fluouracil/capecitabine, oxaliplatin, irinotecan (regardless of combination in 1 or 2 lines of therapy), with or without the association with mAbs (e.g., bevacizumab or cetuximab). Repeat use of the same regimen is considered as additional lines of therapy, including adjuvant therapy.
o Free of liver metastasis
o No prior immunotherapy
MSS CRC - ADG126 + pembrolizumab and trifluridine/tipiracil + bevacizumab
• Adult patients with MSS CRC previously treated with fluoropyrimidine‑, oxaliplatin‑, or irinotecan‑based chemotherapy, and who have been previously treated with or cannot be treated with an anti-VEGF therapy and, if RAS wild type, an anti‑EGFR therapy
• No prior treatment with trifluridine/tipiracil
MSS CRC – ADG126 + pembrolizumab + fruquintinib
• Adult patients with MSS CRC who have been previously treated with fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, anti-VEGF therapy, and, if RAS wildtype and medically appropriate, an anti-EGFR therapy and who have progressed on or are intolerant to treatment with either trifluridine/tipiracil or regorafenib.
• No prior treatment with fruquintinib
• No current or active liver metastasis as assessed by baseline CT scan. Previously resected or ablated lesions are acceptable if the patient has been liver-metastases free by CT or magnetic resonance imaging (MRI) for at least 4 months from their liver
Docusign Envelope ID: B43FB761-D42F-40EC-AC1F-8FDB887C532A
Protocol Number: ADG126-P001/KEYNOTE-C98 v7.0
Date: 09 July 2025
Confidential 84 of 193
directed procedure. For questionable cases, PET-CT is required to rule out liver metastasis. Patients with prior treatment with stereotactic body radiotherapy (SBRT) or Yttrium-90 (Y90) will not be eligible.
• Patients progressed on the ADG126 + pembrolizumab and trifluridine/tipiracil + bevacizumab may continue with the ADG126 + pembrolizumab + fruquintinib
Dose Optimization: MSS CRC –ADG126 + pembrolizumab
• Adult patients with metastatic MSS CRC who have received at least 2 and no more than 3 prior systemic lines of therapies including fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapies (Repeated use of the same regimen is considered an additional line of therapy), an anti-VEGF therapy, and, if RAS wildtype and medically appropriate, an anti-EGFR therapy.
• No current or active liver metastasis as assessed by baseline CT scan. Previously resected or ablated lesions are acceptable if the patient has been liver-metastases free by CT or MRI for at least 4 months from their liver-directed procedure. For questionable cases, PET-CT is required to rule out liver metastasis. Patients with prior treatment with SBRT or Y90 will not be eligible. HNSCC who have previously been treated with an immunotherapy agent
• Advanced H
Exclusion Criteria
Pregnant or breastfeeding females.
Females of childbearing potential and males whose partners are of childbearing potential who do not agree to the use of 2 forms of highly effective contraception during the treatment period and for 6 months after the last dose of study drug.
Treatment with any investigational drug or palliative radiation therapy within 2 weeks prior to the first dose of study drug.
Prior treatment with a PD-1, PD-L1 targeting agent or a next-generation anti-CTLA-4 therapy with enhanced ADCC function (not including ipilimumab/ipilimumab-like molecules or bispecific molecules containing an ipilimumab-like arm).
Grade ≥3 irAEs or irAE that led to discontinuation of prior immunotherapy, and prior Grade ≥2 pneumonitis or hypophysitis related to immunotherapy.
Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 8 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 21 days prior to first dose of study treatment.
History of hypersensitivity or known to be allergic to protein drugs or recombinant proteins or any ingredients contained in the ADG126, pembrolizumab, trifluridine/tipiracil, bevacizumab, or fruquintinib drug formulations, as applicable.
Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
Patients requiring systemic treatment with corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive medications within 21 days before the planned first dose of study drug. Ophthalmologic, nasal, inhaled, and intra-articular injections of steroids are allowed.
Patients receiving G-CSF, granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin, or blood [RBC or platelet] transfusion within 14 days prior to the first dose of the study drug.
Patients with active viral (any etiology) hepatitis are excluded, except for patients with controlled hepatitis B or C who meet the following criteria:
- The disease is clinically controlled. Antiviral therapy for hepatitis B virus (HBV) must be given for at least 4 weeks prior to Cycle (C) 1 Day (D) 1
Docusign Envelope ID: B43FB761-D42F-40EC-AC1F-8FDB887C532A
Protocol Number: ADG126-P001/KEYNOTE-C98 v7.0
Date: 09 July 2025
Confidential 87 of 193 - Patients with anti-hepatitis B core antibody but with undetectable HBV DNA (<200 IU/mL) and negative for surface antigen of HBV.
- Patients with resolved or treated hepatitis C virus (HCV) (i.e., HCV antibody positive but undetectable HCV RNA, HCV viral load <15 IU/mL) in the study
Any uncontrolled active infections requiring systemic antimicrobial treatment (viral, bacterial, or other), or uncontrolled or poorly controlled diabetes as evidenced by screening (baseline) hemoglobin A1c (Hgb A1c) ≥8 [For those with borderline Hgb A1c (8-8.5), fasting glucose < 130 mg/dL is acceptable], uncontrolled asthma or chronic obstructive pulmonary disease (COPD), or other conditions that pose a risk to the patient participating on study.
Has a known history of human immunodeficiency virus (HIV) infection.
Patients with any type of primary immunodeficiency or autoimmune disorder requiring treatment.
History of prior malignancy other than the cancer under treatment in the study, except for adequately treated in situ cancer, basal cell, or squamous cell skin cancer, or other cancer (e.g., breast, prostate)
