MC# 21-43 - A Phase Ia/Ib, Open-label, Multicenter Trial Investigating the Safety, Tolerability, and Preliminary Anti-neoplastic Activity of S095029 (Anti-NKG2A) as Monotherapy and in Combination with Sym021 (Anti-PD-1) in Patients with Advanced Solid Tumor Malignancies followed by an Expansion Part with Triplet Combinations of S095029 and Sym021 and an Anti-HER2 mAb or Anti-EGFR mAbs (futuximab/modotuximab) in Patients with Metastatic Gastric or Colorectal Cancers
Agent(s): S095029, Sym021, SYM004
Disease Type(s): Colorectal, Gastric, Solid Tumor
Drug Classification(s): Immunotherapy, Monoclonal Antibody, Targeted Therapy
Molecular Target(s): EGFR, PD-1, NKG2A
Mechanism of Action
SYM004 is a mixture of two antibodies directed against different epitopes of epidermal growth factor receptor. Binding of these antibodies to EGFR may prevent activation of EGFR by ligand binding and subsequent dimerization of the receptor resulting in inhibition of EGFR-dependent tumor cell proliferation and metastasis.
Sym021 is an antibody against the inhibitory PD-1 signal molecule with the potential to restore T cell mediated immune responses against tumor cells.
S095029 (Sym025) is a monoclonal antibody candidate against NKG2A, a receptor for natural killer cells.
In this study, the sponsor and investigators want to learn:
- How much of S095029 can be given alone and in combination with Sym021 with an acceptable level of side effects
- The effects of S095029 when given alone and in combination with Sym021 (good and bad)
- How much of the study drug(s) are absorbed into the blood and how fast they are removed
- If research tests can be used in the future to predict who will benefit from the study drugs
- Male or female patient aged ≥ 18 years of age
- Patients with histologically or cytologically confirmed unresectable, locally advanced or metastatic solid tumor malignancies
- Patients with a malignancy that is not currently amenable to surgical intervention due to either medical contraindications or non-resectability of the tumor
- Patients with measurable disease according to RECIST v1.1 and must have had radiologic assessment of progression on the prior therapy before study entry
- Patients who have disease progression after treatment with available standard of care therapies that are known to confer clinical benefit or who are intolerant to treatment
- Study-specific tumor biopsies:
- Part 1a: Back-filled patients must agree to mandatory paired biopsies at screening and C1 D22-28 window (biopsies are optional for main patients).
- Part 1b: Both main and back-filled patients must agree to mandatory paired biopsies at screening and C1 D22-28 window. Tumor biopsy at the time of disease progression or end of treatment is optional.
- Sponsor reserves the right to make these mandatory biopsies to be optional at any point without an amendment if it impedes recruitment.
- Estimated life expectancy ≥ 12 weeks
- ECOG PS 0 or 1
- Documented radiographic progression on prior line of therapy
- Adequate hematological, renal and hepatic function based on the last assessment performed within 7 days prior to the first IMP administration
- Women of childbearing potential (WOCBP) must use a highly effective method of birth control during study treatment beginning within 2 weeks prior to the first IMP dose and continuing at least 6 months after the last dose of IMP. In case of use of oral contraception, women should have been stable on the same contraceptive drug (i.e. same active principle) for at least 3 months prior to IMP administration.
- Male patients with WOCBP partners must use a condom during the study and until at least 6 months after the last dose of IMP. In addition, contraception should be considered for their female partners. Contraceptive measures do not apply if the patient is sterile, vasectomized or sexually abstinent. Sperm donation will not be allowed during the study and for 6 months after the last dose of IMP.
- WOCBP tested positive in a serum pregnancy test within 7 days prior to the first day of IMP administration
- Major surgery within 4 weeks prior to the first IMP administration or patients who have not recovered from side effects of the surgery
- Patients with any other serious/active/uncontrolled infection, any infection requiring parenteral antibiotics, within 2 weeks prior to first IMP administration
- Active hepatitis B virus infection determined as HBsAg positive or Active Hepatitis C Virus infection determined as detection of HCV RNA in serum or plasma by a sensitive quantitative molecular method
- Carriers of HIV antibodies (patients with controlled HIV RNA are allowed if stable on medication and undetectable per standard management)
- Patients with a history of organ transplantation (e.g., stem cell or solid organ transplant)
- Patients with active thrombosis, or a history of DVT or pulmonary embolism, within 4 weeks prior to IMP administration, unless adequately treated and considered by the investigator to be stable
- Patients with active uncontrolled bleeding or a known bleeding diathesis
- Patients with a known clinically significant cardiovascular disease or condition
- History of gastrointestinal perforation, or intra-abdominal abscess within 28 days of inclusion
- History of cirrhosis or serious chronic liver condition
- History of pulmonary fibrosis or relevant uncontrolled chronic pulmonary condition in the opinion of the investigator
- Patients with non-healing wounds on any part of the body
- Patients who have received prior:
- Small molecule inhibitors, and/or other similar investigational agent: ≤ 2 weeks or 5 half-lives, whichever is shorter
- Chemotherapy, other monoclonal antibodies, antibody-drug conjugates, or other similar experimental therapies: ≤ 3 weeks or 5 half-lives, whichever is shorter
- Radioimmunoconjugates or other similar experimental therapies ≤ 6 weeks or 5 half-lives, whichever is shorter
- Patients must have recovered from any AE (from previous anti-cancer therapy) to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) V5.0 Grade 1 or lower except for alopecia, vitiligo or endocrinopathy managed with replacement therapy. Patients receiving replacement hormone therapy due to previous AEs will not be excluded from participation in this study if the associated AE has recovered to Grade 1 with replacement therapy prior to first administration on study. Non-clinically significant Grade 2 toxicities at baseline due to prior therapies will be allowed based on investigators discretion and in agreement with the medical sponsor representative.
- Patients who have received anti-NKGA mAb in the past
- Patients with known, untreated CNS or leptomeningeal metastases, or spinal cord compression; patients with any of these not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required. Only patients with CNS metastases clinically and radiographically stable for 4 weeks and with low corticosteroids treatment are allowed to participate (≤ 10 mg/day prednisone or equivalent is permitted if being administered for 4 weeks)
- Other malignancies including those which were radically treated and adequately medically managed and for which the remission period at the time of screening is less than 5 years. Exemptions for this minimally required duration of remission period may be applied for malignancies with a negligible risk of metastasis or death such as localized low grade prostate cancers, carcinoma in situ of the cervix, basal cell skin cancer, squamous cell skin cancer, ductal carcinoma in situ or superficial (non-muscle invasive) bladder cancer under control with cytoscopic intervention, that are deemed to be cured by adequate treatment.
- Treatment with systemic immunosuppressive therapy, inhaled, intranasal, intraocular, topical & intra-articular joint injections are allowed
- Prior radiotherapy if completed less than 4 weeks before first IMP administration, except if provided as a short course for symptoms palliation only
- Active autoimmune disease that might deteriorate when receiving an immunostimulatory agents. Patients with type 1 diabetes mellitus, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
- Administration of a live vaccine within 28 days prior to inclusion
- Known prior severe hypersensitivity to investigational products or any component in their formulations, including known severe hypersensitivity reactions to monoclonal antibodies
- In the investigator’s opinion, any clinically significant medical condition or laboratory abnormality likely to jeopardize the patient’s safety or to interfere with the conduct of the study
- Dallas, TX - Mary Crowley Cancer Research - Medical City