Phase I Study of SM2275 Injection in Patients With Advanced Solid Tumors

Official title

A First-in-Human, Open-Label, Multicenter, Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Preliminary Antitumor Activity of SM2275 in Patients With Advanced Solid Tumors

Overview

This is a first-in-human, multicenter, open-label Phase Ia/Ib study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary antitumor activity of SM2275 in patients with advanced or metastatic solid tumors who have progressed after standard therapy or for whom no standard treatment is available. Phase Ia includes dose escalation to evaluate safety, identify dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D). Phase Ib will further evaluate safety, PK, PD, and preliminary antitumor activity in expansion cohorts.

Detailed description

SM2275 is an investigational tetravalent VHH-based multispecific antibody targeting EGFR, PD-L1, CD28, and HSA.

SM2275 is designed to selectively promote CD28-mediated T-cell costimulation through simultaneous engagement of EGFR and PD-L1 expressed in the tumor microenvironment while blocking the PD-L1 immune checkpoint pathway. The HSA-binding domain is incorporated to prolong systemic exposure.

This first-in-human Phase Ia/Ib study will evaluate intravenous SM2275 in patients with advanced solid tumors.

Phase Ia will evaluate escalating dose levels using an adaptive dose-escalation strategy to characterize safety, identify DLTs, determine the MTD and/or RP2D, and characterize PK and PD.

Following dose escalation, Phase Ib will further evaluate safety and preliminary efficacy in selected expansion cohorts.

Interventions

• Drug SM2275
  Concentrated solution for injection, 100 mg/4 mL/vial. Administered intravenously according to preset dose levels and cycle intervals defined in protocol v1.0.

Primary outcome measures

• Incidence of Treatment-Emergent Adverse Events (TEAEs) [Time frame: From first dose through 28 days after the last dose (up to approximately 12 months)]
• Incidence of Dose-Limiting Toxicities (DLTs) [Time frame: Cycle 1 (21 days)]
• Maximum Tolerated Dose (MTD) [Time frame: During dose escalation (up to approximately 12 months)]
• Recommended Phase II Dose (RP2D) [Time frame: End of dose escalation (up to approximately 12 months)]

Secondary outcome measures (11)

• Maximum Observed Plasma Concentration (Cmax) [Time frame: From first dose through end of treatment (up to approximately 12 months)]
• Time to Maximum Plasma Concentration (Tmax) [Time frame: From first dose through end of treatment]
• Area Under the Plasma Concentration-Time Curve (AUC) [Time frame: From first dose through end of treatment]
• Terminal Elimination Half-life (t½) [Time frame: From first dose through end of treatment]
• Apparent Clearance (CL) [Time frame: From first dose through end of treatment]
• Apparent Volume of Distribution (Vz) [Time frame: From first dose through end of treatment]
• Incidence of Anti-drug Antibodies (ADA) [Time frame: Baseline through end of study (up to approximately 12 months)]
• Objective Response Rate (ORR) [Time frame: From first documented response until disease progression or study completion (up to approximately 24 months)]
• Disease Control Rate (DCR) [Time frame: Up to approximately 24 months]
• Duration of Response (DoR) [Time frame: Up to approximately 24 months]
• Progression-Free Survival (PFS) [Time frame: Up to approximately 24 months]

Eligibility criteria

Inclusion criteria

• Male or female participants aged 18 years or older.
• Able to understand the study requirements and voluntarily provide written informed consent before any study-specific procedures.
• Histologically or cytologically confirmed advanced or metastatic EGFR-positive and PD-L1-positive solid tumor that has progressed following standard therapy, is intolerant to standard therapy, or for which no effective standard therapy is available, including but not limited to head and neck squamous cell carcinoma, non-small cell lung cancer, unresectable advanced colorectal cancer, and renal clear cell carcinoma.
• Able to provide archived tumor tissue or other tumor samples as required by the protocol during the screening period.
• At least one measurable lesion according to RECIST Version 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy of at least 12 weeks.
• Adequate hematologic, hepatic, renal, cardiac, and other organ function as defined in the protocol.
• Left ventricular ejection fraction (LVEF) greater than 50% as determined by echocardiography (ECHO) or multigated acquisition (MUGA) scan.
• Female participants of childbearing potential must have a negative serum pregnancy test within 7 days before the first dose of study treatment.
• Male participants and female participants of childbearing potential must agree to use highly effective contraception during the study and for at least 6 months after the last dose of study treatment.

Exclusion criteria

• Insufficient washout period from prior anticancer therapy before the first dose of study treatment.
• Prior anticancer immunotherapy permanently discontinued due to immune-related toxicity, history of Grade 3 or higher immune-related adverse events (irAEs), or history of Grade 2 or higher immune-related myocarditis considered by the investigator to make the participant unsuitable for study participation.
• History of severe infusion-related reactions associated with prior EGFR-targeted therapy.
• Receipt of antitumor vaccines or cellular immunotherapy within 3 months before the first dose of study treatment.
• Presence of another active malignancy requiring treatment.
• Adverse events from prior anticancer therapy that have not recovered to Grade 1 or baseline, except for alopecia, skin pigmentation of any grade, or Grade 2 or lower peripheral sensory neuropathy.
• Active autoimmune disease requiring systemic immunosuppressive therapy.
• Major surgery, open biopsy, or significant traumatic injury within 4 weeks before the first dose; planned major surgery during the study; or incomplete recovery from prior surgery.
• Active central nervous system (CNS) tumors.
• Symptomatic heart failure (New York Heart Association Class II or higher).
• Uncontrolled hypertension (systolic blood pressure greater than 150 mmHg or diastolic blood pressure greater than 100 mmHg despite optimal medical therapy).
• Fridericia-corrected QT interval (QTcF) greater than 470 milliseconds based on the average of triplicate screening electrocardiograms.
• Acute coronary syndrome, acute myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG) surgery within 6 months before the first dose.
• Cardiomyopathy of any etiology or clinically significant valvular heart disease.
• Clinically significant arrhythmias requiring medical treatment (well-controlled atrial fibrillation is permitted).
• Transient ischemic attack (TIA) or stroke within 6 months before screening.
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring drainage at least once per month or ongoing clinical intervention.
• Active infection requiring systemic antibacterial or antiviral therapy within 14 days before the first dose. Participants receiving stable antiviral therapy for hepatocellular carcinoma or controlled hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are permitted.
• Active or uncontrolled hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Participants with controlled HBV or HCV receiving stable antiviral therapy may be eligible.
• Known human immunodeficiency virus (HIV) infection.
• Receipt of systemic immunosuppressive medication within 14 days before the first dose, unless permitted by the protocol.
• History of interstitial lung disease (ILD), pneumonitis, suspected ILD or pneumonitis that cannot be excluded by screening imaging, or severe chronic obstructive pulmonary disease (COPD).
• History of severe hypersensitivity to monoclonal antibodies or history of anaphylaxis within 6 months before screening.
• History of allogeneic organ transplantation or graft-versus-host disease (GvHD).
• Receipt of a live vaccine within 4 weeks before the first dose.
• Known substance abuse or psychiatric disorder that, in the opinion of the investigator, would interfere with study participation or protocol compliance.
• Pregnant or breastfeeding women, or participants planning to conceive or father a child during the study and for at least 6 months after the last dose of study treatment.
• Any medical condition, laboratory abnormality, or other clinical circumstance that, in the opinion of the investigator, would make the participant unsuitable for study participation or could interfere with the interpretation of study results.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Cancer Hospital, Chinese Academy of Medical Sciences — Beijing

Identifiers

NCT: NCT07750132 · SM2275-CN-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗