A Study to Evaluate the Safety, Pharmacokinetics and Efficacy of TJ101 in Patients With Advanced/Metastatic Solid Tumors

This is a first-in-human, Phase I, open-label, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary efficacy of TJ101, a bispecific antibody-drug conjugate (ADC) targeting EGFR and B7-H3, in patients with advanced or metastatic solid tumors.

Study Objectives Phase Ia (Dose Escalation)

• Primary: Assess safety/tolerability; determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended dose(s) for expansion (RDEs).
• Secondary: Characterize PK profile, assess preliminary anti-tumor activity, and evaluate immunogenicity.

Phase Ib (Dose Expansion)

• Primary: Further assess safety and preliminary anti-tumor activity of TJ101 at the selected RDEs.
• Secondary: Further characterize PK profile and immunogenicity.

Study Design

• Part 1: Dose Escalation (Phase Ia)
• Up to 72 patients with advanced/metastatic solid tumors.
• Six planned dose cohorts: IV every 3 weeks (Q3W).
• Accelerated titration for first cohort; 3+3 design for subsequent cohorts.
• Backfill cohorts (6-12 patients each) may be added at promising dose levels to refine safety, PK, and efficacy data.
• DLT evaluation window: 21 days after first infusion (Cycle 1).
• Safety Monitoring Committee (SMC) reviews all data to guide escalation, backfill, and RDE selection.

Part 2: Dose Expansion (Phase Ib)

• 40-180 patients, across tumor-specific cohorts
• Patients randomized to 2-3 RDEs of TJ101.
• 20-30 subjects per tumor type/dose level.
• Expansion will refine safety/PK and assess anti-tumor activity in biomarker-selected subgroups.
• Dosing: IV infusion on Day 1 of each 21-day cycle; continued until progression, unacceptable toxicity, withdrawal, or investigator decision.

Study Procedures & Monitoring

• Screening: within 28 days prior to first dose.
• Safety Monitoring: continuous AE collection, labs, vitals, ECOG, ECGs, ophthalmologic exams, skin checks.
• Efficacy Assessments: imaging at baseline, then every 6 weeks (first 24 weeks), every 9 weeks thereafter, and every 12 weeks from year 2 until progression or new therapy.
• PK/Immunogenicity Sampling: intensive during Cycles 1 and 3; serial sampling in later cycles.
• Follow-up:

• 30-day safety follow-up after last dose.
• Survival follow-up every 3 months until death or study termination.

Enrollment & Duration

• Estimated enrollment: up to 252 patients.
• Study duration: ~ 2-3 years.

Inclusion criteria

• Histological and/or cytological diagnosis of advanced/metastatic solid tumors, who have failed standard treatment, or have no standard therapy.
• Have at least one measurable lesion by RECIST v1.1 (Eisenhauer et al., 2009) for solid tumors.
• Men or women ≥18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status (Oken et al., 1982) of 0 to 1.
• Life expectancy of ≥ 12 weeks;
• Patients with adequate organ function and the laboratory test criteria specifically defined as follows within 7 days prior to the first dosing.

• Hepatic function: AST and ALT ≤ 2.5 x upper limit of normal (ULN); if liver metastases, then ≤ 5 x ULN. Total bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN in the presence of documented Gilbert's Syndrome.
• Albumin ≥3g/dL.
• Coagulation function: International normalized ratio (INR) ≤ 1.5×ULN; APTT≤1.5×ULN.
• Renal function: Creatinine clearance ≥ 60 mL/min (calculated by Cockcroft and Gault equation) (Cockcroft DW, 1976)
• Hematopoietic function (without infusion of blood product, use of G-CSF or other treatments to correct blood count within 14 days): Hemoglobin (HGB) ≥ 90 g/L; Platelet count (PLT) ≥ 100×109/L; Absolute neutrophil count (ANC) ≥ 1.5×109/L;
• Serum pregnancy test (for female of childbearing potential) negative within 7 days prior to first dosing of study treatment. Male and female patients of childbearing potential must agree to use effective methods of contraception from the time of informed consent, throughout the study and for 6 months after the last dose of the investigational product.
• Willing to participate in the clinical trial, understand and sign the informed consent, and comply with the study visits and procedures.

Exclusion criteria

• Has received treatment of topoisomerase 1 inhibitors (TOP1i), including topotecan, irinotecan, belotecan, and TOP1i-based antibody-drug conjugates (ADCs, eg, sacituzumab govitecan, trastuzumab deruxtecan, zalontamab brengitecan, sacituzumab tirumotecan etal);
• Has known hypersensitivity to any component of TJ101 or has a history of severe hypersensitivity reactions to other monoclonal antibodies;
• Has received mitomycin and nitrosoureas treatment within 6 weeks prior to the first administration; oral fluorouracil-like drugs such as S-1, capecitabine, or palliative radiotherapy within 2 weeks prior to the first administration; Has received other chemotherapy, biological therapy, immunotherapy, major surgery, radical radiotherapy, targeted therapy (including small molecule inhibitor of tyrosine kinase) and other anti-tumor therapy within 5 half-lives or 28 days, whichever is shorter, prior to the first administration of TJ101; Has received anti-tumor herbal medicine within 14 days prior to first dose of TJ101;
• Has received a strong or moderate CYP3A4 inhibitor within 3 half-lives;
• Received an investigational drug within 28 days or 2 half-lives (whichever is shorter) prior to first dose of TJ101; Current participation in other interventional clinical studies (participation in survival follow-up is allowed);
• Toxic effects of prior anti-tumor therapy have not recovered to NCI-CTCAE V5.0 Grade ≤1 (excluding alopecia and skin pigmentation). Subject with irreversible toxicities caused by prior anti-tumor therapy (eg, hearing loss) that will not increase the safety risk may be eligible at the discretion of the Investigator.
• Has a history of (non-infectious) interstitial lung disease (ILD) that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis can't be ruled out by imaging at screening.
• Presence of severe dry eye syndrome, severe keratitis, severe conjunctivitis, or other severe conditions that may increase the risk of corneal epithelial damage at the discretion of investigator.
• Uncontrolled or significant cardiovascular disease, including:

Prolongation of the average Corrected QT interval (QTc, Fridericia's correction formula used) (> 470 ms regardless of sex).

Clinically significant arrhythmia, unstable angina pectoris, congestive heart failure (class II-IV of New York Heart Association [NYHA]) or acute myocardial infarction within preceding 6 months.

History of additional risk factors for Torsades de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).

Uncontrolled hypertension defined as systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg while receiving more than one kind of antihypertensive drug.

• For patients with documented positive virology status of hepatitis, as confirmed by Screening hepatitis B virus (HBV) and hepatitis C virus (HCV) tests, only the following patients may be eligible as evaluated by the sponsor and investigator:

Patients with active hepatitis B: HBV DNA ≤500 IU/mL during Screening. Patients who are hepatitis C virus antibody positive (HCV Ab+), who have controlled infection (HCV RNA≤ULN by polymerase chain reaction [PCR] either spontaneously or in response to a successful prior course of anti-HCV therapy at Screening). Patients with controlled infections must undergo periodic monitoring of HCV RNA as per treating physician.

• Known HIV infection;
• Severe infection, including but not limited to hospitalization due to infection, bacteraemia, or severe pneumonia complications, occurs within 4 weeks prior to initiation of study treatment; Or patients who received therapeutic oral or intravenous antibiotics within two weeks prior to starting study treatment, and who received prophylactic antibiotics (e.g., for the prevention of urinary tract infection or chronic obstructive pulmonary disease);
• Active central nervous system (CNS) metastases or meningeal metastases. Subjects may be enrolled in the study if their CNS metastases have received adequate local therapy and have been clinical stable for at least 4 weeks (ie, imaging shows no progression of the brain lesion and neurologically relevant symptoms are stable), and require a dose of prednisone of ≤20 mg/day (or equivalent dose).
• Other malignancies within 3 years prior to initiation of TJ101 treatment (other than non-melanoma basal cell carcinoma or squamous cell carcinoma of the skin, breast/cervical carcinoma in situ, superficial bladder carcinoma that have received radical treatment and no evidence of disease recurrence) will confound safety/efficacy of this trial or pose a risk to the participants;
• Female patients who are lactating or breastfeeding.
• The investigator believes that the subject may have other factors that may affect the results of the study and interfere with the subject's participation in the entire study process, including previous or existing physical conditions, abnormal treatment or laboratory tests, and the subject's unwillingness to comply with all procedures, restrictions, and requirements of the study.