Phase I Study of Single-Agent KGX105 in Patients With Advanced or Metastatic Solid Tumors

Inclusion criteria

• Male or female participants with age ≥18 years, at the time of signing the informed consent.
• Dose Escalation Phase (Phase Ia):

Participants with histologically or cytologically confirmed locally advanced or metastatic malignant solid tumors meeting any of the following conditions:

• Have received prior standard systemic anti-tumor therapy recommended by current guidelines for their tumor type and stage, and experienced disease progression or unacceptable toxicity during or after treatment;
• Have no effective standard therapy available at present;
• Meet any of the following conditions rendering standard therapy unsuitable:

• Presence of known standard contraindications to standard therapy for their tumor type; •② Prior discontinuation of standard therapy due to intolerable toxicity; •③ Explicit refusal to receive available standard therapy.
• Priority: Non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), nasopharyngeal carcinoma (NPC), pancreatic cancer, and other EGFR-positive* solid tumors such as gastroesophageal junction adenocarcinoma, gastric cancer, and esophageal squamous cell carcinoma.
• Dose Expansion Phase (Phase Ib):

• Cohort 1 (EGFR-positiveNSCLC):*
• Participants with driver gene-positive NSCLC must have received approved targeted therapy for the identified driver gene unless contraindicated; treatment discontinuation must be due to disease progression or intolerable toxicity. Driver genes primarily include: EGFR exon 19 deletion, L858R mutation, or exon 20 insertion mutation.
• Participants with EGFR protein overexpression or gene amplification in driver gene-negative NSCLC must have received platinum-based chemotherapy and anti-PD-(L)1 antibody therapy (concurrent or sequential), unless contraindicated; treatment discontinuation must be due to disease progression or intolerable toxicity.
• Cohort 2 (EGFR-positiveHNSCC, NPC):*
• HNSCC participants must have received immune checkpoint inhibitors and/or platinum-based chemotherapy (with or without cetuximab).
• NPC participants must have received platinum-based chemotherapy, with or without anti-PD-(L)1 antibodies.
• Cohort 3 (Other EGFR-positivesolid tumors):*
• Pancreatic cancer, gastric cancer, gastroesophageal junction adenocarcinoma, and esophageal squamous cell carcinoma that have progressed after at least one line of standard therapy.
• Definition of EGFR-positivein this study:* Includes any of the following: EGFR protein overexpression (EGFR IHC staining intensity ≥1+), EGFR gene mutation, or EGFR gene amplification (by NGS).
• According to RECIST 1.1, there must be at least one measurable lesion (tumor lesions located in a previously irradiated area or other sites of locoregional therapy generally are not considered measurable unless they have demonstrated clear progression or have persisted for three months after radiation therapy).

Note: Metastatic brain lesions are not considered as target lesions.

• ECOG 0-1.
• Life expectancy of ≥3 months, in the opinion of the investigator.
• Adequate organ function as determined by medical evaluation including:

• Adequate hematologic status, defined as: absolute neutrophil count (ANC) ≥1.5×109/L, hemoglobin ≥90 g/L, platelets ≥100×109/L. Platelet transfusions are not permitted within 7 days, red blood cell transfusions are not permitted within 14 days, hematopoietic growth factors are not permitted within 7 days (14 days for PEGylated G-CSF or erythropoietin) prior to obtaining these laboratory values.
• Adequate hepatic function, defined as: serum TBIL ≤1.5×ULN (in participants with known Gilbert's syndrome, TBIL ≤3×ULN with direct bilirubin ≤1.5×ULN), serum ALT or AST ≤2.5×ULN (or ≤5.0×ULN for documented liver metastasis).
• Adequate renal function, defined as: creatinine clearance ≥60 mL/min (measured or calculated by Cockcroft and Gault equation).
• Adequate coagulation profile, defined as (including if receiving anticoagulation therapy): prothrombin time (PT) <1.5×ULN, activated partial thromboplastin time (APTT) <1.5×ULN. If the participant is on anticoagulation therapy, must be on a stable dose of anticoagulant for ≥1 month prior to study treatment.
• Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to treatment.
• Women of childbearing potential or male partners of women of childbearing potential must agree to use highly effective contraception throughout the treatment period and for 4 months after the last dose.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this study.

Exclusion criteria

• Diagnosis of another malignancy within 5 years prior to the first dose, except for:

• Curatively resected basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or carcinoma in situ;
• Localized prostate cancer or papillary thyroid carcinoma post curative resection.
• Presence of leptomeningeal metastasis, spinal cord compression, symptomatic brain metastases, or brain metastases requiring steroids/antiepileptic drugs or showing radiographic progression within 4 weeks prior to enrollment.

•Exception:Asymptomatic brain metastases, or those stable for >4 weeks post-treatment without requiring steroids/antiepileptics, with a single lesion ≤1.5 cm and total number of lesions ≤5, are allowed.

• History of allogeneic organ transplantation, allogeneic peripheral hematopoietic stem cell transplantation, or bone marrow transplantation.
• Pregnant or breastfeeding women, or individuals planning to donate sperm/eggs during the study period (from ICF signing to 4 months after the last dose).

•Note:Breastfeeding women may be enrolled if they agree to stop breastfeeding prior to dosing and have no intention of resuming.

• Any severe or uncontrolled systemic disease, including:

• Active bleeding or known bleeding diathesis;
• Cardiac dysfunction or clinically significant cardiovascular disease, including any of the following:

•Uncontrolled cardiac disease, such as congestive heart failure requiring treatment (NYHA > Class II);

•Uncontrolled hypertension (resting BP ≥160/100 mmHg);

•Poorly controlled arrhythmias;

•ECG with QTcF >470 ms (female) or >450 ms (male) (QTcF = QT/RR¹/³), or congenital long QT syndrome;

•Echocardiogram: Left Ventricular Ejection Fraction (LVEF) ≤50%;

•Acute myocardial infarction or unstable angina within 6 months prior to study entry;

• Uncontrolled diabetes mellitus or poor compliance with hypoglycemic agents;
• Other chronic diseases that, in the investigator's opinion, may compromise participant safety or preclude completion of the study.
• Active infections:

• Known Human Immunodeficiency Virus (HIV) infection, Treponema pallidum (TP) infection;
• Active Hepatitis B [i.e., HBsAg positive and HBV DNA >1000 copies/mL (or 200 IU/mL), or HBV DNA above the lower limit of detection (if the LLOQ at the site is >200 IU/mL)];
• Hepatitis C Virus (HCV) infection (i.e., HCV antibody positive and HCV-RNA positive);
• Other active infections requiring systemic therapy within 2 weeks prior to the first dose.
• Inadequate recovery from any prior surgery, or major organ surgery (excluding core needle biopsy or vascular intervention) within 4 weeks prior to study drug administration.
• Receipt of any of the following treatments:

A. Prior treatment with T-cell engager drugs containing CD3 antibodies. B. Within the respective washout periods or 5 half-lives (whichever is shorter) prior to the first dose: Chemotherapy, biotherapy, or immunotherapy within 4 weeks; targeted therapy, radiotherapy, endocrine therapy, or oral fluoropyrimidines within 2 weeks; anti-tumor traditional Chinese medicine within 1 week; nitrosoureas or mitomycin C within 6 weeks.

C. Live or attenuated live vaccines within 4 weeks prior to the first dose (inactivated vaccines are allowed).

D. Diagnosis of immunodeficiency, receipt of immunosuppressive therapy, or chronic systemic/enteral steroid therapy (>10 mg/day prednisone or equivalent).

E. Interstitial pneumonia, pulmonary fibrosis, pneumoconiosis, drug-induced pneumonitis, radiation pneumonitis requiring steroids or other treatment, or a history of severe pulmonary function impairment/restrictive lung disease.

• Adverse events from prior anti-tumor therapy have not resolved to CTCAE v6.0 Grade ≤1 (except for alopecia, peripheral neuropathy, ototoxicity, or stable endocrinopathies managed with hormone replacement).
• Known hypersensitivity to the active ingredient or any excipients of the investigational product.
• History of immunotherapy-related adverse events ≥ Grade 3 or leading to treatment discontinuation.
• History of active autoimmune disease likely to recur (e.g., SLE, RA, Crohn's, ulcerative colitis, vasculitis), except:

• Clinically stable autoimmune thyroid disease;
• Use of inhaled or topical corticosteroids (ocular, intra-articular, nasal) with daily dose equivalent to ≤10 mg prednisone;
• Short-term corticosteroid use (≤7 days) for prophylaxis (e.g., contrast allergy);
• Replacement therapy (e.g., thyroxine for hypothyroidism, insulin for diabetes, physiological steroid replacement for adrenal/pituitary insufficiency).
• Presence of symptomatic pleural, peritoneal, or pericardial effusion requiring paracentesis/drainage at screening.

•(Exclusion applies if drainage/intracavitary therapy was performed more than once [i.e., ≥2 times] for any cavity within 14 days prior to the first dose).

• History of active tuberculosis within 1 year prior to enrollment.
• History of thrombotic events (arterial or venous) within 6 months prior to screening, including cerebrovascular accidents (e.g., hemorrhage, infarction), deep vein thrombosis (DVT), and pulmonary embolism (PE).

• Exception:Catheter-related thrombosis due to PICC or port placement may be allowed if deemed stable, asymptomatic, or adequately treated with no bleeding risk by the investigator.