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

A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of Single-Agent KGX105 in Participants With Locally Advanced or Metastatic Solid Tumors

This is a first-in-human, open-label, multicenter, Phase I study to evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD), and preliminary antitumor activity of single-agent KGX105 in participants with locally advanced or metastatic solid tumors. The study consists of two parts: Phase 1a dose escalation and Phase 1b dose expansion.

Inclusion Criteria:

1. Male or female participants with age ≥18 years, at the time of signing the informed consent.

2. 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.

3. 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).

4. 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.

5. ECOG 0-1.

6. Life expectancy of ≥3 months, in the opinion of the investigator.

7. 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.

8. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to treatment.

9. 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.

10. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this study.

Exclusion Criteria:

1. 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.

2. 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.

3. History of allogeneic organ transplantation, allogeneic peripheral hematopoietic stem cell transplantation, or bone marrow transplantation.

4. 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.

5. Any severe or uncontrolled systemic disease, including:

   1. Active bleeding or known bleeding diathesis;

   2. 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;

   3. Uncontrolled diabetes mellitus or poor compliance with hypoglycemic agents;

   4. Other chronic diseases that, in the investigator's opinion, may compromise participant safety or preclude completion of the study.

6. Active infections:

   1. Known Human Immunodeficiency Virus (HIV) infection, Treponema pallidum (TP) infection;
   2. 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)];
   3. Hepatitis C Virus (HCV) infection (i.e., HCV antibody positive and HCV-RNA positive);
   4. Other active infections requiring systemic therapy within 2 weeks prior to the first dose.

7. 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.

8. 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.

9. 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).

10. Known hypersensitivity to the active ingredient or any excipients of the investigational product.

11. History of immunotherapy-related adverse events ≥ Grade 3 or leading to treatment discontinuation.

12. 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).

13. 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).

14. History of active tuberculosis within 1 year prior to enrollment.

15. 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.