A Phase I Clinical Study to Evaluate the Efficacy and Safety of GB18 Injection in Patients With Tumor Cachexia

A Phase I Clinical Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of GB18 Injection in Patients With Tumor Cachexia

KXZY-GB18-101(1B) is an extension of KXZY-GB18-101, a first-in-human, dose-escalation trial in healthy adult participants to evaluate the safety, tolerability, PK, PD, and immunogenicity of GB18.

As a humanized GDF15 monoclonal antibody, GB18 is expected to improve anorexia and weight loss caused by metabolic disorders driven by overactivation of the GDF15-GFRAL-RET signaling pathways. With favorable readouts of KXZY-GB18-101, this study aims to evaluate the effects of GB18 in patients with tumor cachexia. This open-label, multiple-ascending-dosing study will enroll 18-36 participants into 3 dosing-level cohorts (B1-B3, each with 6-12 participants).

KXZY-GB18-101(1B) is an extension of KXZY-GB18-101, a first-in-human, dose-escalation trial in healthy adult participants to evaluate the safety, tolerability, PK, PD, and immunogenicity of GB18.

As a humanized GDF15 monoclonal antibody, GB18 is expected to improve anorexia and weight loss associated with metabolic disorders by targeting the overactivation of GDF15-GFRAL-RET signaling pathways. With favorable readouts of KXZY-GB18-101, KXZY-GB18-101(1B) aims to evaluate the efficacy and safety of GB18 in patients with tumor cachexia. This open-label, multiple-ascending-dosing study will enroll 18-36 participants into 3 dosing-level cohorts (each with 6-12 participants). The treatment and follow-up period will be 12 weeks each. Each participant will undergo safety and efficacy assessments, including vital sign measurements, physical examinations, 12-lead electrocardiograms, and laboratory tests before and after GB18 administration. Blood samples will also be collected to evaluate pharmacokinetic and pharmacodynamic properties, as well as the immunogenicity.

The aims of this study include:

• To evaluate the safety and tolerability of GB18 after multiple subcutaneous injections of GB18 in Chinese participants with tumor cachexia.
• To evaluate the efficacy of multiple subcutaneous injections of GB18 in Chinese participants with tumor cachexia.
• To evaluate the PK characteristics of Chinese tumor cachexia participants after multiple subcutaneous injections of GB18.
• To evaluate the PD characteristics of Chinese participants with tumor cachexia after multiple subcutaneous injections of GB18.
• To evaluate the immunogenicity of multiple subcutaneous injections of GB18 in Chinese participants with tumor cachexia.

Key Inclusion Criteria:

• Voluntarily serve as a participant and sign the informed consent form;

• Age ≥ 18 years;

• Histologically or cytologically confirmed, non-resectable, locally advanced, recurrent, or metastatic solid tumors with failed standard treatment or have no standard treatment options. This includes, but is not limited to, colorectal cancer, pancreatic cancer, gastric cancer, esophageal cancer, biliary tract cancer, non-small cell lung cancer, prostate cancer, breast cancer, or ovarian cancer.

• Diagnosed with cancer cachexia: BMI < 18.5 kg/m², and no unintentional weight loss > 2% within 6 months before screening, or no unintentional weight loss > 5% within 6 months before screening regardless of BMI.

• A serum GDF15 concentration ≥ 1.5 ng/mL.

• Laboratory Test Requirements:

  1. Absolute neutrophil count ≥ 1.0 × 10⁹/L, platelet count ≥ 75 × 10⁹/L, hemoglobin ≥ 80 g/L.
  2. Serum creatinine ≤ 1.5 × ULN (Upper Limit of Normal).
  3. Total bilirubin ≤ 1.5 × ULN, AST and ALT ≤ 3 × ULN (or ≤ 5 × ULN for patients with liver metastasis).
  4. Activated partial thromboplastin time ≤ 1.5 × ULN, International Normalized Ratio ≤ 1.5.
  5. Left Ventricular Ejection Fraction > 50% as assessed by echocardiogram.

• Eastern Cooperative Oncology Group (ECOG) performance status score: 0-2 points

• Expected survival period ≥ 4 months.

Key Exclusion Criteria:

• Known active/symptomatic central nervous system metastases and/or carcinomatous meningitis.
• Plan to receive radiotherapy as a component of the primary antitumor treatment regimen.
• BMI > 26 kg/m².
• Presence of reversible causes for reduced food intake, including but not limited to NCI CTCAE grade 3 or 4 oral mucositis; NCI CTCAE grade 3 or 4 nausea, vomiting, diarrhea, or constipation; mechanical obstruction preventing oral intake.
• Comorbid conditions unrelated to tumor cachexia that cause difficulty in eating or malabsorption.
• Cachexia due to other investigator-determined or clearly defined causes. History within the past 6 months of any of the following: myocardial infarction, congenital long QT syndrome, second- or third-degree atrioventricular block, arrhythmias (including sustained ventricular tachycardia or ventricular fibrillation), unstable angina, acute coronary syndrome, symptomatic congestive heart failure (NYHA class III or IV) of coronary or peripheral origin, stroke, transient ischemic attack, or symptomatic pulmonary embolism or other clinically significant thromboembolic disease.
• Hypertension with unsatisfactory control despite antihypertensive therapy (defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg).
• Patients receiving tube feeding or parenteral nutrition (total or partial) within 28 days before the first administration of the investigational drug.
• Initiation of new systemic glucocorticoid therapy from 28 days before the first dose of the investigational drug to the end of the study.
• Major surgery not yet recovered from within 28 days before the first dose of the investigational drug (central venous access placement and tumor biopsy are not considered major surgery), or anticipated major surgery during the study period.
• Prior participation in clinical trials targeting the GDF-15/GFRAL signaling pathways, or receipt of other investigational agents within 28 days or five half-lives (whichever is shorter) before the first dose of the investigational drug.
• Severe infection requiring intravenous antibiotics, antivirals, or antifungal agents within 14 days before the first dose of the investigational drug.