An Phase I/IIa Clinical Study to Evaluate the Safety/Tolerability, Pharmacokinetics and Preliminary Efficacy of INB301 Injection in Patients With Cancer Cachexia

An Open-label, Multicenter Phase I/IIa Clinical Study to Evaluate the Safety/Tolerability, Pharmacokinetics and Preliminary Efficacy of INB301 Injection in Patients With Cancer Cachexia

This is an open-label, multicenter, multiple-dose Phase I/IIa clinical study to assess the safety/tolerability, PK characteristics,immunogenicity, and preliminary efficacy of INB301 Injection in patients with cancer cachexia.

The indication to be explored for Phase I is malignant solid tumor with cachexia; Phase IIa will determine the specific study cohort after discussion between the investigator and the sponsor based on the previously obtained clinical trial data and the benefit/risk ratio of the subjects, and preliminarily consider 3 cohorts of tentative 20-30 patients each, including non-small cell lung cancer, pancreatic cancer and colorectal cancer with cachexia.

The screening will be completed within 28 days before administration. Subjects who pass the screening will receive subcutaneous injection of INB301 until the investigator determines that the risk of continued treatment outweighs the benefit, toxicity becomes intolerable, or other criteria for withdrawal or treatment discontinuation are met, whichever occurs first. The end-of-study/early withdrawal visit will be completed at 28 days (±7 days) after the last dose.

If the anti-cancer treatment is suspended, modified, interrupted, or the protocol is changed during INB301 treatment, it is not considered a protocol deviation, and administration of INB301 will continue as specified in the protocol. Adjustments to standard of care, drug dosage or course of anti-cancer treatment, including treatment breaks, are at the discretion of the investigator.

Phase I dose escalation phase:

The dose escalation phase uses a standard 3+3 design to determine the maximum tolerated dose (MTD) or recommended expansion dose(RED). Enrolled subjects are sequentially assigned to 6 dose levels (50 mg, 100 mg, 200 mg, 300 mg, 400 mg, and 500 mg) to receive subcutaneous injection of INB301 every 3 weeks as a cycle. The starting dose of INB301 is based on a Minimum Anticipated Biological Effect Level (MABEL) approach, integrating nonclinical pharmacokinetic/pharmacodynamic (PK/PD) modeling, target engagement considerations, and available safety margins.

Phase I dose expansion phase:

In the dose expansion phase, the dose level (e.g., 200 mg, 400 mg) and dosing frequency will be determined based on the dose-escalation results, following discussion and consensus by the SMC, which is composed of the Investigator and the Sponsor. The RP2D will be confirmed during the dose expansion phase. It is tentatively planned to enroll 7-10 subjects per dose cohort.

Phase IIa:

After the RP2D is determined (e.g., 400 mg Q4W) based on the Phase I data, a cohort study in single tumor type with cachexia will be conducted to further evaluate the efficacy, safety, and tolerability of the investigational medicinal product.

Inclusion Criteria:

• Subjects who voluntarily participate in the study and voluntarily sign the informed consent form;

• Male or female ≥ 18 years of age;

• Subjects with histologically or cytologically confirmed malignant solid tumors (including pathologically confirmed non-small cell lung cancer, colorectal cancer, pancreatic cancer, esophageal cancer or breast cancer, etc.) who are receiving or have completed anti-cancer treatment and have no significant cancer progression 28 days before the first dose, and in the investigator's expectation are unlikely to change the anti-cancer regimen due to disease progression or do not require any anti-cancer treatment within the first cycle (21 days) of the study;

• Definitely diagnosed as cancer cachexia according to the 2025 Definition and Classification of Cancer Cachexia: An International Consensus" combined with clinical practice: one of the following occurs within 6 months (recognized documentation is required for past weight data): involuntary weight loss > 5%, or weight loss > 2% when BMI < 18.5 kg/m² ;

• Serum GDF-15 level ≥ 1200 pg/mL within 28 days prior to the first dose (only applicable to Phase I dose expansion and Phase IIa);

• Adequate organ function, i.e., meeting laboratory criteria:

  • Hematology: absolute neutrophil count ≥ 1.0×10⁹/L, platelets ≥ 75×10⁹/L, hemoglobin ≥ 80 g/L;
  • Renal: serum creatinine ≤ 1.5 × ULN (if serum creatinine > 1.5 × ULN, creatinine clearance calculated with Cockcroft formula ≥ 30 mL/min is required);
  • Hepatic: total bilirubin ≤ 1.5 × ULN, AST and ALT ≤ 3 × ULN or AST and ALT ≤ 5 × ULN in case of liver metastasis;
  • Coagulation function: activated partial thromboplastin time (APTT) ≤ 1.5 × ULN, international normalized ratio (INR) ≤ 1.5;

• ECOG PS score ≤ 2;

• Expected survival ≥ 4 months;

• Eligible subjects of childbearing potential should take adequate contraceptive measures from the time of signing the informed consent form until 6 months after the last dose: for female patients of childbearing age, the blood pregnancy test must be negative within 7 days before the first dose. In addition, subjects should avoid donating sperm/eggs for the time period specified above.

Exclusion Criteria:

• Other causes that may lead to reduced food intake or seriously affect digestion and absorption during the screening period, as determined by the investigator, including but not limited to: oral mucositis of NCI CTCAE Grade 3 or above, gastrointestinal disease of NCI CTCAE Grade 3 or above (nausea, vomiting, diarrhea and constipation, etc.), gastrointestinal obstruction, and active inflammatory bowel disease;

• Radiotherapy is planned as part of the primary anti-cancer treatment regimen (except local radiotherapy for symptom relief);

• Known active/symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis (for subjects with previously treated brain metastases, enrollment may be considered if all of the following criteria are met: the clinical condition has remained stable with no imaging evidence of disease progression within 4 weeks before the first investigational drug treatment, and corticosteroid treatment has not been required within 4 weeks before first dose; asymptomatic subjects with brain metastases (i.e., no neurologic symptoms, no requirement for corticosteroids, and no brain metastatic lesion with a longest diameter > 1.5 cm) may be enrolled, provided that regular imaging examination and assessment for brain metastatic lesions are performed);

• Gavage or parenteral nutrition (total or partial) is received during the screening period;

• History of other diseases that may cause cachexia within 6 months prior to screening, including but not limited to: severe and above COPD, NYHA class 3-4 heart failure;

• Human immunodeficiency virus antibody (HIVAb) positive, active hepatitis B (HBsAg and/or HBcAb positive and HBV-DNA > 500IU/mL or upper limit of normal, whichever is higher), or hepatitis C (anti-HCV positive and HCV-RNA above lower limit of detection). History of hepatitis B vaccination is acceptable;

• Blood pressure ≥ 140 mmHg (systolic) or ≥ 90 mmHg (diastolic) at screening, measured after at least 5 minutes of rest. If the blood pressure exceeds the standard, the measurement should be repeated twice, and the mean of the three measurements is used to determine whether the subject meets the criterion;

• Screening 12-lead electrocardiogram (ECG) shows clinically relevant abnormalities that may affect subject safety or interpretation of study results (e.g., baseline QTcF > 450 milliseconds or QRS > 120 milliseconds). If the baseline uncorrected QT interval is > 450 milliseconds, Fridericia's method should be used for correction and QTcF should be used for decision-making. If QTcF > 450 milliseconds or QRS > 120 milliseconds, the ECG should be repeated twice, and the mean of the three measurements should be used for judgment. Computer-read ECG should be reviewed by experienced physician before excluding a subject;

• Serious infection for which intravenous antibiotics, antivirals, or antifungals are being administered within 14 days prior to screening or during the screening period;

• Subjects who have taken any prescription drugs that affect appetite or improve body weight within 28 days before the first dose or 5 half-lives, including but not limited to anamorelin, megestrol acetate, cannabinol, medical marijuana, Chinese patent medicines to improve appetite and traditional Chinese medicine preparations;

• Subjects who have received systemic glucocorticoids (prednisone > 10 mg/day or equivalent dose of similar product) or other immunosuppressants within 28 days before the first dose, except for anti-cancer treatment or pretreatment of examination;

• Baseline BMI > 26 kg/m² (for Chinese people)；

• Previously received anti-GDF-15, GFRAL and iso-mechanism antibodies;

• Subjects with massive serous effusion within 14 days before screening or during screening, such as pericardial effusion or pleural/peritoneal effusion;

• Received major surgery within 28 days before the first dose, or major surgery is expected during the study;

• History of serious cardiovascular and cerebrovascular diseases, including but not limited to:

  • Serious cardiac rhythm or conduction abnormalities, such as ventricular arrhythmia requiring clinical intervention, second-third degree atrioventricular block;
  • Acute coronary syndrome, congestive heart failure, stroke or other grade 3 or above cardiovascular and cerebrovascular events occurred within 6 months prior to the first dose of study drug;
  • Left ventricular ejection fraction (LVEF) < 50%;

• Treated with other clinical investigational drug within 28 days before the first dose or 5 half-lives (whichever is longer);

• Known allergy to INB301 or its components, or a history of severe allergic reactions or uncontrolled allergic asthma;

• Other serious physical or mental illness or laboratory abnormality at screening that may increase the risk of study participation or interfere with study results, and other causes that make the subject unsuitable for this clinical study in the opinion of the investigator.