Phase Ib/IIa Open-label Study, to Evaluate Safety, Tolerability, and Antitumor Activity of HCB101 in Combination With Multiple Agents in Subjects With Advanced Gastric or Gastro-esophageal (GEJ) Adenocarcinoma

Phase Ib/IIa Open-label Study, to Evaluate Safety, Tolerability, and Antitumor Activity of HCB101 in Combination With Multiple Agents in Subjects With Advanced Gastric or Gastro-esophageal (GEJ) Adenocarcinoma

This is an open-label, dose-escalation and dose-expansion phase Ib/IIa clinical study to evaluate the safety, tolerability, and preliminary efficacy of HCB101 in combination therapies in subjects with gastric or GEJ adenocarcinoma. A total of about 40 subjects will be enrolled in this study.

Part-I: Dose-Escalation Phase (Phase Ib)

This phase includes Screening, Treatment, and Follow-up Periods:

Screening Period: Screening period is up to 28 days (D-28 to D-1) prior to receiving the first dose of HCB101.

Treatment Period: This period includes repeat dosing treatment period (42 days per cycle). During the treatment period, subjects from different cohorts will receive HCB101 in combination therapy. Treatment will continue until one of the following occurs: unacceptable adverse event (AE), radiographic or clinically documented disease progression, withdrawal of consent, loss to follow-up, death, or termination of the study, whenever occurs first.

Follow-up Period: This period will include Safety and Survival Follow-up Visits. After the last dose in the study, subjects are required to undergo a Safety Follow-up Visit, which will take place 30 (±7) days after the last dose of HCB101, and they will also undergo the Survival Follow-up Visit every 8 weeks (±14 days).

The end of treatment (EOT) Visit will coincide with the subject has permanently terminated the study intervention. If the EOT Visit is performed within the time window for the Safety Follow-up Visit, re-examination is not required.

Dose Escalation Criteria The study includes four planned dose levels of HCB101(8 mg/kg, 12 mg/kg, 18 mg/kg and 24 mg/kg) The maximum tolerated dose (MTD) will be determined using the standard 3+3 method.

To enhance safety during dose escalation, a staggered dosing approach will be applied. The second subject in each dose level should receive treatment staggered by at least 5 days after the first subject has received the 1st dose, provided that no significant safety concerns have been observed.

1. Dose Escalation: The trial begins with the lowest dose, escalating in a stepwise manner. The observation period for dose limiting toxicities (DLT) is from the start of the first dose to day 28 post-dose. The next dose cohort may proceed only after the previous cohort has completed the 28-day DLT observation period and it is confirmed that the subjects are safely tolerated.
2. Initial Cohort: Each dose cohort initially enrols three subjects. If none of these three subjects experience a DLT during the observation period, the next dose cohort will be enrolled.
3. One DLT in a Cohort (1/3): If one out of three subjects experience a DLT, an additional three subjects will be enrolled at that dose level, totally six subjects.

1) Two or More DLTs (2+/6): If one or more of the additional three subjects experience a DLT (resulting in two or more DLTs at this dose level), dose escalation will stop, and the previous dose will be designated as the MTD, or the SRC may decide to use an intermediate dose for further investigation.

2) No Additional DLTs (1/6): If none of the additional three subjects experience a DLT (resulting in one DLT out of six), the trial will proceed to the next higher dose level.

4) Two or More DLTs in a Cohort (≥2/3): If two or more out of three subjects experience a DLT, dose escalation will conclude, and the previous dose will be considered the MTD, or the SRC may determine whether to use an intermediate dose for the next level of investigation.

5) *Maximum Dose Level: If the dose escalation reaches the highest level of 24 mg/kg without establishing an MTD, the MTD and/or the (potential) RP2D or effective dose may be confirmed based on safety, tolerability and efficacy data obtained. Additionally, it may be decided whether new dose levels are required for further escalation studies.

After all subjects in each dose level have completed the DLT assessment, the SRC will decide whether to proceed with dose escalation, explore intermediate/higher doses, terminate the dose escalation study, proceed with a dose extension study or adjust the tumor type for dose extension, etc., based on the data obtained on safety, tolerability and antitumor activity (if required), etc. The SRC may also adjust the dose and frequency of administration, etc.; the SRC may also decide during a dose escalation whether to adjust the tumor type enrolled. Based on the provision of a reasonable basis, appropriate methods may be used to combine the pre-adjustment data with the post-adjustment data, or with data obtained from studies conducted by HCB101.

During the dose-escalation phase, if a subject does not experience a Grade ≥ 2 AE related to the trial treatment (including HCB101 or in combination with standard-of-care drugs), intra-subject dose escalation is permitted after the DLT evaluation period. A maximum of two intra-individual dose escalations per subject is allowed.

Inclusion Criteria:

1. Subjects are able to understand and willing to provide signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol, including study visits and study-related procedures.

2. Male and female subjects of ≥18 years of age, inclusive, at the time of signing the informed consent.

3. With histologically/cytologically confirmed diagnosis of advanced gastric and gastro-esophageal adenocarcinoma as described below:

   • Unresectable locally advanced, or metastatic HER2 (-) gastric or GEJ adenocarcinoma cancer, whose tumors are CLDN 18.2 positive (defined as ≥ 75% of tumor cells demonstrating moderate to strong membranous CLDN 18.2 immunohistochemical staining using an FDA-approved test ( http://www.fda.gov/CompanionDiagnostics).

4. Must have at least 1 measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

5. Must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at Screening.

6. Have a life expectancy of ≥12 weeks (according to the Investigator's judgment).

7. Have adequate organ function, as indicated by the following laboratory parameters below (had not received a blood transfusion, apheresis infusion, erythropoietin, granulocyte colony-stimulating factor, and other relevant medical support within 14 days before the administration of the first dose of study intervention).

   1. Absolute neutrophil count ≥1.5 × 109/L
   2. Platelets ≥100 × 109/L
   3. Hemoglobin ≥9.0 g/dL
   4. Total bilirubin ≤1.5 × upper limit of normal (ULN), <3.0 × ULN if known Gilbert's disease
   5. Alanine aminotransferase and aspartate aminotransferase ≤3× ULN and ≤5× ULN for subjects with liver metastasis
   6. Creatinine clearance ≥30 mL/min (using Cockcroft Gault equation)
   7. Coagulation: International normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) ≤1.5× ULN (The INR applies only to subjects who do not receive therapeutic anticoagulation)

8. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test during the Screening Period (within 7 days before the first dose of the study intervention).

9. Subjects must have tumors that are not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

10. Subjects must not have received any prior systemic anti-cancer and immune checkpoint inhibitor therapy.

Exclusion Criteria:

1. Medical Conditions:

   1. With a known history of hypersensitivity to any components of the study intervention.

   2. Subjects who have other malignancies requiring treatment within 2 years before the first dose of study intervention will be excluded, except for radically treated locally curable basal or squamous cell skin cancer and other malignancies that have been treated with no relapse within 2 years.

   3. Primary tumor in the central nervous system (CNS), or active or untreated CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate, provided they are clinically stable for at least 28 days and have no evidence of new or enlarging brain metastases and no requirements for high-dose corticosteroids 14 days before dosing with study intervention. Subjects on low-dose corticosteroids (<20 mg prednisone or equivalent per day) may participate.

   4. Clinically significant cardiovascular condition, including

      1. History of congestive heart failure (New York Heart Association Class >2), with only heart failure with preserved ejection fraction (HFpEF) included;
      2. History of unstable angina within 6 months before the first dose of study intervention;
      3. New-onset angina or myocardial infarction within 6 months before the first dose of study intervention;
      4. New-onset of atrial fibrillation, supraventricular arrhythmia, or ventricular arrhythmia within 6 months before the first dose of study intervention and still in unstable condition and requiring treatment or intervention. History of atrial fibrillation, supraventricular arrhythmia, or ventricular arrhythmia will be allowed, provided the condition is stably controlled.

   5. History or presence of an abnormal ECG that, in the Investigator's opinion, is clinically meaningful (including QT interval corrected for heart rate using Fridericia's correction [QTcF] >470 msec at Screening, pacemaker installation, or previous diagnosis of congenital long QT syndrome).

   6. Any previous treatment-related toxicities which have not recovered to ≤ Grade 1 as evaluated by National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 or baseline, except alopecia and anemia (Note: subjects with chronic Grade 2 toxicities which are well managed and stable may be eligible per the discretion of the Investigator, e.g., Grade 2 chemotherapy-induced neuropathy.)

   7. With known inherited or acquired bleeding disorders or bleeding diathesis.

   8. Have RBC transfusion dependence defined as requiring more than 2 units of RBC transfusions every 28 days over a period of 3 months before Screening.

   9. With a previously documented diagnosis of hemolytic anemia or Evans Syndrome in the last 3 months.

2. Prior/Concomitant Therapy/Treatment

   1. Subjects who have undergone major surgery or radical radiotherapy within 28 days before the first dose of study intervention.
   2. Subjects who have undergone palliative radiotherapy within 14 days before the first dose of study intervention.
   3. Subjects who have used a radioactive drug (Strontium, Samarium, etc.) within 56 days before the first dose of the study intervention.
   4. Subjects who have undergone any investigational or approved systemic cancer therapy (including chemotherapy, immunotherapy, hormonal therapy, and herbal/alternative therapies with anti-cancer indications or targeted therapy) within 14 days or 5 half-lives, whichever is longer, before the first dose of the study intervention.
   5. Subjects who have used herbal medication within 14 days before the first dose of the study intervention.
   6. Subjects who are active using of vitamin K antagonist anticoagulant like warfarin. Use of low molecular weight heparin and factor Xa inhibitors will be permitted on a case-by-case basis. Daily low dose of aspirin use (≤ 100 mg/QD) is allowed.
   7. Subjects who have received any treatment targeting the CD47 or SIRPα pathway.

3. Participation in another clinical study with an investigational product administered in the last 14 days or 5 half-lives (whichever is longer) before receiving the first dose of study intervention. An investigational device was used within 28 days before the first dose of study intervention.

4. Reproductive and breastfeeding

   1. Women of reproductive potential who are unable to use effective contraception during treatment and for 6 months after the last dose.
   2. Women who are breastfeeding during treatment and for 6 months after the last dose.

5. Infections:

   1. An uncontrolled acute infection, an active infection requiring systemic treatment, or subjects who have received systemic antibiotics within 14 days before the first dose of the study intervention (Note: prophylaxis use of systemic antibiotics treatment for upper tract infection is allowed as long as there is no violation of the requirement of concomitant medications).
   2. Known history of human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome or positive HIV testing having CD4+ T-cell counts <350 cells/µL or subjects with unknown HIV infection status who are unwilling to undergo HIV testing.
   3. Known active hepatitis B or C. Subjects with hepatitis B virus surface antigen (HBsAg) or hepatitis C virus (HCV) antibody positive test results during Screening must be further tested for hepatitis B virus (HBV) deoxyribonucleic acid (DNA) titer (excluding subjects with a DNA titer of more than 2500 copies [cps]/mL or 500 IU/mL) and HCV ribonucleic acid (RNA) (excluding subjects with an HCV RNA concentration exceeding the lower detection limit of the assay) to exclude active hepatitis B or hepatitis C infection requiring treatment. Hepatitis B virus carriers, i.e., subjects with stable hepatitis B infection after drug treatment (DNA titer not exceeding 2500 cps/mL or 500 IU/mL) and hepatitis C infected subjects who received treatment and achieved sustained virologic response for at least 12 weeks can be enrolled. Note: If the lower detection limit of the HBV DNA assay is higher than 2500 cps/mL or 500 IU/mL, the subjects with an HBV DNA assay result lower than the lower detection limit of the assay can be enrolled.
   4. Active tuberculosis or latent tuberculosis infection (LTBI).

6. Known to have a history of alcoholism or drug abuse.

7. Any other medical (e.g., Child-Pugh class B or C, pulmonary, metabolic, congenital, endocrinal or CNS disease, etc.), psychiatric, or social condition deemed by the Investigator to be likely to interfere with a subject's rights, safety, welfare or ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results.

8. Subjects with current pneumonitis or a history of severe pneumonitis, including but not limited to immune-related pneumonitis or radiation-induced pneumonitis.