Phase I/IIa Clinical Trial of IMC001 in Patients With Advanced Epithelial Solid Tumors.

Phase I/IIa Clinical Trial Evaluating the Safety and Efficacy of IMC001 in Patients With Advanced Epithelial Solid Tumors.

This is an open -label phase I /IIa study designed to evaluate the safety and efficacy of IMC001 in patients with advanced epithelial solid tumors. The study comprises two parts: a phase I dose-escalation phase and a phase IIa phase to further explore and validate efficacy .In the Phase I dose-escalation phase of this study, approximately 7-15 subjects with advanced epithelial solid tumors will be recruited to evaluate the safety and tolerability of autologous IMC001 treatment . In the expansion phase, at least two dose groups will be selected , each recruiting 5-10 subjects. Combined with the subjects from the escalation phase, each dose group will be expanded to approximately 10 subjects to determine the recommended RP2D dose for progression to Phase IIa . DLT ( digestive tract aging) assessment will be performed on subjects in each cohort within 28 days of IMC001 infusion . the RP2D is determined , approximately 6-20 subjects will be initially enrolled at this dose for each selected tumor type to further explore the efficacy and safety of autologous IMC001 for this indication. Subsequently, the protocol may be revised based on statistical hypotheses and regulatory requirements to continue enrolling subjects in the selected tumor types to further validate the efficacy and safety in specific tumor types.the date on which the last participant completes a two-year follow-up visit, is lost to follow up, withdraws informed consent, or dies (whichever occurs first) . It is important to note that for long-term follow-up programs such as ADA, RCL, and VIS (up to 15 years), which require protocol-based follow-up, these follow-ups will be conducted continuously according to protocol and regulatory requirements. However, the actual study participation time for each participant will vary depending on screening requirements, response to treatment, long-term follow-up arrangements, and survival status .

Inclusion Criteria:

1. to provide a signed and dated informed consent form before conducting any research-related procedures , and willing and able to comply with all research procedures.

2. Applicants must be 18 years of age or older and 75 years of age or younger; both male and female applicants are welcome .

3. Subjects with histologically or cytologically confirmed locally advanced/metastatic epithelial solid tumors , including but not limited to subjects with advanced gastric cancer/gastroesophageal junction adenocarcinoma, triple-negative breast cancer, biliary tract tumors, ovarian cancer, colorectal cancer, pancreatic cancer, gastrointestinal and pancreatic neuroendocrine tumors, etc.

4. Disease progression or intolerance to standard systemic therapy , including:

   • Gastric cancer and gastroesophageal junction adenocarcinoma that have failed or are intolerant of at least two lines of standard systemic therapy. If first-line three-drug combination therapy has failed or is intolerant, enrollment may be made after thorough investigator evaluation.
   • Triple-negative breast cancer: Subjects with unresectable locally advanced or metastatic triple-negative breast cancer who have failed at least two lines of standard systemic therapy. All subjects must have previously received taxane therapy, regardless of the stage of disease at the time of treatment.
   • Other subjects with epithelial solid tumors who have failed or are intolerant of standard treatment.

5. Tumor tissue samples (primary or metastatic, archived or newly collected) from the expected subjects, tested by the central laboratory, are EpCAM histologically positive (defined as tumor cell positivity ≥10% and staining intensity ≥1+).

6. The expected survival period of the subjects is ≥12 weeks .

7. According to RECIST 1.1 criteria, there should be at least one stably measurable target lesion (where the largest lesion should be ≤4). In the 3×10⁵ CAR -T cells/kg dose group, subjects with evaluable lesions (unmeasurable lesions) can be admitted.

8. ECOG performance status score 0-1 .

9. The subject has adequate organ and bone marrow function. Laboratory screening must meet the following criteria: all laboratory test results should be within the stable ranges outlined below, and there should be no ongoing supportive treatment. If any laboratory test result is abnormal according to the following criteria, a repeat test may be performed within one week. If the test results still do not meet the following criteria, the subject's screening has failed.

   1. Blood tests [No intensive blood transfusions (≥2 times within 1 week), platelet transfusions, or cell growth factor injections (excluding recombinant erythropoietin)) within 7 days prior to the test]: Neutrophil count (ANC) ≥1.5×10⁹ / L; Platelet count (PLT) ≥100 × 10⁹ / L; Hemoglobin content (Hb) ≥9.0g / dL; Lymphocyte count ( ALC ) ≥0.5× 10⁹ /L ;
   2. Liver function: alanine aminotransferase (ALT) ≤ 2.5 × ULN, aspartate aminotransferase (AST) ≤ 2.5 × ULN, serum total bilirubin (TB) ≤ 2 × ULN; for subjects with liver metastases, AST and ALT < 5 × ULN ;
   3. Kidney function: Serum creatinine ≤1.5×ULN; if serum creatinine >1.5×ULN, creatinine clearance rate >50mL/min is required (according to the Cockcroft-Gault formula); qualitative urine protein ≤1+; if qualitative urine protein ≥2+, a 24-hour urine protein quantification test is required (if the 24-hour urine protein quantification test is <1g, it is acceptable).
   4. Amylase and lipase ≤1.5×ULN; alkaline phosphatase (ALP) ≤2.5×ULN, and for subjects with bone metastases, ALP <5×ULN ;
   5. Coagulation function: Activated partial thromboplastin time ≤ 1.5 ULN, prothrombin time ≤ 1.5 × ULN ;

10. All toxicities resulting from prior antitumor therapy were reduced to grade 0-1 (according to NCI CTCAE version 5.0) or to a level acceptable to the inclusion criteria. Other toxicities, such as alopecia and vitiligo, which the investigators deemed not to pose a safety risk to the subjects, were excluded .

Reproductive status: Female subjects of reproductive age or male subjects whose sexual partners are women of reproductive age, who are willing to use medically approved and highly effective contraceptive methods, such as intrauterine devices or condoms, from the time they sign the informed consent form until 12 months after cell infusion (women of reproductive age include premenopausal women and women within 24 months after menopause) .

Exclusion Criteria:

1. Pregnant and breastfeeding women .

2. Positive for human immunodeficiency virus (HIV) antibodies; hepatitis B virus infection ( if the subject is positive for hepatitis B surface antigen, regardless of whether the core antibody is negative or positive, they can also be enrolled if the viral DNA load is negative, and prophylactic antiviral treatment should be considered ); acute or chronic active hepatitis C (positive for HCV antibodies); positive for syphilis antibodies; Epstein-Barr virus (EBV) infection ( positive for IgM or known EBV infection ); cytomegalovirus (CMV) infection (positive for IgM); positive for human T-lymphotropic virus (HTLV). The results of the above pathogen tests are subject to the results of the central laboratory .

3. Severe infections that are in an active phase or poorly controlled clinically .

4. The patients had uncontrollable pleural effusion, pericardial effusion, and ascites before enrollment .

5. Extensive or diffuse lung metastases , extensive or diffuse liver metastases , extensive or diffuse bone metastases .

6. Subjects with intestinal obstruction or obstructive jaundice who are deemed unsuitable for participation in this trial by the researchers .

7. Blood oxygen saturation ≤95% without oxygen supplementation .

8. Patients with other serious lung diseases that may limit their participation in this study, such as pulmonary embolism, chronic obstructive pulmonary disease, symptomatic or poorly controlled interstitial lung disease, or clinically significant abnormalities in pulmonary function tests .

9. Subjects with a known history or current hepatic encephalopathy requiring treatment; subjects with a current or history of central nervous system disorders, such as seizures, cerebral ischemia/hemorrhagic disease, dementia, cerebellar disease, or any autoimmune disease involving the central nervous system .

10. Central nervous system metastasis or meningeal metastasis .

11. Currently, patients have unstable heart disease requiring treatment or heart disease that cannot be controlled by treatment, or hypertension that is poorly controlled according to investigators (defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure >100 mmHg after standard antihypertensive drug treatment); or diabetes that is poorly controlled despite standard treatment (fasting blood glucose ≥10.2 mmol/L) .

12. If any of the following cardiac clinical symptoms or conditions exist within 6 months prior to cell infusion:

    1. Left ventricular ejection fraction (LVEF) < 50%;
    2. History of myocardial infarction within the past year; or unstable angina; or percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG); or use of a pacemaker;
    3. Resting electrocardiogram examination: QTc F > 450ms (male) or QTc F > 470ms (female);
    4. An electrocardiogram at rest reveals clinically significant abnormalities (such as abnormalities in heart rate, conduction, or morphological characteristics) or complete left bundle branch block or third-degree atrioventricular block or a PR interval >250 ms.

13. Evidence of a significant coagulation disorder or other obvious risk of bleeding, including:

    1. Abnormal coagulation function that is clinically significant;
    2. History of intracranial hemorrhage or spinal cord hemorrhage;
    3. Patients with tumor lesions invading major blood vessels and posing a significant risk of bleeding;
    4. Subjects who currently have unstable or active ulcers or active gastrointestinal bleeding;
    5. An embolic event occurred within 6 months prior to cell reinfusion;
    6. Within one month prior to cell reinfusion, there has been clinically significant hemoptysis or obvious bleeding from tumor lesions;
    7. Had a major trauma or major surgery within one month prior to enrollment;
    8. The presence of any bleeding disorder, such as hemophilia, von Willebrand disease, etc.;
    9. The patient has received anticoagulation therapy (excluding low molecular weight heparin) for therapeutic purposes within 2 weeks prior to cell reinfusion.
    10. Subjects are receiving routine anticoagulation therapy (such as warfarin or heparin). Subjects require long-term antiplatelet therapy (aspirin >300 mg/day; clopidogrel >75 mg/day); dipyridamole, ticlopidine, or cilostazol, etc.

14. The patient has received systemic steroids equivalent to >15 mg/day of prednisone for more than 3 days within 2 weeks prior to apheresis, excluding inhaled steroids .

15. Subjects requiring systemic therapy with corticosteroids or other immunosuppressive drugs during treatment. Subjects with any active autoimmune disease, or a history of autoimmune disease with anticipated relapse (including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, and asthma requiring medical intervention with bronchodilators). Exceptions include: type 1 diabetes; skin diseases not requiring systemic treatment (e.g., vitiligo, psoriasis); alopecia; hypothyroidism requiring only hormone replacement therapy; asthma that was completely remitted in childhood and requires no intervention in adulthood; or other conditions not expected to relapse in the absence of external triggers .

16. Subjects with a prior or concurrent history of other malignant tumors, except in the following circumstances:

    1. Basal cell or squamous cell carcinoma that has undergone adequate treatment (sufficient wound healing is required before enrollment in the study).
    2. Cervical cancer or breast cancer in situ, cured and with no signs of recurrence for at least 3 years prior to the study;
    3. The primary malignant tumor has been completely removed and has been in complete remission for ≥5 years ; d ) The concurrent malignant tumor was an epithelial tumor that expressed EpCAM .

17. Subjects who have previously received other gene therapies, including but not limited to CAR-T therapy and TCR-T therapy .

18. The following treatments or medications were received before cell reinfusion: chemotherapy, targeted therapy, biotherapy, endocrine therapy, immunotherapy, or other anti-tumor treatments (excluding treatments that meet the protocol requirements before reinfusion, such as lymph node pretreatment and bridging therapy); less than 28 days or less than 5 half-lives since the first infusion treatment in this study (whichever is shorter); or traditional Chinese medicine treatment with anti-tumor indications received within 2 weeks before cell reinfusion .

19. of severe allergies, such as anaphylactic shock .

20. Subjects with severe mental disorders .

21. Subjects who develop new cardiac arrhythmias, including but not limited to arrhythmias that cannot be controlled by medication; hypotension requiring vasopressors; or bacterial, fungal, or viral infections requiring intravenous antibiotics. Subjects receiving antibiotics to prevent infection may continue to participate in the trial at the investigator's discretion .

22. The patient had participated in other interventional clinical studies and used investigational drugs within one month prior to the planned infusion of IMC001 .

23. Subjects who received a live attenuated vaccine within 4 weeks prior to the planned single-donor administration or who are scheduled to receive a live attenuated vaccine during the study.

24. Subjects with any other concurrent serious and /or uncontrolled medical conditions that the investigators deem unsuitable for participation in this trial.

Researchers assessed that participants were unable or unwilling to comply with the requirements of the research protocol .