A Phase I, Single-Arm, Open-Label Clinical Study to Evaluate the Safety, Pharmacokinetics, and Preliminary Efficacy of CHT101 Injection in Subjects With Relapsed/Refractory T-Cell and B-Cell Hematological Malignancies

A Phase I, Single-Arm, Open-Label Clinical Study to Evaluate the Safety, Pharmacokinetics, and Preliminary Efficacy of CHT101 Injection in Subjects With Relapsed/Refractory T-Cell and B-Cell Hematological Malignancies

Primary Objective: To evaluate the safety, tolerability, and dose-limiting toxicity of CD70-targeted chimeric antigen receptor allogeneic T-cell injection (CHT101) in the treatment of subjects with CD70-positive relapsed/refractory T-cell and B-cell hematological malignancies.

Primary Endpoint: MTD, RP2D or biologically effective dose; to assess the incidence, severity and relatedness of AEs and SAEs.

Indication: CD70-positive relapsed or refractory T-cell and B-cell hematological malignancies

Inclusion Criteria:

1. Prior to performing any study-related assessments/procedures, understand and voluntarily sign the Informed Consent Form (ICF)；

2. Age between 18 and 70 years (inclusive) at the time of signing the ICF;

3. Tumor cells in bone marrow or peripheral blood are CD70-positive as detected by flow cytometry; or CD70-positive by immunohistochemistry (IHC) testing of tumor tissue;

4. Relapsed/refractory T-cell malignancies with measurable disease defined by modified Severity-Weighted Assessment Tool (mSWAT) score or peripheral blood tumor burden, or at least one measurable lesion detected by imaging (PET-CT or CT) per Lugano criteria (lymph node lesion: any diameter >1.5 cm; extranodal lesion: any diameter >1.0 cm), and meeting the following criteria: relapsed/refractory peripheral T-cell lymphoma (including but not limited to peripheral T-cell lymphoma-not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma, adult T-cell leukemia/lymphoma) or cutaneous T-cell lymphoma (including but not limited to mycosis fungoides or Sézary syndrome [Stage IIB or higher, disease involving two or more regions, or single-region disease with large-cell transformation]), and have received prior systemic therapy: patients with peripheral T-cell lymphoma must have received at least 1 line of therapy; patients with cutaneous T-cell lymphoma must have received at least 2 lines of therapy; for anaplastic large-cell lymphoma (ALCL), subjects must have relapsed following prior brentuximab vedotin-containing therapy, or relapsed after ≥2 prior lines of therapy (if anaplastic lymphoma kinase-positive)；

5. Relapsed/refractory B-cell malignancies with at least one measurable lesion and meeting at least one of the following criteria:

   Indolent lymphoma (FL, MCL, MZL): relapsed or refractory after at least two lines of therapy, with prior treatment regimens containing anti-CD20 antibody; Chronic lymphocytic leukemia (CLL): relapsed or refractory after at least two lines of therapy, with prior treatment regimens containing both BTK inhibitor and venetoclax; Aggressive or highly-aggressive lymphoma (DLBCL, Burkitt lymphoma, high-grade B-cell lymphoma [double-hit, triple-hit, primary mediastinal DLBCL]): relapsed or refractory after at least two lines of therapy, with prior treatment regimens containing anti-CD20 antibody and anthracycline, and the subject is ineligible for autologous stem cell transplantation (conditions for ineligibility for autologous stem cell transplantation include lack of disease response after salvage therapy and failure of stem cell mobilization precluding transplantation); Acute lymphoblastic leukemia (ALL): relapsed or refractory after at least two lines of prior therapy；

6. Histopathologically confirmed classical Hodgkin lymphoma (cHL), which is relapsed or refractory (after brentuximab vedotin and PD-1 inhibitor therapy), with at least one measurable lesion consistent with Lugano 2014 lymphoma response evaluation criteria；

7. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 at the time of signing the ICF;

8. Expected survival of no less than 12 weeks;

9. Fertile males and females of child-bearing potential must agree to use effective contraceptive measures from the time of signing the Informed Consent Form (ICF) until 2 years after administration of the study drug. Females of child-bearing potential include pre-menopausal women and women within 2 years post-menopause. A serum pregnancy test must be negative for females of child-bearing potential at screening.

Exclusion Criteria:

1. Central nervous system (CNS) metastasis, leptomeningeal disease or metastatic spinal cord compression; or prior history of CNS diseases, including but not limited to seizure, paralysis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, etc；

2. History of organ transplantation;

3. History of other primary malignancies within 5 years prior to study treatment, with the following exceptions:

   1. Cervical carcinoma in situ that has been adequately treated and cured;
   2. Localized basal-cell carcinoma or squamous-cell carcinoma of the skin;

4. Subjects with positive hepatitis B surface antigen (HBsAg) at screening should be excluded; for subjects with negative HBsAg but positive hepatitis B core antibody (HBcAb), those with peripheral blood hepatitis B virus (HBV) DNA above the lower limit of detection should be excluded; subjects with positive hepatitis C virus (HCV) antibody and positive HCV RNA should be excluded; subjects with positive human immunodeficiency virus (HIV) antibody; subjects with both positive treponema-specific antibody and non-specific syphilis antibody tests；

5. Subjects with hypersensitivity to any components of the investigational products used in this study, including but not limited to lymphodepleting agents (cyclophosphamide, fludarabine), and contrast media for imaging examinations；

6. Prior receipt of anti-CD70-targeted anti-tumor therapy, including but not limited to CD70-targeted cell therapy (autologous or allogeneic), TCR-T therapy, etc；

7. Prior receipt of CAR-T therapy or other cell/gene therapy;

8. Presence of acute or moderate-to-severe chronic graft-versus-host disease (GVHD) within 4 weeks prior to ICF signing, or receipt of systemic pharmacological therapy for GVHD within 4 weeks prior to the first infusion；

9. Receipt of any investigational drug or systemic anti-tumor therapy within 28 days (or 5 half-lives of the drug, whichever is deemed more appropriate by the Investigator) prior to the first infusion;

10. Receipt of extensive-field radiotherapy within 28 days prior to the time of signing the ICF, except for local radiotherapy for symptom relief to non-target lesions administered within 14 days prior to ICF signing or anticipated to be administered during the study period；

11. Receipt of major surgical procedure within 28 days prior to the time of signing the ICF, or anticipated major surgical procedure during the study period；

12. Uncontrolled active infection requiring parenteral antibiotic, antiviral or antifungal therapy at the time of signing the ICF or within 4 weeks prior to the first infusion;

13. History of active pulmonary tuberculosis infection within 1 year prior to screening (subjects with history of active pulmonary tuberculosis infection more than 1 year ago are excluded unless the Investigator judges that there is no current evidence of active pulmonary tuberculosis)；

14. Concurrent or prior history of interstitial lung disease or interstitial pneumonitis;

15. Subject has active or previously-treated autoimmune disease with potential for recurrence (including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vasculitis, psoriasis), or is at risk for such disease；

16. Requirement for systemic corticosteroids at a dose equivalent to or greater than 10 mg/day prednisone, or other immunosuppressive therapy within 2 weeks prior to the time of signing the ICF or during the study period, except for the following:

    1. Intranasal, inhaled, topical steroids or local steroid injections (e.g., intra-articular injection);
    2. Systemic corticosteroid therapy at prednisone-equivalent physiological dose no more than 10 mg/day;
    3. Steroids used for prophylaxis against allergic reactions (e.g., pre-medication prior to computed tomography [CT] scanning).

17. Clinically significant thyroid dysfunction as judged by the Investigator；

18. Clinically significant cardiovascular disease, including any of the following:

    1. Fridericia-corrected QT interval (QTcF) > 470 msec;
    2. New York Heart Association (NYHA) class II or higher heart failure;
    3. Left ventricular ejection fraction (LVEF) ≤ 50%;
    4. Uncontrolled hypertension (systolic blood pressure ≥ 150 mm Hg and/or diastolic blood pressure ≥ 95 mm Hg);
    5. Clinically significant arrhythmias requiring anti-arrhythmic therapy, including but not limited to sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes, complete left bundle-branch block;
    6. Unstable angina or acute myocardial infarction within 6 months prior to the time of signing the ICF.

19. Insufficient bone marrow reserve or impaired organ function, defined by any of the following laboratory findings:

    1. Absolute neutrophil count (ANC) < 1.5 × 10⁹/L;
    2. Platelet count < 50 × 10⁹/L;
    3. Hemoglobin < 70 g/L;
    4. Abnormal coagulation tests: international normalized ratio (INR) > 2.0 or prothrombin time (PT) > 1.5 × upper limit of normal (ULN);
    5. Alanine aminotransferase (ALT) > 1.5 × ULN;
    6. Aspartate aminotransferase (AST) > 1.5 × ULN;
    7. Total bilirubin > 1.5 × ULN;
    8. Serum creatinine clearance < 60 mL/min (calculated by the Cockcroft-Gault formula).

20. History of bleeding events within 6 months prior to the time of signing the ICF; clinically significant bleeding requiring medical intervention within 28 days prior to screening, including esophageal variceal bleeding;

21. Receipt of live-attenuated or inactivated vaccines within 28 days prior to the time of signing the ICF, or planned administration of live-attenuated or inactivated vaccines during the screening period;

22. Subject has comorbidities or other conditions that, in the Investigator's opinion, may impair protocol compliance or render the subject unsuitable for participation in this study;

23. Female subjects who are pregnant or breastfeeding.