A Clinical Study to Evaluate CHT101 Injection in Subjects With Relapsed/Refractory T-Cell and B-Cell Hematologic Malignancies

A Phase I, Single-Arm, Open-Label 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 anti-CD70 chimeric antigen receptor allogeneic T-cell injection (CHT101) in the treatment of CD70-positive relapsed/refractory T-cell and B-cell hematological malignancies.

Secondary Objectives: To characterize the PK profiles of CHT101; to evaluate the clinical efficacy of CHT101 for CD70-positive relapsed/refractory T-cell and B-cell hematological malignancies.

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

Inclusion Criteria:

1. Understand and voluntarily provide written informed consent (ICF) prior to any study-related assessments/procedures;

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

3. CD70-positive tumor cells detected in bone marrow or peripheral blood by flow cytometry, or positive CD70 immunohistochemistry in tumor tissue;

4. Subjects with relapsed/refractory T-cell malignancies with measurable disease as defined by modified Severity-Weighted Assessment Tool (mSWAT) score or peripheral blood tumor burden, or at least one measurable lesion identified by imaging (PET-CT or CT) according to Lugano criteria (lymph node lesion with any diameter >1.5 cm; extranodal lesion with 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 with disease involving two or more regions, or single-region disease with large-cell transformation]), and having received prior systemic therapy: subjects with peripheral T-cell lymphoma shall have received at least one line of therapy; subjects with cutaneous T-cell lymphoma shall have received at least two lines of therapy; for anaplastic large-cell lymphoma (ALCL), subjects must have relapsed following prior brentuximab vedotin therapy, or relapsed after ≥2 prior therapies (if anaplastic lymphoma kinase-positive);

5. Subjects with 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 prior lines of therapy containing a CD20 antibody;
   • Chronic lymphocytic leukemia (CLL): relapsed or refractory after at least two prior lines of therapy including 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 prior lines of therapy containing a CD20 antibody and anthracycline, and the subject is ineligible for autologous stem-cell transplantation (conditions for ineligibility for autologous stem-cell transplantation include absence 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 prior lines of therapy;

6. Histopathologically confirmed classical Hodgkin lymphoma (cHL), relapsed or refractory (following BV and PD-1 therapy), with at least one measurable lesion per the Lugano 2014 lymphoma response evaluation criteria;

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

8. Expected survival of at least 12 weeks;

9. Fertile male subjects and female subjects of child-bearing potential must agree to use effective contraception from the time of ICF signing until 2 years after administration of investigational product. Female subjects of child-bearing potential include pre-menopausal women and women within 2 years post-menopause. Serum pregnancy test must be negative for female subjects of child-bearing potential at screening.

Exclusion Criteria:

1. Central nervous system (CNS) metastasis, leptomeningeal disease or metastatic central compression; or prior history of CNS diseases, including but not limited to epilepsy, 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, except for: a) adequately treated and cured carcinoma in situ of the cervix; b) localized basal-cell carcinoma or squamous-cell carcinoma of the skin;
4. Subjects with positive HBV DNA in peripheral blood at screening; subjects positive for hepatitis C virus (HCV) antibody with detectable peripheral blood HCV RNA; subjects positive for human immunodeficiency virus (HIV) antibody; subjects with both positive treponemal-specific antibody and non-treponemal antibody tests for syphilis;
5. Known allergy to any component of study medications, including but not limited to lymphodepleting agents (cyclophosphamide, fludarabine), contrast media for imaging examinations;
6. Prior anti-CD70 antitumor therapy, including but not limited to anti-CD70 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 medicinal treatment for GVHD within 4 weeks prior to first infusion;
9. Receipt of any investigational product or systemic antitumor therapy within 28 days prior to first infusion (or five half-lives of the drug, whichever is more appropriate at the investigator's discretion);
10. Receipt of extensive radiotherapy within 28 days prior to ICF signing, except for local radiotherapy for symptomatic relief of non-target lesions administered within 14 days prior to ICF signing or anticipated during the study period;
11. Major surgical procedure within 28 days prior to ICF signing, or anticipated major surgical procedure during the study period;
12. Any uncontrolled active infection requiring parenteral antibiotic, antiviral or antifungal therapy at the time of ICF signing or within 4 weeks prior to first infusion;
13. History of active pulmonary tuberculosis within 1 year before screening (except for subjects with a history of active pulmonary tuberculosis more than 1 year earlier who are judged by the investigator to have no current evidence of active pulmonary tuberculosis);
14. Concurrent or prior history of interstitial lung disease or interstitial pneumonia;
15. Active or previously-occurred autoimmune diseases with potential for relapse (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vasculitis, psoriasis, etc.), or at risk for such diseases;
16. Requirement for systemic corticosteroids (≥10 mg/day prednisone equivalent) or other immunosuppressive agents within 2 weeks prior to ICF signing or during the study period, except for: a) intranasal, inhaled, topical steroids or local steroid injection (e.g., intra-articular injection); b) systemic corticosteroids at physiological doses ≤10 mg/day prednisone equivalent; c) steroids for prophylaxis against hypersensitivity reactions (e.g., premedication prior to computed tomography [CT]);
17. Clinically significant thyroid dysfunction as judged by the investigator;
18. Clinically significant cardiovascular disease, including any of the following: a) heart-rate-corrected QT interval (QTcF) >470 msec; b) New York Heart Association (NYHA) class II or higher heart failure; c) left ventricular ejection fraction (LVEF) ≤50%; d) uncontrolled hypertension (systolic blood pressure ≥150 mm Hg and/or diastolic blood pressure ≥95 mm Hg); e) arrhythmias of clinical significance or requiring antiarrhythmic therapy (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes, complete left bundle-branch block, etc.); f) unstable angina or acute myocardial infarction within 6 months prior to ICF signing;
19. Insufficient bone marrow reserve or organ function meeting any of the following laboratory criteria: a) absolute neutrophil count <1.5×10⁹/L; b) platelet count <50×10⁹/L; c) hemoglobin <70 g/L; d) abnormal coagulation parameters: international normalized ratio (INR) >2.0 or prothrombin time (PT) >1.5 × upper limit of normal (ULN); e) alanine aminotransferase (ALT) >2.5 × ULN; f) aspartate aminotransferase (AST) >2.5 × ULN; g) total bilirubin >2.5 × ULN; h) serum creatinine clearance <60 mL/min (calculated by the Cockcroft-Gault formula);
20. History of bleeding events within 6 months prior to ICF signing; clinically significant bleeding requiring medical intervention within 28 days before screening, including esophageal variceal bleeding;
21. Vaccination with live-attenuated/inactivated vaccines within 28 days prior to ICF signing, or planned administration of live-attenuated/inactivated vaccines during the screening period;
22. Subjects whose comorbidities or other circumstances, in the investigator's opinion, may impair protocol compliance or render the subject ineligible for study participation;
23. Female subjects who are pregnant or breastfeeding.