Phase 1a/1b Clinical Trials to Evaluate the Safety and Preliminary Efficacy of GNTbm-38.

This study aims to investigate the maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of GNTbm-38. Phase 1a is the dose escalation phase to firstly determine the MTD of patients with solid tumor. Once MTD for solid tumor patients has been established, the next lower dose of this MTD will serve as an initial dose to determine the MTD for patients with R/R PTCL. Phase 1b is the dose expansion phase in which optimal design is utilized to evaluate the safety, tolerability, and efficacy of GNTbm-38 in R/R PTCL patients.

Inclusion criteria

• Female and/or male aged ≥ 18 to ≤ 75 years.
• Histologically or cytologically proven advanced solid tumors or R/R PTCL. For solid tumors, patients must have relapsed or refractory disease after failure of all standard therapies. For R/R PTCL, PTCL subtypes as defined by the WHO classification of tumors (Swerdlow 2022) may be included: PTCL, not otherwise specified (PTCL-NOS), anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL), ALK-negative (ALK-) ALCL, angioimmunoblastic T-cell lymphoma (AITL), etc., except cutaneous form, leukemic form and extra-nodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL). R/R PTCL patients must have relapsed or have refractory disease after at least one line of systemic therapy. Patients with CD30+ PTCL should have received a CD30-targeted agent when applicable, and patients with ALK+ ALCL should have received an ALK inhibitor.
• ECOG performance status of 0 to 2.
• Estimated life expectancy of > 3 months.
• At least 1 measurable lesion confirmed prior to IP administration.
• At the discretion of the Investigator or designee, in good general health with no significant medical history and no clinically significant abnormalities.
• BMI between ≥ 18.0 and ≤ 30.0 kg/m² and weight ≥ 50 kg.
• Laboratory values must meet the following criteria:

• Calculated creatinine clearance > 60 mL/min.
• Proteinuria < 2+ or ≤ 500 mg/24 hours if dipstick ≥ 2+.
• Potassium and corrected calcium within normal limits.
• Troponin I ≤ upper limit of normal (ULN).
• Absolute neutrophil count ≥ 1.5 × 10⁹/L for patients with solid tumors, or Absolute neutrophil count of ≥ 1.0 × 10⁹/L for patients with R/R PTCL.
• Hemoglobin ≥ 9.0 g/dL.
• Platelets ≥ 90 × 10⁹/L.
• Bilirubin ≤ 1.5 × ULN.
• ALP, AST and ALT ≤ 3.0 × ULN (≤ 5.0 × ULN if liver has tumor involvement).
• PT-INR/PTT ≤ 1.5 × ULN.
• All toxicities associated with previous chemotherapy, antibody, or radiotherapy must have recovered to Grade 1 or less (CTCAE Version 6.0), except for alopecia. The following minimum intervals must have elapsed between prior treatment and initiation of IP:

• Chemotherapy: 4 weeks.
• Mitomycin C or Nitrosourea: 6 weeks.
• Radiotherapy: 4 weeks.
• Major surgery: 4 weeks.
• Immunomodulatory drugs: 4 weeks.
• Any antibody agent (Phase Ib): 4 weeks.
• Autologous stem cell transplantation (ASCT): 12 weeks.
• Hormonal therapy: 4 weeks.

Exclusion criteria

• Underlying physical or psychological medical condition that, in the opinion of the Investigator, would make the patient unlikely to comply with the protocol or complete the study.
• Blood or plasma donation or significant blood loss within 30 days prior to the first administration of IP.
• Fever (body temperature > 38°C) or symptomatic viral or bacterial infection within 1 week prior to Screening.
• Infections requiring parenteral antibiotics within 4 weeks prior to Screening.
• History of any other secondary malignancies unless:

• Non-melanoma skin cancer excised more than 2 years ago.
• Cervical intraepithelial neoplasia cured more than 5 years ago.
• Carcinoma in situ of the cervix treated with curative intent.
• Curatively treated prostate cancer with PSA < 0.1 ng/mL.
• Second malignancy in remission for ≥ 2 years.
• Participants will be excluded if any of the following are present in the screening ECG or cardiac evaluation:

a. QTc prolongation > CTCAE Grade 1, or history of congenital long QT syndrome b. Clinically significant cardiac arrhythmias. d. Any other ECG abnormality that, in opinion, of the investigator, would pose an unacceptable risk with GNTbm-38.

• Known central nervous system (CNS) involvement, including primary CNS lymphoma or brain metastases.

• Organ transplant recipients. 8. Allogeneic stem cell transplant recipients. 9. Use of any strong inhibitor or strong inducer of CYP3A4, P gp, and/or BCRP is not permitted.

• Patients using heparin or warfarin/Coumadin-type anticoagulants; however, low-dose (< 2 mg) Coumadin for portacath patency or low-dose subcutaneous heparin for thrombophlebitis prophylaxis are allowed.

• Have been treated with HDAC inhibitors. 12.Subjects with a history of seizures. 13.HBsAg-positive or HCV-Ab-positive. 14. Seropositivity for HIV antibody or known history of HIV/AIDS. 15. History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled peptic ulcer disease, or recurrent pleural effusion requiring repetitive palliative thoracentesis.

• History of immune-mediated toxicity leading to treatment discontinuation. 17. Women who are pregnant or breastfeeding. 18. Female participants who do not agree to refrain from donating oocytes or embryos during treatment and for 90 days after the last dose.

• Male participants who are sexually active with a WOCBP partner and are unwilling or unable to use a condom and ensure that their partner uses at least one highly effective method of contraception during the same period.