A Phase 1a/1b, Open-Label, Dose Escalation and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of GNTbm 38 in Solid Tumors and Relapsed/Refractory Peripheral T-Cell Lymphoma.
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 70
- 主要终点
- Phase 1a: The MTD and DLT of GNTbm-38
研究概览
简要总结
This is a Phase 1a/1b, open-label, dose escalation and expansion study to evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of GNTbm-38 in adult patients with advanced solid tumors and R/R PTCL.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
排除标准
- •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-
- •6. Known central nervous system (CNS) involvement, including primary CNS lymphoma or brain metastases.
- •7. Organ transplant recipients.
- •Allogeneic stem cell transplant recipients.
- •Use of any strong inhibitor or strong inducer of CYP3A4, P gp, and/or BCRP is not permitted.
- •10. 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.
- •11. Have been treated with HDAC inhibitors. 12.Subjects with a history of seizures. 13.HBsAg-positive or HCV-Ab-positive.
- •Seropositivity for HIV antibody or known history of HIV/AIDS.
- •History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled peptic ulcer disease, or recurrent pleural effusion requiring repetitive palliative thoracentesis.
- •16. History of immune-mediated toxicity leading to treatment discontinuation.
- •Women who are pregnant or breastfeeding.
- •Female participants who do not agree to refrain from donating oocytes or embryos during treatment and for 90 days after the last dose.
- •19. 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.
研究组 & 干预措施
To evaluate the MTD and the safety of GNTbm-38 in solid tumor and R/R PTCL
Patients will be given GNTbm-38 capsules administered orally once a day with the following dose levels (if applicable): 2.5, 5, 7.5, 10, 12.5, 15, 20, 25 and 30 mg.
干预措施: GNTbm-38 (Drug)
结局指标
主要结局
Phase 1a: The MTD and DLT of GNTbm-38
时间窗: At the end of Cycle 1 (each cycle is 28 days)
The primary endpoint of the Phase 1a portion of the study was the incidence and severity of dose-limiting toxicities (DLTs) of GNTbm-38 administered orally once daily during the first cycle of evaluation (each cycle is 28 days). The efficacy assessments will be define by RECIST v1.1.
Phase Ia: To define the safety and tolerability
时间窗: At the end of Cycle 1 (each cycle is 28 days)
To evaluate the efficacy of GNTbm-38 via analysis of anti-tumor activity in adult patients with Relapsed or refractory peripheral T-cell lymphoma (R/R PTCL). The efficacy assessments will be define by 2014 Lugano classification.
Phase Ib: To evaluate the efficacy of GNTbm-38 in patients with R/R PTCL.
时间窗: At the end of Cycle 1 (each cycle is 28 days)
Phase 1b dose expansion cohort will be initiated following the MTD from Phase Ia to further evaluate the safety and preliminary efficacy of GNTbm-38 in patients with R/R PTCL, response will be defined by the Lugano criteria.
次要结局
- Maximum plasma concentration (Cmax)(At the end of Cycle 1 (each cycle is 28 days))
- Time to reach maximum concentration (Tmax)(At the end of cycle 1 (each cycle is 28 days))
- Area under the plasma concentration-time curve (AUC)(At the end of Cycle 1 (each cycle is 28 days))
- Trough concentration (Ctrough)(From Cycle 1 Day 1 (each cycle is 28 days) until End of Treatment)