Guidance-04：T-cell Lymphoma Series：A Genotype-guided Therapy in Newly Diagnosed Patients With Peripheral T-cell Lymphoma （THEORY Study）
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 264
- 试验地点
- 1
- 主要终点
- Recommended Phase 2 Dose (RP2D) for Phase I
研究概览
简要总结
This study includes Phase I and Phase II stages. Phase I is an open-label trial to confirm RP2D of oral targeted agents in three genetic subtypes. Phase II is a multicenter, prospective, randomized, open-label, controlled trial to evaluate the efficacy and safety of genotype-guided targeted agents plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP-X2) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with peripheral T-cell lymphoma.
详细描述
Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. Standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy is still the most widely used front-line treatment of PTCL except Brentuximab-CHP application in anaplastic large cell lymphoma (ALCL). The CR rate ranges from 31%-56% in different studies with different PTCL histology compositions. With the exception for ALCL-anaplastic lymphoma kinase (ALK)-positive, the 5-year overall survival (OS) rate is approximately 30%-40% for most subtypes of PTCL patients in current situation, remaining as the unmet medical needs in this disease. Based on genetic subtypes in PTCL, and our previous study exploring targeted agents plus CHOP based on genetic mutations (Guidance-03 study), we conducted this multicenter, prospective, randomized, open-label, controlled trial to evaluate the efficacy and safety of genotype-guided targeted agents plus CHOP (CHOP-X2) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with PTCL. It includes phase I and phase II stages. Patients will receceived stardard CHOP for the first cycle and then obtain the genetic subtypes from tumor NGS befor Cycle 2. In phase I, recommended phase 2 dose (RP2D) of oral targeted agents will be confirmed by traditional "3+3" dose escalation methods. In phase II, patients will receive standard CHOP for the first cycle and then 1:1 be randomized to CHOPX2 or CHOP regimen in each genetic subtypes.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Histologically-confirmed Peripheral T-cell lymphoma
- •Availability of archival or freshly collected tumor tissue before study enrollment enough for NGS
- •Evaluable lesion by PET-CT or CT scan
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
- •Life expectancy greater than or equal to (>/=) 3 months
- •Informed consent
排除标准
- •Patients with ALCL and cutaneous TCL
- •Patients with central nervous system (CNS) lymphoma
- •History of malignancies except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
- •Uncontrolled cardio- and cerebro-vascular disease, blood clotting disorders, connective tissue diseases, serious infectious diseases and other diseases
- •Laboratory measures meet the following criteria at screening (unless caused by lymphoma):
- •Neutrophils<1.0×10^9/L Platelets<75×10^9/L (Platelets<50×10^9/L in case of bone marrow involvement) ALT or AST is 2.5 times higher than the upper limits of normal (ULN), AKP and bilirubin are 1.5 times higher than the ULN.
- •Creatinine is 1.5 times higher than the ULN.
- •HIV-infected patients
- •Active hepatitis infection
- •Patients with psychiatric disorders or patients who are known or suspected to be unable to fully comply with the study protocol
- •Pregnant or lactation
- •Other medical conditions determined by the researchers that may affect the study For T3 should exclude patiens with active autoimmune disease
研究组 & 干预措施
T1: CHOP+selinexor+5-Azacitidine (CHOPX2) vs CHOP
Phase I: Patients in this arm will receive cyclophosphamide 750 mg/m² IV, doxorubicin 50 mg/m² IV, and vincristine 1.4 mg/m² IV (maximum 2 mg) on day 1, and prednisone 100 mg/day PO on days 1-5 of every 21-day cycle for the first cycle. If tumor NGS indicates T1 genetic subtype, for the remaining 5 cycles, they will receive 5-Azacitidine ih d-7-d-1 and selinexor 40mg or 60mg qw (d-7, 1, 8) by traditional "3+3" dose escalation methods and decide RP2D of selinexor.
Phase II: Patients will receive CHOP for the first cycle. If tumor NGS indicates T1 genetic subtype, then 1:1 randomized to experimental (CHOPX2) or standard CHOP regimen for 5 cycles of every 21-day cycle.
干预措施: CHOP+selinexor+5-Azacitidine (Drug)
T1: CHOP+selinexor+5-Azacitidine (CHOPX2) vs CHOP
Phase I: Patients in this arm will receive cyclophosphamide 750 mg/m² IV, doxorubicin 50 mg/m² IV, and vincristine 1.4 mg/m² IV (maximum 2 mg) on day 1, and prednisone 100 mg/day PO on days 1-5 of every 21-day cycle for the first cycle. If tumor NGS indicates T1 genetic subtype, for the remaining 5 cycles, they will receive 5-Azacitidine ih d-7-d-1 and selinexor 40mg or 60mg qw (d-7, 1, 8) by traditional "3+3" dose escalation methods and decide RP2D of selinexor.
Phase II: Patients will receive CHOP for the first cycle. If tumor NGS indicates T1 genetic subtype, then 1:1 randomized to experimental (CHOPX2) or standard CHOP regimen for 5 cycles of every 21-day cycle.
干预措施: standard CHOP (Drug)
T2: CHOP+duvelisib+5-Azacitidine vs CHOP
Phase I: Patients in this arm will receive cyclophosphamide 750 mg/m² IV, doxorubicin 50 mg/m² IV, and vincristine 1.4 mg/m² IV (maximum 2 mg) on day 1, and prednisone 100 mg/day PO on days 1-5 of every 21-day cycle for the first cycle. If tumor NGS indicates T2 genetic subtype, for the remaining 5 cycles, they will receive 5-Azacitidine ih d-7-d-1 and duvelisib 25mg or 50mg bid (d1-14) by traditional "3+3" dose escalation methods and decide RP2D of duvelisib.
Phase II: Patients will receive CHOP for the first cycle. If tumor NGS indicates T1 genetic subtype, then 1:1 randomized to experimental (CHOPX2) or standard CHOP regimen for 5 cycles of every 21-day cycle.
干预措施: CHOP+duvelisib+5-Azacitidine (Drug)
T2: CHOP+duvelisib+5-Azacitidine vs CHOP
Phase I: Patients in this arm will receive cyclophosphamide 750 mg/m² IV, doxorubicin 50 mg/m² IV, and vincristine 1.4 mg/m² IV (maximum 2 mg) on day 1, and prednisone 100 mg/day PO on days 1-5 of every 21-day cycle for the first cycle. If tumor NGS indicates T2 genetic subtype, for the remaining 5 cycles, they will receive 5-Azacitidine ih d-7-d-1 and duvelisib 25mg or 50mg bid (d1-14) by traditional "3+3" dose escalation methods and decide RP2D of duvelisib.
Phase II: Patients will receive CHOP for the first cycle. If tumor NGS indicates T1 genetic subtype, then 1:1 randomized to experimental (CHOPX2) or standard CHOP regimen for 5 cycles of every 21-day cycle.
干预措施: standard CHOP (Drug)
T3: CHOP+chidamide+tislelizumab （CHOPX2）vs CHOP
Phase I: Patients in this arm will receive cyclophosphamide 750 mg/m² IV, doxorubicin 50 mg/m² IV, and vincristine 1.4 mg/m² IV (maximum 2 mg) on day 1, and prednisone 100 mg/day PO on days 1-5 of every 21-day cycle for the first cycle. If tumor NGS indicates T3 genetic subtype, for the remaining 5 cycles, they will receive tislelizumab 200mg d0 ivgtt and chidamide 20mg or 30mg biw (d1,4,8,11) by traditional "3+3" dose escalation methods and decide RP2D of chidamide.
Phase II: Patients will receive CHOP for the first cycle. If tumor NGS indicates T3 genetic subtype, then 1:1 randomized to experimental (CHOPX2) or standard CHOP regimen for 5 cycles of every 21-day cycle.
干预措施: CHOP+chidamide+tislelizumab (Drug)
T3: CHOP+chidamide+tislelizumab （CHOPX2）vs CHOP
Phase I: Patients in this arm will receive cyclophosphamide 750 mg/m² IV, doxorubicin 50 mg/m² IV, and vincristine 1.4 mg/m² IV (maximum 2 mg) on day 1, and prednisone 100 mg/day PO on days 1-5 of every 21-day cycle for the first cycle. If tumor NGS indicates T3 genetic subtype, for the remaining 5 cycles, they will receive tislelizumab 200mg d0 ivgtt and chidamide 20mg or 30mg biw (d1,4,8,11) by traditional "3+3" dose escalation methods and decide RP2D of chidamide.
Phase II: Patients will receive CHOP for the first cycle. If tumor NGS indicates T3 genetic subtype, then 1:1 randomized to experimental (CHOPX2) or standard CHOP regimen for 5 cycles of every 21-day cycle.
干预措施: standard CHOP (Drug)
结局指标
主要结局
Recommended Phase 2 Dose (RP2D) for Phase I
时间窗: DLT time window (28 days from Cycle 2)
Recommended Phase 2 Dose (RP2D) for Phase I of oral targeted agents in each genetic subtypes by traditional "3+3" dose escalation methods
Complete response rate (CRR) for Phase II
时间窗: End of treatment visit (6-8 weeks after last dose on Day 1 of Cycle 6 [Cycle length=21 days])
Percentage of participants with complete response was determined on the basis of investigator assessments according to 2014 Lugano criteria.
次要结局
- Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0(From enrollment to study completion, a maximum of 4 years)
- Progression-free survival(Baseline up to data cut-off (up to approximately 2 years))
- Overall survival(Baseline up to data cut-off (up to approximately 2 years))
研究者
Zhao Weili
Vice President, Ruijin Hospital
Ruijin Hospital