Genotype-guided Treatment in Newly Diagnosed PTCL (THEORY)

Shanghai Jiao Tong University

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Peripheral T Cell Lymphoma

Treatments: Drug: standard CHOP; Drug: CHOP+duvelisib+5-Azacitidine; Drug: CHOP+chidamide+tislelizumab; Drug: CHOP+selinexor+5-Azacitidine

Study type: Interventional

Funder types: Other

Identifiers

NCT05675813

Guidance-04 (NHL-016)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 264 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 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

Exclusion criteria

• 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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264 participants in 3 patient groups

T1: CHOP+selinexor+5-Azacitidine (CHOPX2) vs CHOP

Experimental group

Description:

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.

Treatment:

Drug: CHOP+selinexor+5-Azacitidine

Drug: standard CHOP

T2: CHOP+duvelisib+5-Azacitidine vs CHOP

Experimental group

Description:

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.

Treatment:

Drug: standard CHOP

Drug: CHOP+duvelisib+5-Azacitidine

T3: CHOP+chidamide+tislelizumab （CHOPX2）vs CHOP

Experimental group

Description:

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.

Treatment:

Drug: standard CHOP

Drug: CHOP+chidamide+tislelizumab