Genotype-guided Treatment in Newly Diagnosed PTCL (THEORY)

Guidance-04：T-cell Lymphoma Series：A Genotype-guided Therapy in Newly Diagnosed Patients With Peripheral T-cell Lymphoma （THEORY Study）

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.

Study Overview

• Status: Recruiting
• Conditions: Peripheral T Cell Lymphoma
• Intervention / Treatment: Drug: CHOP+selinexor+5-Azacitidine; Drug: standard CHOP; Drug: CHOP+duvelisib+5-Azacitidine; Drug: CHOP+chidamide+tislelizumab

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 264
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Weili Zhao; Phone Number: 610707 +862164370045; Email: zwl_trial@163.com
• Study Contact Backup: Name: Pengpeng Xu; Phone Number: 610707 +862164370045; Email: pengpeng_xu@126.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200025
      • Recruiting
      • Ruijin Hospital
      • Contact: Mingci Cai, MD; Phone Number: 665251 86-21-64370045
      • Principal Investigator: Weili Zhao, MD
      • Sub-Investigator: Shu Cheng, MD
      • Sub-Investigator: Mingci Cai, MD
      • Sub-Investigator: Yaohui Huang, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: CHOP+selinexor+5-Azacitidine; 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.; Drug: standard CHOP; 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 6 cycles.
Experimental: 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.	Drug: standard CHOP; 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 6 cycles.; Drug: CHOP+duvelisib+5-Azacitidine; 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.
Experimental: 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.	Drug: standard CHOP; 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 6 cycles.; Drug: CHOP+chidamide+tislelizumab; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended Phase 2 Dose (RP2D) for Phase I	Recommended Phase 2 Dose (RP2D) for Phase I of oral targeted agents in each genetic subtypes by traditional "3+3" dose escalation methods	DLT time window (28 days from Cycle 2)
Complete response rate (CRR) for Phase II	Percentage of participants with complete response was determined on the basis of investigator assessments according to 2014 Lugano criteria.	End of treatment visit (6-8 weeks after last dose on Day 1 of Cycle 6 [Cycle length=21 days])

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0	An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.	From enrollment to study completion, a maximum of 4 years
Overall survival	Overall survival was defined as the time from the date of randomization to the date of death from any cause.	Baseline up to data cut-off (up to approximately 2 years)
Progression-free survival	Progression-free survival was defined as the time from the date of randomization until the date of the first documented day of disease progression or relapse, using 2014 Lugano criteria, or death from any cause, whichever occurred first.	Baseline up to data cut-off (up to approximately 2 years)

Collaborators and Investigators

• Sponsor: Ruijin Hospital
• Collaborators: The First Affiliated Hospital of Anhui Medical University; The First Affiliated Hospital of Nanchang University; Peking University People's Hospital; Sun Yat-sen University; Peking University Third Hospital; West China Hospital; Anhui Provincial Cancer Hospital; Beijing Tongren Hospital; The First Affiliated Hospital of Soochow University; The First Affiliated Hospital of Zhengzhou University; The First Hospital of Jilin University; The Second Affiliated Hospital of Harbin Medical University; Wuhan TongJi Hospital; The First Affiliated Hospital of Xiamen University; Nanfang Hospital, Southern Medical University

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2023
• Primary Completion (Estimated): July 15, 2026
• Study Completion (Estimated): July 15, 2028

Study Registration Dates

• First Submitted: December 29, 2022
• First Submitted That Met QC Criteria: December 29, 2022
• First Posted (Actual): January 9, 2023

Study Record Updates

• Last Update Posted (Estimated): January 8, 2024
• Last Update Submitted That Met QC Criteria: January 4, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Biomarker-driven; Precision medicine; Phase 1/2; Complete response rate; Genetic subtypes
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Azacitidine; Tislelizumab
• Other Study ID Numbers: Guidance-04 (NHL-016)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No