New Genotype-guided Treatment in Newly Diagnosed PTCL

Official title

A New Genotype-guided Therapy in Newly Diagnosed Patients With Peripheral T-cell Lymphoma

Overview

This is a phase I/II study evaluate the safety and efficacy targeted agents in combination with standard CHOP in new genotypic subtypes in treatment naive peripheral T-cell lymphoma. Phase I is to confirm RP2D of targeted agent. Phase II is a multicenter, prospective, randomized, open-label, controlled design to evaluate the efficacy and safety of new 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.

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 and Guidance-04 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 targeted agents will be confirmed. In phase II, patients will receive standard CHOP for the first cycle and then 1:1 be randomized to CHOPX2 or CHOP regimen in four genetic subtypes.

Interventions

• Drug Azacitidine plus Selinexor with 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 for the first cycle. If tumor NGS indicates TP53-mutated genetic subtype, then 1:1 randomized to experimental (CHOPX2) or standard CHOP regimen for 5 cycles of every 28-day cycle. Patients in CHOPX2 group will receive azacitidine d-5 to d-1 and Selinexor 40mg qw combined with standard CHOP.
• Drug Decitabine plus Selinexor with 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 for the first cycle. If tumor NGS indicates TP53-mutated genetic subtype, then 1:1 randomized to experimental (CHOPX2) or standard CHOP regimen for 5 cycles of every 28-day cycle. Patients in CHOPX2 group will receive Decitabine RP2D (confrimed by phase I) and Selinexor 40mg qw combined with standard CHOP.
• Drug Zeprumetostat plus chidamide with 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 for the first cycle. If tumor NGS indicates core epigenetic genes-mutated genetic subtype, then 1:1 randomized to experimental (CHOPX2) or standard CHOP regimen for 5 cycles of every 28-day cycle. Patients in CHOPX2 group will receive Zeprumetostat RP2D (confrimed by phase I) and chidamide 20mg biw combined with s
• Drug Azacitidine plus Golidocitinib with 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 for the first cycle. If tumor NGS indicates other genetic subtype, then 1:1 randomized to experimental (CHOPX2) or standard CHOP regimen for 5 cycles of every 28-day cycle. Patients in CHOPX2 group will receive Azacitidine ih d-5-d-1 and Golidocitinib RP2D (confirmed by Phase I) combined with standard CHOP.
• Drug 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 for cycle 1 to cycle 6.

Primary outcome measures

• Recommended Phase 2 Dose (RP2D) for Phase I [Time frame: Dose Limiting Toxicity (DLT) time window (28 days from Cycle 2)]
• Complete response rate (CRR) for Phase II [Time frame: End of treatment visit (6-8 weeks after last dose on Day 1 of Cycle 6 [Cycle length=28 days])]

Secondary outcome measures (4)

• Progression-free survival [Time frame: Baseline up to data cut-off (up to approximately 2 years)]
• Overall survival [Time frame: Baseline up to data cut-off (up to approximately 2 years)]
• Overall response rate (ORR) [Time frame: End of treatment visit (6-8 weeks after last dose on Day 1 of Cycle 6 [Cycle length=28 days])]
• Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0 [Time frame: From enrollment to study completion, a maximum of 4 years]

Eligibility criteria

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, MEITL, HSTCL, T-PLL, etc.
• 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<1.5×10\^9/L Platelets<75×10\^9/L (Neutrophils<1.0×10\^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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Ruijin Hospital — Shanghai

Identifiers

NCT: NCT07706959 · Guidance-08

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗