Peripheral T-cell Lymphoma (PTCL)
Conditions
Keywords
Biomarker-driven, Genetic subtypes, Precision medicine, Peripheral T Cell Lymphoma
Brief summary
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
DRUGAzacitidine 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.
DRUGDecitabine 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.
DRUGZeprumetostat 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 standard CHOP.
DRUGAzacitidine 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.
DRUGCHOP
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.
Sponsors
Ruijin Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase 2 Dose (RP2D) for Phase I | Dose Limiting Toxicity (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 BOIN methods |
| Complete response rate (CRR) for Phase II | End of treatment visit (6-8 weeks after last dose on Day 1 of Cycle 6 [Cycle length=28 days]) | Percentage of participants with complete response was determined on the basis of investigator assessments according to 2014 Lugano criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival | Baseline up to data cut-off (up to approximately 2 years) | 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. |
| Overall survival | Baseline up to data cut-off (up to approximately 2 years) | Overall survival was defined as the time from the date of randomization to the date of death from any cause. |
| Overall response rate (ORR) | End of treatment visit (6-8 weeks after last dose on Day 1 of Cycle 6 [Cycle length=28 days]) | Percentage of participants with complete and partial response was determined on the basis of investigator assessments according to 2014 Lugano criteria. |
| Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0 | From enrollment to study completion, a maximum of 4 years | 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. |
Countries
China
Contacts
CONTACTWeili Zhao Zhao
CONTACTPengpeng Xu
Outcome results
None listed