Ignite Creation Date:
2024-05-06 @ 7:55 PM
Last Modification Date:
2024-10-26 @ 3:17 PM
Study NCT ID:
NCT06186648
Status:
RECRUITING
Last Update Posted:
2024-04-19
First Post:
2023-12-06
Brief Title:
Evaluation of Treatment by Glofitamab in Combination With Rituximab or Obinutuzumab Plus CHOP in Patients With RIchter Syndrome
Sponsor:
French Innovative Leukemia Organisation
Organization:
French Innovative Leukemia Organisation
Study Overview
Official Title:
A Phase 2 Study Evaluating the Bispecific CD3xCD20 Antibody GLOfitamab in Combination With Rituximab or Obinutuzumab Plus Cyclophosphamide Doxorubicin Vincristine and Prednisone CHOP in Patients With RIchter Syndrome as Frontline therapY
Status:
RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
GLORIFY
Brief Summary:
This is a national clinical trial multicentric 28 centers non-randomized phase 2 study
Population Patients with previously untreated Richters syndrome RS defined as the occurrence of an aggressive lymphoma of diffuse large B-cell lymphoma histology in a patient with chronic lymphocytic leukemia CLL
Study treatment
The duration of each cycle is 21 days
Cycle 1
Participants will receive standard of care doses of R-CHOP in cycle 1 as follows
Rituximab 375 mgm² IV Day 1
Cyclophosphamide 750 mgm² IV Day 1
Doxorubicin 50 mgm² IV Day 1
Vincristine 14 mgm² capped at 20 mg IV Day 1
Prednisone 60 mgm2 per day PO Day 1-5
Cycle 2
In order to minimize cytokine release syndrome CRS participants will then receive G-CHOP as cycle 2 with obinutuzumab and glofitamab
Obinutuzumab 1000 mg single dose IV Day 1
Cyclophosphamide 750 mgm² IV Day 1
Doxorubicin 50 mgm² IV Day 1
Vincristine 14 mgm² capped at 20 mg IV Day 1
Prednisone 60 mgm2 per day PO Day 1-5
Glofitamab administered intravenously IV as a step-up dose on Days 8 25 mg and 15 10 mg
Cycle 3-6
Participants will receive standard of care doses of R-CHOP and Glofitamab as follows
Rituximab 375 mgm² IV Day 1
Cyclophosphamide 750 mgm² IV Day 1
Doxorubicin 50 mgm² IV Day 1
Vincristine 14 mgm² capped at 20 mg IV Day 1
Prednisone 60 mgm2 per day PO Day 1-5
Glofitamab 30 mg IV Day 8
Cycle 7 and 8 only for patient in Complete Response or Partial response after Cycle 6
Cycle 7 and 8 consist of 2 infusions of glofitamab only at D8C7 and D8C8
Glofitamab 30 mg IV Day 8
Primary endpoint Percentage of participants with a complete response as assessed by the investigator using the Cheson IWG 2014 Lugano Classification ie Deauville scale 1-3 after 6 cycles of RG-CHOP glofitamab or at permanent treatment discontinuation
End of treatment is defined as after 6 cycles of RG-CHOP glofitamab Permanent treatment discontinuation is defined as the discontinuation of all treatments RG-CHOP glofitamab
Population Patients with previously untreated Richters syndrome RS defined as the occurrence of an aggressive lymphoma of diffuse large B-cell lymphoma histology in a patient with chronic lymphocytic leukemia CLL
Study treatment
The duration of each cycle is 21 days
Cycle 1
Participants will receive standard of care doses of R-CHOP in cycle 1 as follows
Rituximab 375 mgm² IV Day 1
Cyclophosphamide 750 mgm² IV Day 1
Doxorubicin 50 mgm² IV Day 1
Vincristine 14 mgm² capped at 20 mg IV Day 1
Prednisone 60 mgm2 per day PO Day 1-5
Cycle 2
In order to minimize cytokine release syndrome CRS participants will then receive G-CHOP as cycle 2 with obinutuzumab and glofitamab
Obinutuzumab 1000 mg single dose IV Day 1
Cyclophosphamide 750 mgm² IV Day 1
Doxorubicin 50 mgm² IV Day 1
Vincristine 14 mgm² capped at 20 mg IV Day 1
Prednisone 60 mgm2 per day PO Day 1-5
Glofitamab administered intravenously IV as a step-up dose on Days 8 25 mg and 15 10 mg
Cycle 3-6
Participants will receive standard of care doses of R-CHOP and Glofitamab as follows
Rituximab 375 mgm² IV Day 1
Cyclophosphamide 750 mgm² IV Day 1
Doxorubicin 50 mgm² IV Day 1
Vincristine 14 mgm² capped at 20 mg IV Day 1
Prednisone 60 mgm2 per day PO Day 1-5
Glofitamab 30 mg IV Day 8
Cycle 7 and 8 only for patient in Complete Response or Partial response after Cycle 6
Cycle 7 and 8 consist of 2 infusions of glofitamab only at D8C7 and D8C8
Glofitamab 30 mg IV Day 8
Primary endpoint Percentage of participants with a complete response as assessed by the investigator using the Cheson IWG 2014 Lugano Classification ie Deauville scale 1-3 after 6 cycles of RG-CHOP glofitamab or at permanent treatment discontinuation
End of treatment is defined as after 6 cycles of RG-CHOP glofitamab Permanent treatment discontinuation is defined as the discontinuation of all treatments RG-CHOP glofitamab
Detailed Description:
Study design
Open label multicenter phase 2 trial
Population
Patients with previously untreated Richters syndrome RS defined as the occurrence of an aggressive lymphoma of diffuse large B-cell lymphoma histology in a patient with chronic lymphocytic leukemia CLL
Primary objective
The primary objective is to determine the objective response regarding the RS to 6 cycles of RG-CHOP glofitamab in patients with RS
Secondary objectives
The secondary objectives are to investigate the safety and toxicity of 6 cycles RG-CHOP glofitamab the response to 6 cycles of RG-CHOP glofitamab and the patient outcome
Sample size 40 patients Length of study Inclusion period 18 months Treatment duration 6 months 24 weeks Follow-up period 12 months Duration of the study 36 months
Study treatment
The duration of each cycle is 21 days
Cycle 1
Participants will receive standard of care doses of R-CHOP in cycle 1 as follows
Rituximab 375 mgm² IV Day 1 Cyclophosphamide 750 mgm² IV Day 1 Doxorubicin 50 mgm² IV Day 1 Vincristine 14 mgm² capped at 20 mg IV Day 1 Prednisone 60 mgm2 per day PO Day 1-5
Cycle 2
In order to minimize cytokine release syndrome CRS participants will then receive G-CHOP as cycle 2 with obinutuzumab and glofitamab
Obinutuzumab 1000 mg single dose IV Day 1 Cyclophosphamide 750 mgm² IV Day 1 Doxorubicin 50 mgm² IV Day 1 Vincristine 14 mgm² capped at 20 mg IV Day 1 Prednisone 60 mgm2 per day PO Day 1-5 Glofitamab administered intravenously IV as a step-up dose on Days 8 25 mg and 15 10 mg
Cycle 3-6
Participants will receive standard of care doses of R-CHOP and Glofitamab as follows
Rituximab 375 mgm² IV Day 1 Cyclophosphamide 750 mgm² IV Day 1 Doxorubicin 50 mgm² IV Day 1 Vincristine 14 mgm² capped at 20 mg IV Day 1 Prednisone 60 mgm2 per day PO Day 1-5 Glofitamab 30 mg IV Day 8 Evaluation will be performed after C4 and C6 see 623 and 624 Responding patients with response CR or PR according to Cheson IWG 2014 Lugano Classification ie Deauville scale 1-3 after C6 will receive two more infusions of glofitamab day 8 of C7 and C8
Cycle 7 and 8
Cycle 7 and 8 consist of 2 infusions of glofitamab only at D8C7 and D8C8
Glofitamab 30 mg IV Day 8
Study procedures
Screening period
Assessments may be done up to 28 days before the treatment start and will include
Clinical assessments Medical history including demographics previous and current diseases medications included previous CLL treatments Physical examination B symptoms weight height tumor lesion assessment including peripheral nodes location and two dimensional diameters vital signs pulse blood pressure body temperature Binet staging appendix 3 ECOG performance status appendix 4 Ann Arbor staging appendix 5 Assessment of the international Prognostic Index IPI appendix 6 Determination of the CIRS score appendix 7 Standard laboratory assessments Hematology Biochemistry Other exams HIV 1-2 HBV and HCV serology Ag HBs Ac anti-HBs Ac anti-HBc Ac anti-VHC SARS-COV-2 serology and PCR Pregnancy test beta-HCG for women of child-bearing potential Coagulation test fibrinogen APTT PT Specific assessments Immunophenotyping including CD38 of peripheral lymphocytes and Matutes RMH score Karyotype and 4-color FISH analysis for 17p13 deletion 11q22 deletion 13q14 deletion and trisomy 12 of either blood or marrow CLL cells IGHV mutational status on CLL samples at baseline or before IGHV status should also be performed on the Richter specimen DNA in order to determine the clonal relationship between RS and CLL
TP53 gene sequencing according to ERIC recommendation on CLL cells Bone marrow biopsy Imaging exams Whole-body CT scan thorax abdomen pelvis and measurement in two perpendicular dimensions and response assessments according to the revised Lugano criteria appendix 1 Whole body PET-scan with SUV measurement and response assessments according to the revised Lugano criteria appendix 1
Other exams 12-lead ECG Assessment of left ventricular ejection function by either cardiac ultrasound or isotopic ventriculography
Treatment period
Before each cycle RG-CHOP
Clinical assessment
Physical examination Concomitant medications Adverse events serious adverse events and adverse events of special interest Hematology Biochemistry Before each cycle Glofitamab alone
Clinical assessment
Vital signs pulse blood pressure body temperature Concomitant medications Adverse events serious adverse events and adverse events of special interest Hematology Biochemistry Electrolytes sodium potassium calcium phosphore Total protein glycemia urea uric acid serum creatinine and creatinine clearance Cockroft and Gault formula Bilirubin ASAT ALAT GGT alkaline phosphatases LDH C-reactive protein After 4 cycles of RG-CHOP glofitamab W12 and after 6 cycles of RG-CHOP glofitamab W18
Clinical assessment
Physical examination B symptoms weight height ECOG performance status tumor lesion assessment including peripheral nodes location and two dimensional diameters Vital signs pulse blood pressure body temperature Writing test C6 only Concomitant medications Adverse events serious adverse events and adverse events of special interest Hematology Biochemistry
Imaging exams Whole-Body CT scan Whole body PET-scan with suv measurement and response assessment according to the revised Lugano criteria appendix 1 will also be performed
Only after 6 cycles of RG-CHOP glofitamab W18 Bone marrow biopsy only if CR criteria obtained in both CT scan and PET Follow up assessments The follow-up will be performed every 3 months for 12 months FU3 FU6 FU9 FU12 after the end of last treatment by glofitamab C8D8 or if patient stopped treatment prematurely without initiate a new treatment
End of treatment EOT
A visit will be performed within 30 days after the last administration of study treatment for patient stop treatment prematurely and Withdrawn of the study A discontinuationwithdrawal form will be sent to the Filo secretary and head of project
For patient continue follow up visits no EOT is required
End of study EOS
The end of study becomes effective after the end of last study visit of last patient enrolled and performed the FU12 visit
The end of study visit corresponds to the last follow-up visit FU12 For patient withdraw during follow up period no end of study visit is required
Observational study
For all patient without withdrawn at FU12 visit see paragraph 92 definition of withdrawal
After this last study visit and if patient consents the Survival date will be collected every year in the eCRF Survival date andor event date form until death for analyse the survival
Date of last news Patient status alivedeathlost of sight Patient response Initiation of new treatment
Investigational product
Obinutuzumab Gazyvaro Obinutuzumab is a humanized glycoengineered type II anti-CD20 monoclonal antibody that recognizes the CD20 antigen present on normal and malignant B cells and is being developed for the treatment of hematological malignancies including NHL and CLL
Glofitamab
Glofitamab is a 21 T-cell bispecific humanized monoclonal antibody that binds to human CD20 on B cells through two fragment antigen-binding domains and to the human CD3 epsilon subunit CD3e of the T-receptor TCR complex on T cells through a single Fab domain
Safety
Patient safety will be assessed based on clinical and laboratory evaluations physical examinations vital signs and monitoring of adverse events AEs
Open label multicenter phase 2 trial
Population
Patients with previously untreated Richters syndrome RS defined as the occurrence of an aggressive lymphoma of diffuse large B-cell lymphoma histology in a patient with chronic lymphocytic leukemia CLL
Primary objective
The primary objective is to determine the objective response regarding the RS to 6 cycles of RG-CHOP glofitamab in patients with RS
Secondary objectives
The secondary objectives are to investigate the safety and toxicity of 6 cycles RG-CHOP glofitamab the response to 6 cycles of RG-CHOP glofitamab and the patient outcome
Sample size 40 patients Length of study Inclusion period 18 months Treatment duration 6 months 24 weeks Follow-up period 12 months Duration of the study 36 months
Study treatment
The duration of each cycle is 21 days
Cycle 1
Participants will receive standard of care doses of R-CHOP in cycle 1 as follows
Rituximab 375 mgm² IV Day 1 Cyclophosphamide 750 mgm² IV Day 1 Doxorubicin 50 mgm² IV Day 1 Vincristine 14 mgm² capped at 20 mg IV Day 1 Prednisone 60 mgm2 per day PO Day 1-5
Cycle 2
In order to minimize cytokine release syndrome CRS participants will then receive G-CHOP as cycle 2 with obinutuzumab and glofitamab
Obinutuzumab 1000 mg single dose IV Day 1 Cyclophosphamide 750 mgm² IV Day 1 Doxorubicin 50 mgm² IV Day 1 Vincristine 14 mgm² capped at 20 mg IV Day 1 Prednisone 60 mgm2 per day PO Day 1-5 Glofitamab administered intravenously IV as a step-up dose on Days 8 25 mg and 15 10 mg
Cycle 3-6
Participants will receive standard of care doses of R-CHOP and Glofitamab as follows
Rituximab 375 mgm² IV Day 1 Cyclophosphamide 750 mgm² IV Day 1 Doxorubicin 50 mgm² IV Day 1 Vincristine 14 mgm² capped at 20 mg IV Day 1 Prednisone 60 mgm2 per day PO Day 1-5 Glofitamab 30 mg IV Day 8 Evaluation will be performed after C4 and C6 see 623 and 624 Responding patients with response CR or PR according to Cheson IWG 2014 Lugano Classification ie Deauville scale 1-3 after C6 will receive two more infusions of glofitamab day 8 of C7 and C8
Cycle 7 and 8
Cycle 7 and 8 consist of 2 infusions of glofitamab only at D8C7 and D8C8
Glofitamab 30 mg IV Day 8
Study procedures
Screening period
Assessments may be done up to 28 days before the treatment start and will include
Clinical assessments Medical history including demographics previous and current diseases medications included previous CLL treatments Physical examination B symptoms weight height tumor lesion assessment including peripheral nodes location and two dimensional diameters vital signs pulse blood pressure body temperature Binet staging appendix 3 ECOG performance status appendix 4 Ann Arbor staging appendix 5 Assessment of the international Prognostic Index IPI appendix 6 Determination of the CIRS score appendix 7 Standard laboratory assessments Hematology Biochemistry Other exams HIV 1-2 HBV and HCV serology Ag HBs Ac anti-HBs Ac anti-HBc Ac anti-VHC SARS-COV-2 serology and PCR Pregnancy test beta-HCG for women of child-bearing potential Coagulation test fibrinogen APTT PT Specific assessments Immunophenotyping including CD38 of peripheral lymphocytes and Matutes RMH score Karyotype and 4-color FISH analysis for 17p13 deletion 11q22 deletion 13q14 deletion and trisomy 12 of either blood or marrow CLL cells IGHV mutational status on CLL samples at baseline or before IGHV status should also be performed on the Richter specimen DNA in order to determine the clonal relationship between RS and CLL
TP53 gene sequencing according to ERIC recommendation on CLL cells Bone marrow biopsy Imaging exams Whole-body CT scan thorax abdomen pelvis and measurement in two perpendicular dimensions and response assessments according to the revised Lugano criteria appendix 1 Whole body PET-scan with SUV measurement and response assessments according to the revised Lugano criteria appendix 1
Other exams 12-lead ECG Assessment of left ventricular ejection function by either cardiac ultrasound or isotopic ventriculography
Treatment period
Before each cycle RG-CHOP
Clinical assessment
Physical examination Concomitant medications Adverse events serious adverse events and adverse events of special interest Hematology Biochemistry Before each cycle Glofitamab alone
Clinical assessment
Vital signs pulse blood pressure body temperature Concomitant medications Adverse events serious adverse events and adverse events of special interest Hematology Biochemistry Electrolytes sodium potassium calcium phosphore Total protein glycemia urea uric acid serum creatinine and creatinine clearance Cockroft and Gault formula Bilirubin ASAT ALAT GGT alkaline phosphatases LDH C-reactive protein After 4 cycles of RG-CHOP glofitamab W12 and after 6 cycles of RG-CHOP glofitamab W18
Clinical assessment
Physical examination B symptoms weight height ECOG performance status tumor lesion assessment including peripheral nodes location and two dimensional diameters Vital signs pulse blood pressure body temperature Writing test C6 only Concomitant medications Adverse events serious adverse events and adverse events of special interest Hematology Biochemistry
Imaging exams Whole-Body CT scan Whole body PET-scan with suv measurement and response assessment according to the revised Lugano criteria appendix 1 will also be performed
Only after 6 cycles of RG-CHOP glofitamab W18 Bone marrow biopsy only if CR criteria obtained in both CT scan and PET Follow up assessments The follow-up will be performed every 3 months for 12 months FU3 FU6 FU9 FU12 after the end of last treatment by glofitamab C8D8 or if patient stopped treatment prematurely without initiate a new treatment
End of treatment EOT
A visit will be performed within 30 days after the last administration of study treatment for patient stop treatment prematurely and Withdrawn of the study A discontinuationwithdrawal form will be sent to the Filo secretary and head of project
For patient continue follow up visits no EOT is required
End of study EOS
The end of study becomes effective after the end of last study visit of last patient enrolled and performed the FU12 visit
The end of study visit corresponds to the last follow-up visit FU12 For patient withdraw during follow up period no end of study visit is required
Observational study
For all patient without withdrawn at FU12 visit see paragraph 92 definition of withdrawal
After this last study visit and if patient consents the Survival date will be collected every year in the eCRF Survival date andor event date form until death for analyse the survival
Date of last news Patient status alivedeathlost of sight Patient response Initiation of new treatment
Investigational product
Obinutuzumab Gazyvaro Obinutuzumab is a humanized glycoengineered type II anti-CD20 monoclonal antibody that recognizes the CD20 antigen present on normal and malignant B cells and is being developed for the treatment of hematological malignancies including NHL and CLL
Glofitamab
Glofitamab is a 21 T-cell bispecific humanized monoclonal antibody that binds to human CD20 on B cells through two fragment antigen-binding domains and to the human CD3 epsilon subunit CD3e of the T-receptor TCR complex on T cells through a single Fab domain
Safety
Patient safety will be assessed based on clinical and laboratory evaluations physical examinations vital signs and monitoring of adverse events AEs
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None