Ignite Creation Date:
2025-12-24 @ 4:16 PM
Ignite Modification Date:
2025-12-24 @ 4:16 PM
Study NCT ID:
NCT06547866
Status:
NOT_YET_RECRUITING
Last Update Posted:
2025-11-26
First Post:
2024-07-30
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
Study Evaluating the Efficacy and Tolerance of a Zanubrutinib and BGB-11417 Combination in Patients Previously Treated for Waldenström Macroglobulinemia
Sponsor:
French Innovative Leukemia Organisation
Organization:
Study Overview
Official Title:
Open Label Phase 2 Study Evaluating the Efficacy and Tolerance of a Zanubrutinib and BGB-11417 Combination in Patients Previously Treated for Waldenström Macroglobulinemia. A FILO Study
Status:
NOT_YET_RECRUITING
Status Verified Date:
2025-11
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:
WAZABI
Brief Summary:
This is a French multicenter open label non-randomized Phase II trial evaluating the efficacy and tolerance of a combination of oral zanubrutinib and BGB-11417 in subjects aged 18 years and older with previously treated Waldenström macroglobulinemia (WM) who require therapy according to the consensus panel criteria from the Second International Workshop on Waldenström's macroglobulinemia.
population : Patients with previously treated Waldenstrom macroglobulinemia
The investigational medicinal products (IMP) are Zanubrutinib (BGB- 3111) and BGB-11417.Treatment will be administered for a total of twenty 28 day cycles:
* Cycle 1 with zanubrutinib only
* Cycle 2 with zanubrutinib plus BGB-11417 ramp-up
* cycle 2, day 1 : 10mg
* cycle 2, day 2 : 20 mg
* cycle 2, day 3 : 40mg
* cycle 2, day 4-7 : 80md daily
* cycle 2, day 8 and beyond : 160 mg daily
* Cycles 3-20 with zanubrutinib plus BGB-11417 full dose
population : Patients with previously treated Waldenstrom macroglobulinemia
The investigational medicinal products (IMP) are Zanubrutinib (BGB- 3111) and BGB-11417.Treatment will be administered for a total of twenty 28 day cycles:
* Cycle 1 with zanubrutinib only
* Cycle 2 with zanubrutinib plus BGB-11417 ramp-up
* cycle 2, day 1 : 10mg
* cycle 2, day 2 : 20 mg
* cycle 2, day 3 : 40mg
* cycle 2, day 4-7 : 80md daily
* cycle 2, day 8 and beyond : 160 mg daily
* Cycles 3-20 with zanubrutinib plus BGB-11417 full dose
Detailed Description:
study design : Open label, multicenter phase 2 trial
population : Patients with previously treated Waldenstrom macroglobulinemia
Primary objective :
To evaluate the efficacy of a combination of zanubrutinib and BGB-11417 given for a limited duration of time in Refractory/Relapsing (R/R) WM by the proportion of subjects achieving either a Complete Response (CR) or Very Good Partial Responses (VGPR).duration of time in Refractory/relapsing (R/R) Waldenstrom macroglobulinemia (WM)
Secondary objectives:
* To further evaluate the efficacy of a combination of zanubrutinib and BGB-11417 given for a limited duration of time in R/R WM
* To determine the incidence and severity of serum M-protein (monoclonal IgM) rebound after planned cessation of the combination of zanubrutinib and BGB-11417-101 in R/R WM
* To evaluate the safety and tolerability of a combination of zanubrutinib and BGB-11417 given for a limited duration of time in R/R WM
Sample size : 102 patients Length of study: Inclusion period: 24 months Treatment duration: 18 months (twenty 28-days cycles) Follow-up period: 3 years
Study treatment :
The investigational medicinal products (IMP) are Zanubrutinib (BGB- 3111) and BGB-11417.Treatment will be administered for a total of twenty 28 day cycles:
* Cycle 1 with zanubrutinib only
* Cycle 2 with zanubrutinib plus BGB-11417 ramp-up
* Cycle 2 with zanubrutinib plus BGB-11417 ramp-up
\*cycle 2, day 1 : 10mg
* cycle 2, day 2 : 20 mg
* cycle 2, day 3 : 40mg
* cycle 2, day 4-7 : 80md daily
* cycle 2, day 8 and beyond : 160 mg daily
* Cycles 3-20 with zanubrutinib plus BGB-11417 full dose
All patient will receive both drugs.
Study procedures:
Screening period:
Assessments may be done up to 28 days before the treatment start and will include:
Clinical assessments
\- Medical history, WM history including prior treatment lines, previous IPSS WM score, histology, known cytogenetics and molecular features including MYD88, CXCR4 and TP53 mutational status
* Concomitant therapies
* Complete physical examination, including weight, height, vital signs, ECOG performance status, B symptoms, detailed evaluation of lymph nodes, liver and spleen and infection monitoring (including COVID-19 nasal test)
* IPSS WM score
Biological assessments
* Standard hematology tests including CBC (hemoglobin, WBC count, absolute differential count, platelet count)
* Blood coagulation tests including: prothrombin time, activated cephalin time, fibrinogen, von Willebrand factor (vWF; including vWF antigen \[vWF:Ag\] and vWF:Activity \[WF:Act\]; evaluation according to ABO blood group) and FVIII\* \*If acquired Willebrand syndrome according to hemorrhagic risk assessment, further analysis is encouraged.
* Blood chemistry tests including sodium, potassium, chloride, bicarbonate, fasting glucose, phosphate, blood urea nitrogen (BUN), creatinine, calcium, phosphate, magnesium, total, direct and indirect bilirubin, total protein, albumin, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), lactate dehydrogenase (LDH), alkaline phosphatase (PAL), uric acid, C-reactive protein (CRP), beta2microglobulin and pregnancy test
* Troponin; NT-proBNP will be performed on blood
* Serum "M-protein" (monoclonal IgM) quantification based on protein electrophoresis or alternate methods (according to appendix 3), immunofixation, nephelometry, free light chains kappa and lambda, cryoglobulinemia
* IgG, IgA and IgM levels
* Serologies for HBV, HCV and HIV
Cardiovascular assessments:
* Cardiovascular evaluation by investigator:
o 12-lead ECG and QTc calculation
o blood pressure after 5 minutes rest, average of 3 measurements separated by ≥ 1 minute.
* Cardiovascular evaluation by cardiologist\*:
* 12-lead ECG with QTc calculation
* echocardiography
* 24h Holter ECG monitoring
* 24h Ambulatory blood pressure monitoring (ABPM)
Imaging assessments:
-Whole-Body CT scan (neck, thorax, abdomen, pelvis) with tumor measurements
Specific assessments:
* BM biopsy\* (local laboratory).
\*This can be omitted if already done within the past 3 months.
* BM aspirate for oLocal laboratory for Cytogenetic analysis and FISH for 17p oFILOthèque central laboratory, storage for future analysis: unsorted and CD19+ sorted cells for mutational profile.
* Blood MRD assessment on plasmatic cell-free tumor DNA (FILOthèque central laboratory).
Treatment period
Clinical assessment:
* Concomitant therapies and adverse events, severe adverse events and adverse events of special interest (AE, SAE and AESI)
* Complete physical examination, including evaluation of lymph nodes, liver and spleen
Cardiovascular assessments:
-Cardiovascular evaluation by investigator after 1, 3, 6, 9, 12, 15 and 18 cycles: o12-lead ECG and QTc calculation\* oblood pressure after a 5 minute rest, average of 3 measurements separated by ≥ 1 minute.
* The 12-lead ECG by investigator is not mandatory if already done or planned during the cardiology consultation within one month (at cycle 3, 6, 12, and 18)
-Cardiovascular evaluation by cardiologist after 3, 6, 12, and 18 cycles: ocardiology consultation o24h Holter ECG monitoring\* o24h ABPM\*\* oEchocardiography\*\*\*
* 24h Holter ECG will be repeated only at cycles 3, 6 and 18 (only risk patient)
* 24h ABMP will be repeated only at cycles 3, 12 and 18
* Echocardiography will be repeated at cycle 18.
Biological assessments (at day 1 +/- 7 days of each cycle):
* Standard hematology tests including CBC (hemoglobin, WBC count, absolute differential count, platelet count)
* Blood chemistry: including sodium, potassium, chloride, bicarbonate, fasting glucose, phosphate, BUN, creatinine, calcium, phosphate, magnesium, total, direct and indirect bilirubin, total protein, albumin, ALAT, ASAT, LDH, PAL, uric acid, CRP and pregnancy test.
During ramp up period: serum creatinine, sodium, potassium, chloride, bicarbonate, calcemia, phosphoremia, LDH is mandatory before initiation of any ramp up dose of BGB-11417, and 8 and 24 hours after drug intake.
* Troponin and NT-proBNP at cycles 1, 3, 6, 9, 12, 15 and 18
* Serum "M-protein" (monoclonal IgM) quantification based on protein electrophoresis or alternate methods (according to appendix 3) with additional immunofixation (to confirm CR)
* IgG, IgA and IgM levels
Imaging assessments:
-Whole-body CT scan (neck, thorax, abdomen, pelvis) every 24 weeks (6 cycles) i.e. after cycles 3, 6, 12 and 18 in all subjects who had measurable nodal/extranodal disease at screening.
Specific assessments:
-FILOthèque central laboratory: Blood on specific tube for MRD assessment on plasmatic cell-free tumor DNA (at cycles 3, 6, 12 and 18), storage.
Response evaluation:
Throughout the treatment period, especially before "end of treatment (EOT) + 3 months (EVAL 2 ) evaluation":
* if a CR is suspected (negative IF), an unscheduled CT scan should be done followed by biological evaluations including BM biopsy (local laboratory) to confirm CR
* If a VGPR is suspected (≥90% reduction in serum M-protein (monoclonal IgM) level from baseline (but still detectable) and decreased lymphadenopathy/ splenomegaly (if present at baseline), an unscheduled CT scan should be done to confirm VGPR.
Evaluation 1 (EVAL 1): 1 month after the end of treatment This evaluation takes place 1 month after EOT either after completion of cycle 20 or after the last cycle in case of early discontinuation. This evaluation may detect M-protein rebound with or without other features of early progression.
Clinical assessments:
* Concomitant therapies
* AE, SAE and AESI
* Complete physical examination including evaluation of lymph nodes, liver and spleen
Cardiovascular assessments:
-Cardiovascular evaluation by investigator: o12-lead ECG and QTc calculation oBlood pressure after a 5 minute rest, average of 3 measurements separated by ≥ 1 minute
Biological assessments:
* Standard hematology tests including CBC (hemoglobin, WBC count, absolute differential count, platelet count)
* Blood chemistry: sodium, potassium, chloride, bicarbonate, fasting glucose, phosphate, BUN, creatinine, calcium, phosphate, magnesium, total, direct and indirect bilirubin, total protein, albumin, ALAT, ASAT, LDH, PAL, uric acid, CRP, and pregnancy test.
* Serum "M-protein" (monoclonal IgM) quantification based on protein electrophoresis or alternate methods (according to appendix 3) with additional immunofixation (to confirm a CR)
* IgG, IgA and IgM levels
Evaluation 2 (=EVAL 2): 3 months after the end of treatment This evaluation takes place 3 months after EOT either after completion of cycle 20 or after the last cycle in case of early discontinuation. This evaluation may detect M-protein rebound with or without other features of early progression.
Clinical assessments:
* Concomitant therapies
* AE, SAE and AESI
* Complete physical examination, including evaluation of lymph nodes, liver and spleen
Cardiovascular assessments:
-Cardiovascular evaluation by investigator: o12-lead ECG and QTc calculation oBlood pressure after 5 minutes rest, average of 3 measurements separated by ≥ 1 minute
-Cardiovascular evaluation by a cardiologist: oCardiology consultation o24h Ambulatory blood pressure monitoring (ABPM) oEchocardiography
Biological assessments:
* Standard hematology tests including CBC (hemoglobin, WBC count, absolute differential count, platelet count)
* Blood chemistry: sodium, potassium, chloride, bicarbonate, fasting glucose, phosphate, BUN, creatinine, calcium, phosphate, magnesium, total, direct and indirect bilirubin, total protein, albumin, ALAT, ASAT, LDH, PAL, uric acid, CRP
* NT-proBNP
* Serum "M-protein" (monoclonal IgM) quantification based on protein electrophoresis or alternate methods (according to appendix 3) with additional immunofixation (to confirm a CR)
* IgG, IgA and IgM levels
Imaging and BM assessments:
* Whole body CT scan
* BM biopsy (local laboratory) if not performed during the treatment period for CR or progression.
* BM aspirate (FILOthèque central laboratory) for storage and analysis for molecular studies without CD19 sorting.
* Blood collected on specific tube (FILOthèque central laboratory) for assessment of plasmatic cell-free tumor DNA
Evaluation in case of suspected CR At any time throughout the study, especially before "EOT evaluation" when a CR is suspected based on a negative immunofixation, an additional evaluation should be realized in order to confirm the CR.
This additional evaluation includes primarily:
* Repeated screening for cryoglobulinemia, in patients known to have significant cryoglobulinemia at screening.
* CT scan
Then, if both immunofixation and CT scan are consistent with CR, a biological assessment should be scheduled with:
-BM biopsy (local laboratory)
Evaluation in case of suspected VGPR At any time throughout the study, especially before "EOT evaluation", when a VGPR is suspected based on ≥90% reduction in M-protein (monoclonal IgM) level from baseline (but still detectable) and decreased lymphadenopathy/splenomegaly (if present at baseline), an additional evaluation should be realized in order to confirm the VGPR.
This additional evaluation includes:
* Repeated screening for cryoglobulinemia, in patients known to have significant cryoglobulinemia at screening.
* CT scan: to confirm the reduction of deep-seated lymphadenopathy and splenomegaly (if present at baseline)
Evaluation in case of progression during treatment and follow-up period
* BM biopsy optional (local laboratory)
* BM aspirate, indicated according to study only in case of progression for :
* local laboratory: cytogenetics and FISH for 17p
* FILOthèque central laboratory: storage of unsorted and CD19+ sorted cells for molecular analyzes.
* Blood collected on specific tube for assessment of plasmatic cell-free tumor DNA (FILOthèque central laboratory).
Post-treatment follow-up period after EVAL 2 Two follow-up evaluations scheduled at 1 month (EVAL 1) and at 3 months (EVAL 2) have been already detailed above. Thereafter, all patients enrolled in the study will be followed until progression or death every 3 months the first year (FU6, FU9 and FU12), then every 6 months for a total follow up period of three years (FU18, FU24, FU30 and FU36).
Clinical assessments:
* Concomitant therapies
* AE, SAE and AESI
* Complete physical examination, evaluation of lymph nodes, liver and spleen.
Cardiovascular assessments:
* Cardiovascular evaluation by investigator o12-lead ECG and QTc calculation oblood pressure after 5 minutes rest, average of 3 measurements separated by ≥ 1 minute
* Cardiovascular evaluation by a cardiologist (only at FU36) ocardiology consultation o24h ABPM oEchocardiography
Biological assessments:
* Standard hematology tests including CBC (hemoglobin, WBC count, absolute differential count, platelet count).
* Blood chemistry: sodium, potassium, chloride, bicarbonate, fasting glucose, phosphate, BUN, creatinine, calcium, phosphate, magnesium, total, direct and indirect bilirubin, total protein, albumin, ALAT, ASAT, LDH, PAL, uric acid, CRP
* NT-proBNP (only FU36)
* Serum "M-protein" (monoclonal IgM) quantification based on protein electrophoresis or alternate methods (according to appendix 3) with additional immunofixation (to confirm a CR)
* IgG, IgA and IgM levels
Imaging and BM assessments:
* Whole body CT scan if clinically indicated, especially in case of progression.
* BM biopsy (local laboratory)
* BM aspirate, indicated according to study, only in case of progression
Premature end of treatment (PEOT) A visit will be performed 4 weeks (EVAL 1) and 3 months (EVAL 2) after the last treatment day for patients who discontinue treatment prematurely and for patients withdrawing their consent (if possible),
In case of PEOT for disease progression, patients will be evaluated
End of study (EOS) The end of study becomes effective after the end of the last study visit of the last patient enrolled once the FU36 visit has been achieved. The end of study visit corresponds to the last follow-up visit (FU36). For patients withdrawing consent during the follow up period, no end of study visit is required.
Observational study For all patients if they consent, the survival data will be collected every year for an observational study, in the e-CRF (Survival date and/or event date) until death, for OS analysis.
population : Patients with previously treated Waldenstrom macroglobulinemia
Primary objective :
To evaluate the efficacy of a combination of zanubrutinib and BGB-11417 given for a limited duration of time in Refractory/Relapsing (R/R) WM by the proportion of subjects achieving either a Complete Response (CR) or Very Good Partial Responses (VGPR).duration of time in Refractory/relapsing (R/R) Waldenstrom macroglobulinemia (WM)
Secondary objectives:
* To further evaluate the efficacy of a combination of zanubrutinib and BGB-11417 given for a limited duration of time in R/R WM
* To determine the incidence and severity of serum M-protein (monoclonal IgM) rebound after planned cessation of the combination of zanubrutinib and BGB-11417-101 in R/R WM
* To evaluate the safety and tolerability of a combination of zanubrutinib and BGB-11417 given for a limited duration of time in R/R WM
Sample size : 102 patients Length of study: Inclusion period: 24 months Treatment duration: 18 months (twenty 28-days cycles) Follow-up period: 3 years
Study treatment :
The investigational medicinal products (IMP) are Zanubrutinib (BGB- 3111) and BGB-11417.Treatment will be administered for a total of twenty 28 day cycles:
* Cycle 1 with zanubrutinib only
* Cycle 2 with zanubrutinib plus BGB-11417 ramp-up
* Cycle 2 with zanubrutinib plus BGB-11417 ramp-up
\*cycle 2, day 1 : 10mg
* cycle 2, day 2 : 20 mg
* cycle 2, day 3 : 40mg
* cycle 2, day 4-7 : 80md daily
* cycle 2, day 8 and beyond : 160 mg daily
* Cycles 3-20 with zanubrutinib plus BGB-11417 full dose
All patient will receive both drugs.
Study procedures:
Screening period:
Assessments may be done up to 28 days before the treatment start and will include:
Clinical assessments
\- Medical history, WM history including prior treatment lines, previous IPSS WM score, histology, known cytogenetics and molecular features including MYD88, CXCR4 and TP53 mutational status
* Concomitant therapies
* Complete physical examination, including weight, height, vital signs, ECOG performance status, B symptoms, detailed evaluation of lymph nodes, liver and spleen and infection monitoring (including COVID-19 nasal test)
* IPSS WM score
Biological assessments
* Standard hematology tests including CBC (hemoglobin, WBC count, absolute differential count, platelet count)
* Blood coagulation tests including: prothrombin time, activated cephalin time, fibrinogen, von Willebrand factor (vWF; including vWF antigen \[vWF:Ag\] and vWF:Activity \[WF:Act\]; evaluation according to ABO blood group) and FVIII\* \*If acquired Willebrand syndrome according to hemorrhagic risk assessment, further analysis is encouraged.
* Blood chemistry tests including sodium, potassium, chloride, bicarbonate, fasting glucose, phosphate, blood urea nitrogen (BUN), creatinine, calcium, phosphate, magnesium, total, direct and indirect bilirubin, total protein, albumin, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), lactate dehydrogenase (LDH), alkaline phosphatase (PAL), uric acid, C-reactive protein (CRP), beta2microglobulin and pregnancy test
* Troponin; NT-proBNP will be performed on blood
* Serum "M-protein" (monoclonal IgM) quantification based on protein electrophoresis or alternate methods (according to appendix 3), immunofixation, nephelometry, free light chains kappa and lambda, cryoglobulinemia
* IgG, IgA and IgM levels
* Serologies for HBV, HCV and HIV
Cardiovascular assessments:
* Cardiovascular evaluation by investigator:
o 12-lead ECG and QTc calculation
o blood pressure after 5 minutes rest, average of 3 measurements separated by ≥ 1 minute.
* Cardiovascular evaluation by cardiologist\*:
* 12-lead ECG with QTc calculation
* echocardiography
* 24h Holter ECG monitoring
* 24h Ambulatory blood pressure monitoring (ABPM)
Imaging assessments:
-Whole-Body CT scan (neck, thorax, abdomen, pelvis) with tumor measurements
Specific assessments:
* BM biopsy\* (local laboratory).
\*This can be omitted if already done within the past 3 months.
* BM aspirate for oLocal laboratory for Cytogenetic analysis and FISH for 17p oFILOthèque central laboratory, storage for future analysis: unsorted and CD19+ sorted cells for mutational profile.
* Blood MRD assessment on plasmatic cell-free tumor DNA (FILOthèque central laboratory).
Treatment period
Clinical assessment:
* Concomitant therapies and adverse events, severe adverse events and adverse events of special interest (AE, SAE and AESI)
* Complete physical examination, including evaluation of lymph nodes, liver and spleen
Cardiovascular assessments:
-Cardiovascular evaluation by investigator after 1, 3, 6, 9, 12, 15 and 18 cycles: o12-lead ECG and QTc calculation\* oblood pressure after a 5 minute rest, average of 3 measurements separated by ≥ 1 minute.
* The 12-lead ECG by investigator is not mandatory if already done or planned during the cardiology consultation within one month (at cycle 3, 6, 12, and 18)
-Cardiovascular evaluation by cardiologist after 3, 6, 12, and 18 cycles: ocardiology consultation o24h Holter ECG monitoring\* o24h ABPM\*\* oEchocardiography\*\*\*
* 24h Holter ECG will be repeated only at cycles 3, 6 and 18 (only risk patient)
* 24h ABMP will be repeated only at cycles 3, 12 and 18
* Echocardiography will be repeated at cycle 18.
Biological assessments (at day 1 +/- 7 days of each cycle):
* Standard hematology tests including CBC (hemoglobin, WBC count, absolute differential count, platelet count)
* Blood chemistry: including sodium, potassium, chloride, bicarbonate, fasting glucose, phosphate, BUN, creatinine, calcium, phosphate, magnesium, total, direct and indirect bilirubin, total protein, albumin, ALAT, ASAT, LDH, PAL, uric acid, CRP and pregnancy test.
During ramp up period: serum creatinine, sodium, potassium, chloride, bicarbonate, calcemia, phosphoremia, LDH is mandatory before initiation of any ramp up dose of BGB-11417, and 8 and 24 hours after drug intake.
* Troponin and NT-proBNP at cycles 1, 3, 6, 9, 12, 15 and 18
* Serum "M-protein" (monoclonal IgM) quantification based on protein electrophoresis or alternate methods (according to appendix 3) with additional immunofixation (to confirm CR)
* IgG, IgA and IgM levels
Imaging assessments:
-Whole-body CT scan (neck, thorax, abdomen, pelvis) every 24 weeks (6 cycles) i.e. after cycles 3, 6, 12 and 18 in all subjects who had measurable nodal/extranodal disease at screening.
Specific assessments:
-FILOthèque central laboratory: Blood on specific tube for MRD assessment on plasmatic cell-free tumor DNA (at cycles 3, 6, 12 and 18), storage.
Response evaluation:
Throughout the treatment period, especially before "end of treatment (EOT) + 3 months (EVAL 2 ) evaluation":
* if a CR is suspected (negative IF), an unscheduled CT scan should be done followed by biological evaluations including BM biopsy (local laboratory) to confirm CR
* If a VGPR is suspected (≥90% reduction in serum M-protein (monoclonal IgM) level from baseline (but still detectable) and decreased lymphadenopathy/ splenomegaly (if present at baseline), an unscheduled CT scan should be done to confirm VGPR.
Evaluation 1 (EVAL 1): 1 month after the end of treatment This evaluation takes place 1 month after EOT either after completion of cycle 20 or after the last cycle in case of early discontinuation. This evaluation may detect M-protein rebound with or without other features of early progression.
Clinical assessments:
* Concomitant therapies
* AE, SAE and AESI
* Complete physical examination including evaluation of lymph nodes, liver and spleen
Cardiovascular assessments:
-Cardiovascular evaluation by investigator: o12-lead ECG and QTc calculation oBlood pressure after a 5 minute rest, average of 3 measurements separated by ≥ 1 minute
Biological assessments:
* Standard hematology tests including CBC (hemoglobin, WBC count, absolute differential count, platelet count)
* Blood chemistry: sodium, potassium, chloride, bicarbonate, fasting glucose, phosphate, BUN, creatinine, calcium, phosphate, magnesium, total, direct and indirect bilirubin, total protein, albumin, ALAT, ASAT, LDH, PAL, uric acid, CRP, and pregnancy test.
* Serum "M-protein" (monoclonal IgM) quantification based on protein electrophoresis or alternate methods (according to appendix 3) with additional immunofixation (to confirm a CR)
* IgG, IgA and IgM levels
Evaluation 2 (=EVAL 2): 3 months after the end of treatment This evaluation takes place 3 months after EOT either after completion of cycle 20 or after the last cycle in case of early discontinuation. This evaluation may detect M-protein rebound with or without other features of early progression.
Clinical assessments:
* Concomitant therapies
* AE, SAE and AESI
* Complete physical examination, including evaluation of lymph nodes, liver and spleen
Cardiovascular assessments:
-Cardiovascular evaluation by investigator: o12-lead ECG and QTc calculation oBlood pressure after 5 minutes rest, average of 3 measurements separated by ≥ 1 minute
-Cardiovascular evaluation by a cardiologist: oCardiology consultation o24h Ambulatory blood pressure monitoring (ABPM) oEchocardiography
Biological assessments:
* Standard hematology tests including CBC (hemoglobin, WBC count, absolute differential count, platelet count)
* Blood chemistry: sodium, potassium, chloride, bicarbonate, fasting glucose, phosphate, BUN, creatinine, calcium, phosphate, magnesium, total, direct and indirect bilirubin, total protein, albumin, ALAT, ASAT, LDH, PAL, uric acid, CRP
* NT-proBNP
* Serum "M-protein" (monoclonal IgM) quantification based on protein electrophoresis or alternate methods (according to appendix 3) with additional immunofixation (to confirm a CR)
* IgG, IgA and IgM levels
Imaging and BM assessments:
* Whole body CT scan
* BM biopsy (local laboratory) if not performed during the treatment period for CR or progression.
* BM aspirate (FILOthèque central laboratory) for storage and analysis for molecular studies without CD19 sorting.
* Blood collected on specific tube (FILOthèque central laboratory) for assessment of plasmatic cell-free tumor DNA
Evaluation in case of suspected CR At any time throughout the study, especially before "EOT evaluation" when a CR is suspected based on a negative immunofixation, an additional evaluation should be realized in order to confirm the CR.
This additional evaluation includes primarily:
* Repeated screening for cryoglobulinemia, in patients known to have significant cryoglobulinemia at screening.
* CT scan
Then, if both immunofixation and CT scan are consistent with CR, a biological assessment should be scheduled with:
-BM biopsy (local laboratory)
Evaluation in case of suspected VGPR At any time throughout the study, especially before "EOT evaluation", when a VGPR is suspected based on ≥90% reduction in M-protein (monoclonal IgM) level from baseline (but still detectable) and decreased lymphadenopathy/splenomegaly (if present at baseline), an additional evaluation should be realized in order to confirm the VGPR.
This additional evaluation includes:
* Repeated screening for cryoglobulinemia, in patients known to have significant cryoglobulinemia at screening.
* CT scan: to confirm the reduction of deep-seated lymphadenopathy and splenomegaly (if present at baseline)
Evaluation in case of progression during treatment and follow-up period
* BM biopsy optional (local laboratory)
* BM aspirate, indicated according to study only in case of progression for :
* local laboratory: cytogenetics and FISH for 17p
* FILOthèque central laboratory: storage of unsorted and CD19+ sorted cells for molecular analyzes.
* Blood collected on specific tube for assessment of plasmatic cell-free tumor DNA (FILOthèque central laboratory).
Post-treatment follow-up period after EVAL 2 Two follow-up evaluations scheduled at 1 month (EVAL 1) and at 3 months (EVAL 2) have been already detailed above. Thereafter, all patients enrolled in the study will be followed until progression or death every 3 months the first year (FU6, FU9 and FU12), then every 6 months for a total follow up period of three years (FU18, FU24, FU30 and FU36).
Clinical assessments:
* Concomitant therapies
* AE, SAE and AESI
* Complete physical examination, evaluation of lymph nodes, liver and spleen.
Cardiovascular assessments:
* Cardiovascular evaluation by investigator o12-lead ECG and QTc calculation oblood pressure after 5 minutes rest, average of 3 measurements separated by ≥ 1 minute
* Cardiovascular evaluation by a cardiologist (only at FU36) ocardiology consultation o24h ABPM oEchocardiography
Biological assessments:
* Standard hematology tests including CBC (hemoglobin, WBC count, absolute differential count, platelet count).
* Blood chemistry: sodium, potassium, chloride, bicarbonate, fasting glucose, phosphate, BUN, creatinine, calcium, phosphate, magnesium, total, direct and indirect bilirubin, total protein, albumin, ALAT, ASAT, LDH, PAL, uric acid, CRP
* NT-proBNP (only FU36)
* Serum "M-protein" (monoclonal IgM) quantification based on protein electrophoresis or alternate methods (according to appendix 3) with additional immunofixation (to confirm a CR)
* IgG, IgA and IgM levels
Imaging and BM assessments:
* Whole body CT scan if clinically indicated, especially in case of progression.
* BM biopsy (local laboratory)
* BM aspirate, indicated according to study, only in case of progression
Premature end of treatment (PEOT) A visit will be performed 4 weeks (EVAL 1) and 3 months (EVAL 2) after the last treatment day for patients who discontinue treatment prematurely and for patients withdrawing their consent (if possible),
In case of PEOT for disease progression, patients will be evaluated
End of study (EOS) The end of study becomes effective after the end of the last study visit of the last patient enrolled once the FU36 visit has been achieved. The end of study visit corresponds to the last follow-up visit (FU36). For patients withdrawing consent during the follow up period, no end of study visit is required.
Observational study For all patients if they consent, the survival data will be collected every year for an observational study, in the e-CRF (Survival date and/or event date) until death, for OS analysis.
Study Oversight
Has Oversight DMC:
False
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?: