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
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
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
Cycles 3-20 with zanubrutinib plus BGB-11417 full dose
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:
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
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
Biological assessments
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*:
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:
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
Biological assessments (at day 1 +/- 7 days of each cycle):
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.
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":
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:
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:
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:
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:
Imaging and BM assessments:
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:
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:
Evaluation in case of progression during treatment and follow-up period
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:
Cardiovascular assessments:
Biological assessments:
Imaging and BM assessments:
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.
Inclusion Criteria:
Be ≥ 18-year-old.
Have received at least 1 prior line of treatment (excluding treatment with any BTKi or Bcl-2 antagonist, see non-inclusion criteria).
Provide written informed consent.
Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3.
Have adequate renal function defined as creatinine clearance ≥ 50 mL/min as determined by the Cockroft-Gault equation.
Have adequate hepatic function defined as:
Have adequate BM function defined as:
For women of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
Agree to use a highly effective form of contraception with sexual partners throughout study participation (for female and male patients who are fertile). Patients using hormonal contraceptives (eg, birth control pills or devices) must use a barrier method of contraception (eg, condoms) as well.
Ability to comply with study procedures, in the Investigator's opinion.
Patient covered by any social security system
Exclusion Criteria:
Have previously been treated with a BTK inhibitor.
Have been previously treated with a bcl-2 antagonist.
Have active central nervous system (CNS) disease as evidenced by cytology or pathology. In the absence of clinical signs of CNS disease, a lumbar puncture is not mandatory.
Have significant or active cardiovascular disease:
Have a history of stroke or intracranial hemorrhage within 6 months before first dose of study drug, have a history of a severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention:
Have received live vaccine within 4 weeks of inclusion.
Receive other concomitant investigational therapy.
Have a history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, or hepatic condition that, in the opinion of the Investigator, would adversely affect a subject's participation in the study.
Have currently active, clinically significant Child-Pugh Class B or C hepatic impairment.
Present an inability or difficulty swallowing capsules/tablets, malabsorption syndrome, or any disease or medical condition significantly affecting gastrointestinal function.
Have a known allergy to either xanthine oxidase inhibitors or rasburicase or zanubrutinib (patients at risk for G6PD deficiency may be screened before enrolment).
Are pregnant or lactating. Women of childbearing potential must agree to use highly effective contraception from the time of signing informed consent until end-of-treatment visit,
≥90 days after last dose of BGB-11417-101 and Zanubrutinib. Male patients must be abstinent, vasectomized, or agree to the use of barrier contraception in combination with other methods.
Have a history of other active malignancies requiring treatment within 3 years of study entry, with exception of (1) localized basal cell or squamous cell carcinoma of the skin, (2), adequately treated in situ endometrial carcinoma, (3) incidental histology finding of prostate carcinoma, (4) previous malignancy confined and treated locally (surgery or other modality) with curative intent.
Be known to be positive for HIV.
Present evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
Suffer from any condition or illness that, in the opinion of the Investigator or medical monitor, would compromise patient safety or interfere with the evaluation of the safety of the study drugs.
Have received or consumed any of the following within 3 days prior to the first dose of study drugs:
Have received a treatment with any of the following prior to the first dose of study drugs:
Severe or debilitating pulmonary disease.
Major surgery within 4 weeks of the first dose of study drug.
Active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (eg, idiopathic thrombocytopenia purpura).
Ongoing alcohol or drug addiction or any psychiatric condition(s) which would compromise ability to comply with study procedures.
a.lhermitte@filo-leucemie.org+33787888464
v.rouille@filo-leucemie.org+33247473798