Primary Objectives The primary objective of this study is to evaluate the efficacy of the chemotherapy-free combination of ibrutinib and obinutuzumab (GA 101) in patients with previously untreated follicular lymphoma (FL) and a high tumor burden. Primary endpoint to be observed for this is the rate of progression free survival one year after start of therapy. Hypothesis The hypothesis of the study is that ibrutinib in combination with obinutuzumab will achieve response rates (CR and PR), rates of MRD negativity and PFS which are comparable to currently used standard rituximab-chemotherapy combinations such as R-CHOP or R-bendamustine in subjects with previously untreated FL and a high tumor burden.
OVERVIEW OF STUDY DESIGN This is a prospective, multicenter phase 2 study in up to 98 subjects with previously untreated FL and a high tumor burden in advanced stages and in need of therapy. The study will include a central monitoring of MRD by PCR, a central pathologic review and complimentary research projects including monitoring of immune response. The study therapy comprises an initial 6 cycles of ibrutinib plus obinutuzumab followed by an additional 24 months of ibrutinib plus obinutuzumab maintenance. In patients being MRD negative at 30 months, i.e. at the end of ibrutinib plus obinutuzumab maintenance, and without clinical progression no further treatment is given while MRD monitoring is continued. MRD monitoring will be regularly performed on peripheral blood samples collected before the start of therapy and at months 3, 6, 9, 12, 18, 24 and 30 respectively. Subsequently, MRD analyses will be performed every 6 months until clinical progression of the disease or for a maximum of 4 years (until the end of the study). If MRD assessment on peripheral blood samples turns from positive to negative within the first 30 months, confirmatory blood and bone marrow samples should be taken 6 months thereafter. In patients remaining MRD positive at 30 months without clinical progression, single agent ibrutinib therapy is continued for another 12 months. An independent Data Monitoring Committee (DMC) will be formed and constituted. The independent DMC will review the safety of the treatment and make recommendations as to the further conduct of the study. The data generated by this phase II study should serve as the basis for a subsequent randomized phase III study comparing the chemotherapy-free combination of ibrutinib plus obinutuzumab with standard immune-chemotherapy.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
98
Ibrutinib (PCI-32765; JNJ-54179060) is a first-in-class, potent, orally-administered covalently-binding small molecule inhibitor of Bruton's tyrosine kinase currently being co-developed by Janssen Research \& Development, LLC and Pharmacyclics, Inc for the treatment of B-cell malignancies.
Obinutuzumab (GA 101) is a first-in-class, potent, intravenously administered type II anti-CD 20 antibody that is developed by Roche AG for the treatment of B-cell malignancies.
Klinikum der Universität München
München, Bavaria, Germany
Progression free survival
The rate of patients archiving a progression free survival of more than one year after registration (one-year PFS) will serve as early readout for efficacy and will be the primary endpoint of this trial.
Time frame: one year progress free survival
three-year-PFS
Progression free survival after start of therapy (continuous observation) * three-year-PFS
Time frame: three years after start of therapy
CR
CR rates at end of induction CR rates one year after start of therapy CR rates after end of maintenance therapy (at 30 months after start of therapy: CR30)
Time frame: one year after start of therapy and at 30 months after end of maintenance
PR
PR rates at end of induction PR rates one year after start of therapy PR rates after end of maintenance therapy (at 30 months after start of therapy: CR30)
Time frame: one year after start of therapy and at 30 months after end of maintenance
SD
SD rates at end of induction
Time frame: one year after start of therapy and at 30 months after end of maintenance
Duration of response
Duration of Response
Time frame: 4,5 up to 6,5 years through study completion
Percentage of Progression
Percentage of progression during induction and maintenance therapy
Time frame: 4,5 up to 6,5 years through study completion
TTF after start of therapy
Time to treatment failure after start of therapy (failure defined by failure to achieve a CR/PR after 6 months or progression after CR or PR or death in remission)
Time frame: 4,5 up to 6,5 years through study completion
Time to next anti-lymphoma therapy / time to next chemotherapy based treatment
Time to next anti-lymphoma therapy and time to next chemotherapy based treatment
Time frame: 4,5 up to 6,5 years through study completion
Treatment associated adverse events
Treatment associated adverse events
Time frame: 4,5 up to 6,5 years through study completion
Percentage of MRD negative patients during therapy
Percentage of MRD negative patients during induction therapy (midterm), after induction therapy and after maintenance therapy
Time frame: 4,5 up to 6,5 years through study completion
Duration of molecular remission
Duration of molecular remission for MRD negative patients after the end of induction and maintenance
Time frame: 4,5 up to 6,5 years through study completion
Percentage of secondary transformation
Percentage of secondary Transformation to aggressive lymphoma
Time frame: 4,5 up to 6,5 years through study completion
Percentage of secondary malignancies
Percentage of secondary malignancies
Time frame: 4,5 up to 6,5 years through study completion
Time to first secondary malignancy
Time to first secondary malignancy
Time frame: 4,5 up to 6,5 years through study completion
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