Neoplasms

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Lymphoma

Lymphoma, Follicular

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

Lymphosarcoma

Follicular Lymphoma

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Antibodies

Obinutuzumab

Immunoglobulins

Tyrosine Kinase Inhibitors

Ibrutinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Antineoplastic Agents, Immunological

Tyrosine

Initial therapy 6 cycles of Ibrutinib:

Ibrutinib 560 mg once daily every day until start of maintenance for a total of 24 weeks.

1000 mg of GA101 I.V. on days d 1, 8, 15 of cycle 1 and on day 1 of cycles 2-6 (21 day cycles).

Maintenance with another 24 months of ibrutinib plus GA101 in patients with clinical remission after the last induction cycle:

Ibrutinib 560 mg once daily every day. GA101 at a dose of 1000 mg I.V. every 2 months for a total of 24 months. The total duration of ibrutinib plus obinutuzumab therapy will therefore be 30 months.

In patients remaining MRD positive at 30 months without clinical progression, single agent ibrutinib therapy is continued for another 12 months.

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.

GA 101

Wolfgang Hiddemann, Prof.

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.

Combination of PCI-32765 With Obinutuzumab in Untreated Follicular Lymphoma

A Chemotherapy-free Combination of the Bruton's Tyrosine Kinase Inhibitor, Ibrutinib in Combination With GA 101 in Patients With Previously Untreated Follicular Lymphoma and a High Tumor Burden

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.

Progression free survival after start of therapy (continuous observation)

* three-year-PFS

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)

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)

Percentage of progression during induction and maintenance 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 to next anti-lymphoma therapy and time to next chemotherapy based treatment

Percentage of MRD negative patients during induction therapy (midterm), after induction therapy and after maintenance therapy

Duration of molecular remission for MRD negative patients after the end of induction and maintenance

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combination of PCI-32765 With Obinutuzumab in Untreated Follicular Lymphoma	NCT02689869	Indolent Non-Ho...	Ibrutinib GA 101	18 Years -	Ludwig-Maximilians - University of Munich
Combination of PCI-32765 With Obinutuzumab in Untreated Follicular Lymphoma	NCT02689869	Indolent Non-Ho...	Ibrutinib GA 101	18 Years -	Ludwig-Maximilians - University of Munich
Combination of PCI-32765 With Obinutuzumab in Untreated Follicular Lymphoma	NCT02689869	Indolent Non-Ho...	Ibrutinib GA 101	18 Years -	Ludwig-Maximilians - University of Munich

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