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

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.

Inclusion Criteria:

Histologically confirmed follicular lymphoma grade 1, 2 or 3A with a lymph node biopsy performed within 12 months before study entry and with material available for central review and complementary scientific analyses

• Ann Arbor stage III/IV, or stage II not suitable for radiotherapy, or stage II bulky disease

• Age ≥ 18 years

• No prior lymphoma therapy

• Need for start of therapy as defined by:

  • bulky disease at study entry according to the GELF criteria (nodal or extranodal mass >7 cm in its greater diameter)
  • and/or B symptoms (fever, drenching night sweats, or unintentional weight loss of >10% of normal body weight over a period of 6 months or less)
  • and/or hematopoietic insufficiency (granulocytopenia < 1.500/µl, Hb < 10 g/dl, thrombocytopenia < 100.000/µl)
  • compressive syndrome or high risk for compression syndrome
  • and/or pleural/peritoneal effusion
  • and/or symptomatic extranodal manifestations

• At least one bi-dimensionally measurable lesion (> 2 cm in its largest dimension by CT scan or MRI)

• Performance status ≤ 2 on the ECOG scale

• Adequate hematologic function (unless abnormalities are related to NHL), defined as follows:

  • Hemoglobin ≥ 9.0 g/dL
  • Absolute neutrophil count ≥ 1500 /µl
  • Platelet count ≥ 75000 /µl

• Women are not breast feeding, are using highly effective contraception, are not pregnant, and agree not to become pregnant during participation in the trial and during the 18 months thereafter (pregnancy testing is mandatory for premenopausal women).

• Men agree not to father a child during participation in the trial and during the 18 months thereafter.

• Written informed consent

Exclusion Criteria:

• - Transformation to high-grade lymphoma (secondary to "low grade" FL)

• Grade 3B follicular lymphoma

• Presence or history of CNS disease (either CNS lymphoma or leptomeningeal lymphoma).

• Known hypersensitivity to any of the study drugs

• Known sensitivity to murine products

• Regular use of corticosteroids during the last 4 weeks, unless administered at a dose equivalent to < 20 mg/day prednisone.

• Concomitant use of strong CYP3A4 inhibitors and / or oral anticoagulants (warfarin and/or phenprocoumon)

• Prior or concomitant malignancies except:

  • non-melanoma skin cancer or adequately treated in carcinoma in situ of the cervix
  • Other malignant diseases not specified above which have been curatively treated by surgery alone and from which subject is disease-free for ≥5 years without further treatment

• Serious disease interfering with a regular therapy according to the study protocol:

  • Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
  • pulmonary (e.g. chronic lung disease with hypoxemia)
  • endocrine (e.g. severe, not sufficiently controlled diabetes mellitus)
  • renal insufficiency (unless caused by the lymphoma): creatinine > 2x normal value and/or creatinine clearance < 50 ml/min)
  • impairment of liver function (unless caused by the lymphoma): transaminases > 3x normal or bilirubin > 2,0 mg/dl (unless caused by known Morbus Meulengracht [Gilbert-Meulengracht-Syndrome])

• Positive test results for chronic HBV infection (defined as positive HBsAg serology) Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing. Patients who have protective titers of hepatitis B surface antibody (HBsAb) after vaccination or prior but cured hepatitis B are eligible.

• Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing). Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.

• Known history of HIV seropositive status.

• Patients with a history of confirmed PML

• Vaccination with a live vaccine within 28 days prior to registration

• Recent major surgery (within 4 weeks prior to the start of Cycle 1)

• History of stroke or intracranial hemorrhage within 6 months prior to registration

• Serious underlying medical conditions, which could impair the ability of the patient to undergo the treatment offered in the study (e.g. ongoing infection, gastric ulcers, active autoimmune disease)

• Treatment within a clinical trial within 30 days prior to trial entry.

• Prior organ, bone marrow or peripheral blood stem cell transplantation

• Known or persistent abuse of medication, drugs or alcohol

• Any other co-existing medical or psychological condition that will preclude participation in the study or compromise ability to give informed consent.