Ibrutinib in Combination With GA101 (Obinutuzumab) in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients.

A Phase Ib/II Study of Ibrutinib in Combination With GA101 - Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia (CLL) Patients Over 65 Years of Age or With Comorbidities That Preclude the Use of Chemotherapy Based Treatment

The purpose of the study is to determine whether ibrutinib in combination with GA101 - Obinutuzumab might be useful for the treatment of CLL. This study will evaluate if ibrutinib in combination with GA101 - Obinutuzumab can reduce the amount of cancerous cells in body.

This is an open label phase IB/II clinical trial designed to determine the safety and clinical activity of Ibrutinib in combination with GA101 - Obinutuzumab. Safety, tolerability and dose-limiting toxicities (DLTs) will be evaluated during the initial cycle of treatment (Cycle 1; Day 1-28) as part of the phase Ib of this study (safety run-in).

In the phase II the response rate will be determined in all subjects that have received treatment. The study will enroll 32 subjects previously untreated who have active disease requiring treatment (as defined by IWCLL 2008 criteria for initiation of therapy). The study will include a Screening Phase, a Treatment Phase, and a Follow-up Phase. The Screening Phase assessments will be performed within 28 days prior to treatment. The Treatment Phase will extend from first dose until completion of all planned cycles of treatment (#6) or study drug discontinuation.

All subjects will receive Ibrutinib 420 mg (3 x 140-mg capsules) orally once daily for up to 6 cycles. The treatment with Ibrutinib will continue after cycle 6 for the following 3 years until disease progression, unacceptable toxicity or other reason for treatment discontinuation.

Subjects will undergo response assessment two months after completion of the study treatment. The initial follow-up evaluations will be made (after the response assessment) every 3 months during 9 months and later every 6 months until initiation of new treatment for CLL, consent withdrawal or death. During the long-term follow-up phase, subjects will be followed for survival (PFS, TFS and OS). The long-term follow-up phase will continue until disease progression, death, loss to follow up, consent withdrawal, or study end, whichever occurs first.

An evaluation of the End of Study will be performed due to initiation of new treatment for CLL or withdrawal of consent.

Inclusion Criteria:

1. Diagnosis of CLL

2. Indication for treatment as defined by the International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) Guidelines

3. No previous treatment for CLL

4. Males and females 65 years of age and older. Subjects under 65 years of age that meet any of the following criteria:

   A. Documented refusal to be treated with chemotherapy agents B. Subjects that are not candidates for treatment with chemotherapy based on poor performance status (ECOG g>= 2), Cumulative Illness Rating Scale (CIRS score) >= 6 or creatinine clearance less than 70 mL/min

5. Adequate hematologic, hepatic, and renal function

6. Anticipated survival of at least 6 months

7. Effective contraception is required while receiving Ibrutinib in combination with GA101-Obinutuzumab. For women of childbearing potential and men, effective contraception is required while receiving GA101-Obinutuzumab and for 365 days (12 months) after the last dose of the study drug

Exclusion Criteria:

1. Pregnant or nursing women
2. Treatment with chemotherapy, monoclonal antibodies, or biological agents (e.g. lenalidomide) other than the investigational agents during the time of participation in this trial
3. Grade 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
4. Severe or debilitating pulmonary disease
5. Participation in any investigational drug study within 28 days prior to initiation of treatment within this protocol.
6. History of second malignancy, other than non-melanoma skin cancer or in situ carcinoma of the cervix or the breast, unless the tumor was successfully treated at least 2 years before trial entry and with no evidence of relapse or active cancer.
7. Active symptomatic fungal, bacterial and/or viral infection including evidence of infection with HIV, human T-cell leukemia virus 1 (HTLV-1) seropositive status.
8. Evidence of active acute or chronic Hepatitis B (HBV)
9. Evidence of active Hepatitis C (HCV): subjects with positive hepatitis C serology and positive HCV RNA test
10. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
11. Known hypersensitivity to any of the study drugs
12. Major surgery (within 4 weeks prior to the start of Cycle 1), except for procedures that are performed for diagnostic purposes
13. Vaccination with a live vaccine within 28 days of the initiation of treatment.
14. Concomitant use of warfarin or other Vitamin K antagonists
15. Requirement to receive treatment with a strong cytochrome P450 (CYP) 3A inhibitor
16. Chronic liver disease with hepatic impairment (Child-Pugh class B or C)