Ofatumumab & Ibrutinib + Allogeneic Bone Marrow Transplant or Consolidation in High Risk Chronic Lymphocytic Leukemia

A Phase II Study of the Combination of Ofatumumab and Ibrutinib Followed by Allogeneic Bone Marrow Transplant or Consolidation for Pretreated High Risk Patients With Chronic Lymphocytic Leukemia

A clinical study to evaluate a treatment with two drugs, named Ofatumumab and Ibrutinib, in patients with lymphoblastic acute leukemia who have been already treated with other therapies.

This is a phase II multicenter, non-comparative, open label study for high risk previously treated patients with CLL, requiring therapy, aimed at evaluating the efficacy of the Ofatumumab and Ibrutinib combination.

Inclusion Criteria:

1. Male or female, age 18 years or until 65 years;

2. Confirmation of B-CLL previously treated with no more than 1 previous line of treatment .

3. Risk patients with CLL defined as follows:

   • treated patients showing 17p deletion in >20% of the cells by FISH, or TP53 mutation or,
   • resistant (SD/PD) to fludarabine containing combination therapy or relapse within 12 months from a fludarabine-containing combination therapy.

4. Active disease meeting at least 1 of the following IWCLL criteria for requiring treatment:

   • Evidence of progressive marrow failure as manifested by the development of, or worsening of anemia (Hb< 10 g/dL) and/or thrombocytopenia (platelets < 100,000/mL).
   • Massive (≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
   • Massive nodes (at least 10 cm longest diameter), or progressive or symptomatic lymphadenopathy.
   • Progressive lymphocytosis with an increase of more than 50% over a 2-month period or a lymphocyte doubling time (LDT) of < 6 months.
   • Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy.
   • One or more disease-related symptoms:
   • unintentional weight loss > 10% within 6 months prior to screening;
   • significant fatigue (inability to work or perform usual activities);
   • fevers >38.0°C for 2 or more weeks prior to screening;
   • night sweats for more than 1 month prior to screening.

5. Stage B or C of CLL according to Binet staging system;

6. Stage A disease fitting the criteria for treatment according to the IWCLL-NCI criteria (2008) are also included.

7. WHO performance status 0-II.

8. Life expectancy ≥ 6 months.

9. Hematology values must be within the following limits:

   • Absolute neutrophil count (ANC) ≥ 750/mm3 independent of growth factor support;
   • Platelets ≥100,000/mm3 or ≥ 30.000/mm3 if bone marrow involvement independent of transfusion support in either situation.

10. Biochemical values within the following limits:

    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN).
    • Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin.
    • Serum creatinine ≤ 2 x ULN or estimated Glomerular Filtration Rate (Cockroft Gault) ≥ 30 mL/min/1.73m2.

11. Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study For females, these restrictions apply for 1 month after the last dose of ibrutinib and for 12 months after the last dose of Ofatumumab. For males, these restrictions apply for 3 months after the last dose of ibrutinib. Men must agree to not donate sperm during and after the study.

12. Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [β-hCG]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.

13. Sign an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.

Exclusion Criteria:

1. Major surgery within 3 weeks before registration.

2. Known central nervous system lymphoma.

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

4. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon).

5. 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.

6. Vaccinated with live, attenuated vaccines within 4 weeks of registration.

7. Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics.

8. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.

9. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HBDNA test will be performed and if positive the subject will be excluded. ***see attached monitoring criteria for HBcAb+ and HBV DNA negative subjects.

10. Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.

11. Requirement for treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor.

12. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient.

13. Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption.

14. Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis.

15. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.

16. Central nervous system involvement with CLL.

17. Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).

18. Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study.

19. Prior treatment with anti-CD20 monoclonal antibody or alemtuzumab within 3 months prior to the start of therapy.

20. History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae.

    • If HBV DNA is negative, subject may be included but must undergo at least every 2 month HBV DNA PCR testing from the start of treatment during the treatment course. Prophylactic antiviral therapy may be initiated at the discretion of the investigator.