BI-1206 and an Anti-CD20 Antibody in Patients With CD32b Positive B-cell Lymphoma or Leukaemia

Inclusion Criteria:

1. Written (signed and dated) informed consent and be capable of co-operating withtreatment and follow-up.
2. B-cell lymphoma or CLL proven by histology or flow cytometry, relapsed or refractoryto conventional treatment, or for which no conventional therapy exists or is declinedby the patient. Patients should have received at least one line of conventionalprevious therapy which must have included a rituximab based regimen.
3. CD32b positive malignancy as demonstrated centrally by immunohistochemistry or flowcytometry prior to study entry. Available tissue or blood must have been taken withinsix months of study entry.
4. Life expectancy of at least 12 weeks.
5. World Health Organisation (WHO) performance status of 0-2 (Appendix 1).
6. Haematological and biochemical indices within the ranges shown below. Thesemeasurements must be performed within one week before their first dose of mAb (BI-1206and/or rituximab) as part of this study. Laboratory Test Value required Haemoglobin (Hb) ≥9.0 g/dL (red cell support is permissible) Absolute neutrophil count (ANC) ≥1.0 x 10^9/L (or >0.5 x 10^9/L if due to lymphoma),granulocyte - colony stimulating factor (G-CSF) support is not permissible atscreening Platelet count ≥50 x 10^9/L (or ≥30 x 10^9/L if due to malignant involvement of bonemarrow) Either: Serum bilirubin ≤1.5 x upper limit of normal (ULN) unless raised due to Gilbert'ssyndrome in which case up to 3 x ULN is permissible. Or: Alanine amino-transferase (ALT) and /or aspartate amino-transferase (AST) ≤ 2.5 x ULNunless raised due to malignant hepatic involvement in which case up to 5 x ULN ispermissible Either: Calculated creatinine clearance (Cockcroft Gault) ≥30 mL/min (uncorrected value) Or: Isotope clearance measurement ≥30 mL/min (corrected)
7. 18 years or over.
8. B-cell lymphoma patients only: patients has at least one measurable lesion by CT scan (defined as greater than 1.5 cm in one axis) or in the case of Waldenström'smacroglobulinemia, disease must be assessable by the criteria stated in Appendix 6 ofthe protocol.
9. Patients recruited to Arm 2 in Parts A and B (combination arms) only: CD20 positivemalignancy as demonstrated by immunohistochemistry or flow cytometry prior to trialentry.

Exclusion Criteria:

1. Allogenic bone marrow transplant within 12 months prior to the first dose of BI-1206or presence of chronic graft versus host disease.
2. Patients with clinically active leptomeningeal or central nervous systemlymphoma/leukaemia.
3. Doses of prednisolone >10 mg daily (or equipotent doses of other corticosteroids) arenot permitted whilst on the study other than as pre-medication. During the screeningperiod, doses of up to 20 mg per day may be given but the dose must be reduced to 10mg/day by Cycle 1 Day 1 (or Day -7 in the CLL combination expansion).
4. Known or suspected hypersensitivity to study drugs.
5. Cardiac or renal amyloid light-chain (AL) amyloidosis.
6. Radiotherapy, endocrine therapy, immunotherapy, chemotherapy or investigationalmedicinal products during the previous 4 weeks before treatment.
7. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopeciaor certain Grade 1 toxicities, which in the opinion of the Investigator and theSponsor should not exclude the patient.
8. Ability to become pregnant (or already pregnant or lactating). However, those femalepatients who have a negative serum or urine pregnancy test before enrolment and agreeto use two forms of contraception (one highly effective form plus a barrier method) [oral, injected or implanted hormonal contraception and condom; intra-uterine deviceand condom; diaphragm with spermicidal gel and condom] or agree to sexual abstinence^4for four weeks before entering the trial, during the trial and for twelve months aftercompleting treatment are considered eligible.
9. Male patients with partners of child-bearing potential (unless they agree to takemeasures not to father children by using a barrier method of contraception [condomplus spermicide] or to sexual abstinence effective from the first administration ofBI-1206 or rituximab on the study, throughout the trial and for twelve monthsafterwards. Men with partners of child-bearing potential must also be willing toensure that their partner uses an effective method of contraception for the sameduration for example, hormonal contraception, intrauterine device, diaphragm withspermicidal gel or sexual abstinence4). Men with pregnant or lactating partners shouldbe advised to use barrier method contraception (e.g. condom plus spermicidal gel) toprevent exposure to the foetus or neonate.
10. Major thoracic or abdominal surgery from which the patient has not yet recovered.
11. At high medical risk because of non-malignant systemic disease including infection.
12. Known to be serologically positive for Hepatitis B, Hepatitis C or HumanImmunodeficiency Virus (HIV).
13. Patients with an active, known or suspected autoimmune disease (not including CLLauto-immune disease). Patients with Type I diabetes mellitus, hypothyroidism onlyrequiring hormone replacement, skin disorders (such as vitiligo, psoriasis, oralopecia) not requiring systemic treatment, or conditions not expected to recur in theabsence of an external trigger will be permitted to participate.
14. Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA]), prior history of cardiac ischaemia or priorhistory of cardiac arrhythmia.
15. Patients for whom rituximab is contraindicated due to severe previous hypersensitivityor any other reason (Arm 2 in Parts A and B [combination arms] only).
16. Ongoing infection requiring treatment with antibiotics, antifungals or antivirals.Prophylactic use of antibiotics, antifungals or antivirals would not have excludedpatients.
17. Any other condition which in the Investigator's opinion would not make the patient agood candidate for the clinical trial.
18. Is a participant or plans to participate in another interventional clinical study,whilst taking part in this Phase I/IIa study of BI-1206. Participation in anobservational study would be acceptable.
19. Current malignancies of other types, with the exception of adequately treatedcone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cellcarcinoma of the skin. Cancer survivors, who have undergone potentially curativetherapy for a prior malignancy, have no evidence of that disease for three years ormore and are deemed at negligible risk for recurrence, are eligible for the trial.