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

The purpose of this trial is to identify the tolerable dose of BI-1206 (both alone and in combination) for patients with B-cell lymphoma and leukaemia and further evaluate BI-1206 alone and in combination with an anti-CD20 antibody.

The molecule CD32b is thought to be present on many B-cells including the malignant B-cells in some types of lymphoma and leukaemia. The study drug, BI-1206, is an anti-CD32b monoclonal antibody which attaches to CD32b on the surface of B-cells and is thought to act by recruiting host immune cells toward the tumour leading to cancer cell death as well as enhancing the anti-cancer effect of other anti-CD20 antibodies such as rituximab by stopping them being absorbed by cells.

The study is a first in man clinical trial of the drug called BI-1206 on its own and then also in combination with an anti-CD20 antibody (such as rituximab) which is commonly used to treat lymphoma and some types of leukaemia.

The four main aims of this trial are to find out:

* The maximum dose of BI-1206 that can be given safely to patients (to a maximum dose of 800mg) on it's own and in combination with an anti-CD20 antibody, rituximab.
* More about the potential side effects of BI-1206 and how they can be managed.
* What happens to BI-1206 inside the body.
* The effect of BI-1206 treatment (with or without rituximab) on tumour size and survival.

Approximately 81 patients with relapsed or refractory CD32b positive B-cell lymphoma or leukaemia were planned for the trial. Approximately 34 patients to establish the maximum tolerated doses (MTDs) in Part A and a further 40 to 50 patients recruited to two expansion cohorts; one of BI-1206 alone and one of BI-1206 plus rituximab (Part B). The final number depending on the number of dose escalations required to reach the MTD.

Eligibility Criteria:
Inclusion Criteria:

1. Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up.
2. B-cell lymphoma or CLL proven by histology or flow cytometry, relapsed or refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient. Patients should have received at least one line of conventional previous therapy which must have included a rituximab based regimen.
3. CD32b positive malignancy as demonstrated centrally by immunohistochemistry or flow cytometry prior to study entry. Available tissue or blood must have been taken within six 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. These measurements must be performed within one week before their first dose of mAb (BI-1206 and/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 at screening

   Platelet count ≥50 x 10\^9/L (or ≥30 x 10\^9/L if due to malignant involvement of bone marrow)

   Either:

   Serum bilirubin ≤1.5 x upper limit of normal (ULN) unless raised due to Gilbert's syndrome in which case up to 3 x ULN is permissible.

   Or:

   Alanine amino-transferase (ALT) and /or aspartate amino-transferase (AST) ≤ 2.5 x ULN unless raised due to malignant hepatic involvement in which case up to 5 x ULN is permissible

   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's macroglobulinemia, disease must be assessable by the criteria stated in Appendix 6 of the protocol.
9. Patients recruited to Arm 2 in Parts A and B (combination arms) only: CD20 positive malignancy as demonstrated by immunohistochemistry or flow cytometry prior to trial entry.

Exclusion Criteria:

1. Allogenic bone marrow transplant within 12 months prior to the first dose of BI-1206 or presence of chronic graft versus host disease.
2. Patients with clinically active leptomeningeal or central nervous system lymphoma/leukaemia.
3. Doses of prednisolone \>10 mg daily (or equipotent doses of other corticosteroids) are not permitted whilst on the study other than as pre-medication. During the screening period, doses of up to 20 mg per day may be given but the dose must be reduced to 10 mg/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 investigational medicinal products during the previous 4 weeks before treatment.
7. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator and the Sponsor should not exclude the patient.
8. Ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two forms of contraception (one highly effective form plus a barrier method) \[oral, injected or implanted hormonal contraception and condom; intra-uterine device and condom; diaphragm with spermicidal gel and condom\] or agree to sexual abstinence\^4 for four weeks before entering the trial, during the trial and for twelve months after completing treatment are considered eligible.
9. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using a barrier method of contraception \[condom plus spermicide\] or to sexual abstinence effective from the first administration of BI-1206 or rituximab on the study, throughout the trial and for twelve months afterwards. Men with partners of child-bearing potential must also be willing to ensure that their partner uses an effective method of contraception for the same duration for example, hormonal contraception, intrauterine device, diaphragm with spermicidal gel or sexual abstinence4). Men with pregnant or lactating partners should be advised to use barrier method contraception (e.g. condom plus spermicidal gel) to prevent 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 Human Immunodeficiency Virus (HIV).
13. Patients with an active, known or suspected autoimmune disease (not including CLL auto-immune disease). Patients with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence 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 prior history of cardiac arrhythmia.
15. Patients for whom rituximab is contraindicated due to severe previous hypersensitivity or 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 excluded patients.
17. Any other condition which in the Investigator's opinion would not make the patient a good 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 an observational study would be acceptable.
19. Current malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for three years or more and are deemed at negligible risk for recurrence, are eligible for the trial.