Clinical Trials /

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

NCT02933320

Description:

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

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: BI-1206 and an Anti-CD20 Antibody in Patients With CD32b Positive B-cell Lymphoma or Leukaemia
  • Official Title: A Cancer Research UK Phase I/IIa Clinical Trial of BI-1206; an Antibody to FcƔRIIB (CD32b), as a Single Agent and in Combination With an Anti-CD20 Antibody in Patients With CD32b Positive B-cell Malignancy

Clinical Trial IDs

  • ORG STUDY ID: CRUKD16001
  • NCT ID: NCT02933320

Conditions

  • B-cell Lymphoma
  • Chronic Lymphocytic Leukaemia
  • Waldenström Macroglobulinaemia

Interventions

DrugSynonymsArms
BI-1206 single agent dose escalation phasePart A: BI-1206 single agent dose escalation phase
BI-1206 single agent expansion phasePart B: Arm 1: BI-1206 single agent expansion phase
Combination of BI-1206 with RituximabPart B: Arm 2: combination of BI-1206 with Rituximab

Purpose

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

Detailed Description

      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 will be entered into this study. This will include approximately 19 recruited for
      the BI-1206 dose escalation phase (Part A), up to 12 (likely 6) for a combination dose
      escalation and up to a further 50 patients recruited to two dose expansion cohorts; one of
      BI-1206 alone and one of BI-1206 plus rituximab (Part B). The final number will depend on the
      number of dose escalations required to reach the MTD.
    

Trial Arms

NameTypeDescriptionInterventions
Part A: BI-1206 single agent dose escalation phaseExperimentalBI-1206 given by IV infusion to all patients once weekly for a period of four weeks, patients will then have a follow-up period of four weeks (8 week period classified as induction therapy)
  • BI-1206 single agent dose escalation phase
Part B: Arm 1: BI-1206 single agent expansion phaseExperimentalArm 1 will be an expansion cohort of up to 25 patients treated with single agent BI-1206 at the RP2D as determined in Part A. This expansion will include a minimum of 12 chronic lymphocytic leukaemia (CLL) and six mantle cell lymphoma (MCL) patients
  • BI-1206 single agent expansion phase
Part B: Arm 2: combination of BI-1206 with RituximabExperimentalArm 2 will be an investigation of combination treatment of BI-1206 with Rituximab. Arm 2 will involve an initial assessment of the appropriate dose of BI-1206 that can be given in combination with rituximab (combination dose escalation cohorts) and subsequent expansion of up to 25 patients at the identified recommended combination dose. This expansion will include a minimum of 12 CLL and six mantle cell MCL patients. CLL patients recruited to the expansion will receive one rituximab infusion, one week before commencing the four weeks of combination induction therapy.
  • Combination of BI-1206 with Rituximab

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 chronic lymphocytic leukaemia 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 (Day -14 to Day -7 for CLL patients recruited
             to the combination expansion, Day-7 to Day 1 for all other patients).

             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 3xULN 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.

          9. Patients recruited to Part B, Arm 2 (combination arm) only: CD20 positive malignancy
             as demonstrated by immunohistochemistry or flow cytometry prior to study entry.
             Analysis must have been performed within 6 months of study 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. Patients with transformed lymphoma from a pre-existing indolent lymphoma. Patients
             with a previous history of transformation, but on this disease episode have a biopsy
             proven indolent recurrence may be included. Patients with proven or suspected Richter
             transformation are not eligible.

          4. 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).

          5. Known or suspected hypersensitivity to study drugs.

          6. Cardiac or renal amyloid light-chain (AL) amyloidosis.

          7. Radiotherapy, endocrine therapy, immunotherapy, chemotherapy or investigational
             medicinal products during the previous 4 weeks before treatment.

          8. 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 Centre
             for Drug Development (CDD) should not exclude the patient.

          9. 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.

         10. 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.

         11. Major thoracic or abdominal surgery from which the patient has not yet recovered.

         12. At high medical risk because of non-malignant systemic disease including infection.

         13. Known to be serologically positive for Hepatitis B, Hepatitis C or Human
             Immunodeficiency Virus (HIV).

         14. 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.

         15. 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.

         16. Patients for whom rituximab is contraindicated due to severe previous hypersensitivity
             or any other reason (Part B combination arm only).

         17. Active, ongoing infection.

         18. Any other condition which in the Investigator's opinion would not make the patient a
             good candidate for the clinical trial.

         19. 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.

         20. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Documenting Adverse Events (AEs), Serious Adverse Events (SAEs) (graded according to NCI-CTCAE Version 4.02) and laboratory parameters and determining their causality in relation to BI-1206.
Time Frame:53 months
Safety Issue:
Description:To recommend a dose for future trials with BI-1206 by finding the highest safe dose which can be given to patients.

Secondary Outcome Measures

Measure:Measurement of PK parameter values for BI-1206 including AUC using ELISA
Time Frame:Samples taken during treatment and analysed in batches per cohort within 6 months of sampling
Safety Issue:
Description:
Measure:Measurement of PK parameter values for BI-1206 including Cmax using ELISA
Time Frame:Samples taken during treatment and analysed in batches per cohort within 6 months of sampling
Safety Issue:
Description:
Measure:Measurement of PK parameter values for BI-1206 including Tmax using ELISA
Time Frame:Samples taken during treatment and analysed in batches per cohort within 6 months of sampling
Safety Issue:
Description:
Measure:Measurement of PK parameter values for BI-1206 including half life T1/2 using ELISA
Time Frame:Samples taken during treatment and analysed in batches per cohort within 6 months of sampling
Safety Issue:
Description:
Measure:Measurement of anti-drug antibody (ADA) response to BI-1206 during the BI-1206 treatment period using ELISA
Time Frame:64 months
Safety Issue:
Description:To assess immunogenicity of BI-1206 alone and in combination in patients with relapsed or refractory B-cell malignancies
Measure:Measurement of peripheral blood B-lymphocyte depletion during the BI-1206 treatment period using flow cytometry.
Time Frame:Samples taken during the first 8 weeks of treatment and reported in batches per cohort within 6 months of sampling
Safety Issue:
Description:To evaluate the effect of BI-1206 alone and in combination on the depletion of peripheral blood B-cells
Measure:Assessment of best disease response according to criteria for malignant lymphoma (Cheson, 2014) Waldenström macroglobulinaemia assessment criteria (Owen 2013, Kimby 2006) or NCI chronic lymphocytic leukaemia (CLL) criteria (Hallek, 2008).
Time Frame:64 months
Safety Issue:
Description:To look for signs of anti-tumour activity of BI-1206 alone and in combination in patients with relapsed or refractory B-cell malignancies
Measure:Measure progression free survival at 1 year after the first BI-1206 administration on the study for all patients
Time Frame:12 months
Safety Issue:
Description:To measure the time to disease progression and twelve month survival
Measure:Measure overall survival at 1 year after the first BI-1206 administration on the study for all patients
Time Frame:12 months
Safety Issue:
Description:To measure the time to disease progression and twelve month survival

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Cancer Research UK

Trial Keywords

  • Indolent B-cell Lymphoma
  • Chronic Lymphocytic Leukaemia
  • Waldenström Macroglobulinaemia
  • BI-1206
  • CD32b

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