Clinical Trials /

A Phase I Trial of DI-B4 in Patients With Advanced CD19 Positive Indolent B-cell Malignancies

NCT01805375

Description:

The main aims of this clinical study are to find out the maximum dose that can be given safely to patients, the potential side effects of the drug and how they can be managed. The study will also look at what happens to Anti-CD19 (DI-B4) inside the body. DI-B4 is a type of drug called an Anti-CD19 monoclonal antibody which is being used to stop the growth and kill cancerous immune cells by targeting the B-cell marker (CD-19) expressed on their surface. This drug has not been given to patients before. DI-B4 will be given weekly by intravenous infusion for four weeks. The study is in two parts. In Part 1, small groups of patients will be treated at increasing doses to find the highest safest dose and best dose for part 2 of the study. Approximately 16-20 patients will be treated in this part. In Part 2, the dose identified in Part 1 will be given to approximately 20 patients. Patients recruited to the study will receive four weeks (cycles) of treatment. They will attend an end of therapy visit eight weeks after their last dose of DI-B4, and attend follow-up visits up to eighteen months after their first dose of DI-B4. Information on the overall and progression free survival will be collected for a period up to eighteen months after the final patient is treated on the study. Patients will have blood and urine samples taken each week during treatment amongst other clinical tests. CT scans will be performed at the start of the study, at eight weeks post treatment and six months after the study start. Bone marrow biopsies and FDG-PET scans will only be taken if needed. Research blood samples will also be taken to look at what happens to the drug inside the body. It is important to explain that patients will have advanced cancer so it is unlikely that patients will benefit directly from taking part but the study may help improve future treatment of cancer.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Mature B-Cell Lymphoma/Leukemia
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

A Phase I Trial of <span class="go-doc-concept go-doc-intervention">DI-B4</span> in Patients With Advanced CD19 Positive Indolent B-cell Malignancies

Title

  • Brief Title: A Phase I Trial of DI-B4 in Patients With Advanced CD19 Positive Indolent B-cell Malignancies
  • Official Title: A Cancer Research UK Phase I Trial of the Anti-CD19 DI-B4 Monoclonal Antibody Given Intravenously, Weekly for Four Weeks, in Patients With Advanced CD19 Positive Indolent B-cell Malignancies
  • Clinical Trial IDs

    NCT ID: NCT01805375

    ORG ID: CRUKD/12/003

    Trial Conditions

    Indolent B-cell Lymphoma

    Chronic Lymphocytic Leukaemia

    Waldenstrm Macroglobulinaemia

    Trial Interventions

    Drug Synonyms Arms
    DI-B4

    Trial Purpose

    The main aims of this clinical study are to find out the maximum dose that can be given
    safely to patients, the potential side effects of the drug and how they can be managed. The
    study will also look at what happens to Anti-CD19 (DI-B4) inside the body.

    DI-B4 is a type of drug called an Anti-CD19 monoclonal antibody which is being used to stop
    the growth and kill cancerous immune cells by targeting the B-cell marker (CD-19) expressed
    on their surface. This drug has not been given to patients before.

    DI-B4 will be given weekly by intravenous infusion for four weeks. The study is in two
    parts. In Part 1, small groups of patients will be treated at increasing doses to find the
    highest safest dose and best dose for part 2 of the study. Approximately 16-20 patients will
    be treated in this part. In Part 2, the dose identified in Part 1 will be given to
    approximately 20 patients.

    Patients recruited to the study will receive four weeks (cycles) of treatment. They will
    attend an end of therapy visit eight weeks after their last dose of DI-B4, and attend
    follow-up visits up to eighteen months after their first dose of DI-B4. Information on the
    overall and progression free survival will be collected for a period up to eighteen months
    after the final patient is treated on the study.

    Patients will have blood and urine samples taken each week during treatment amongst other
    clinical tests. CT scans will be performed at the start of the study, at eight weeks post
    treatment and six months after the study start. Bone marrow biopsies and FDG-PET scans will
    only be taken if needed. Research blood samples will also be taken to look at what happens
    to the drug inside the body.

    It is important to explain that patients will have advanced cancer so it is unlikely that
    patients will benefit directly from taking part but the study may help improve future
    treatment of cancer.

    Detailed Description

    Patients with relapsed or refractory CD19 positive indolent B-cell lymphoma, Waldenstrm
    Macroglobulinaemia or chronic lymphocytic leukaemia will be entered into this study.

    For the vast majority of patients, B-cell non Hodgkin lymphoma and chronic lymphocytic
    leukaemia are incurable using existing therapeutic approaches.

    Although anti-CD20 directed therapy has improved outcomes, more than fifty percent of
    patients still relapse following treatment or are refractory to it and therefore additional
    novel non-cross resistant therapies are urgently required.

    DI-B4 is a humanised, low-fucosylated anti-CD19 Immunoglobulin (Ig) G1 monoclonal antibody
    with potent antibody-dependent cell-mediated cytotoxicity (ADCC) but minimal complement
    dependent cytotoxicity (CDC). The target antigen, CD19, is the canonical B-cell marker that
    is expressed on all B-cells including the malignant B-cells in NHL, CLL and acute
    lymphoblastic leukaemia (ALL). The CD19 antigen is therefore an attractive B-cell lineage
    specific target for monoclonal antibody therapy. DI-B4 is expected to act through the
    depletion of normal and malignant CD19 positive cells, primarily via ADCC.

    This is a multi-centre, Phase I, dose escalation/dose expansion study. For the first three
    cohorts, an intra-patient dose escalation scheme will be followed unless a DLT is observed.
    From Cohort 4 onwards, a standard 3 + 3 dose escalation schedule of DI-B4 will be continued
    until the maximum tolerated dose (MTD) is defined, up to a maximum dose of 1000mg.

    Trial Arms

    Name Type Description Interventions

    Eligibility Criteria

    Inclusion Criteria:

    1. Histologically proven relapsed or refractory indolent B-cell lymphoma or chronic
    lymphocytic leukaemia. Patients must have received at least one line of previous therapy.

    2. CD19 positive malignancy as demonstrated by immunohistochemistry or flow cytometry

    3. Life expectancy of at least 12 weeks

    4. World Health Organisation (WHO) performance status of 0-1

    5. Haematological and biochemical indices within the ranges shown below. These
    measurements must be performed within one week (Day -7 to Day 1) before the patient
    commences treatment with DI-B4.

    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 bone
    marrow involvement), Platelet count 75 x 10^9/L (or 30 x 10^9/L if bone marrow
    involvement), 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 Alanine amino-transferase
    (ALT) and/or aspartate amino-transferase (AST) 2.5 x (ULN) unless raised due to hepatic
    involvement in which case up to 5 x ULN is permissible

    6. 18 years or over

    7. Written (signed and dated) informed consent and be capable of co-operating with
    treatment and follow-up

    8. Indolent B-cell lymphoma patients only: Patient has either at least one measurable
    lesion by CT scan (defined as >1.5 cm in one axis) or in the case of Waldenstrm's
    macroglobulinemia, disease must be assessable by the protocol criteria.

    Exclusion Criteria:

    1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy,
    chemotherapy or investigational medicinal products during the previous 4 weeks before
    treatment.

    2. 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 Drug
    Development Office (DDO) should not exclude the patient.

    3. Known to be serologically positive for hepatitis B (unless due to vaccination),
    hepatitis C or human immunodeficiency virus (HIV).

    4. Patients with clinically active leptomeningeal or central nervous system
    lymphoma/leukaemia.

    5. 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.

    6. Patients receiving corticosteroids, except where the patient has been on a stable dose
    for the preceding seven days. Doses of prednisolone or equivalent >10 mg daily are not
    permitted whilst on the study, doses up to 20mg can be taken any time prior to Cycle 1,
    Day 1

    7. Concurrent congestive heart failure, prior history of class III/ IV cardiac disease
    (New York Heart Association [NYHA]), history of unstable angina pectoris or myocardial
    infarction up to 1 year prior to patient enrolment into the trial, presence of severe
    valvular heart disease or presence of a ventricular arrhythmia requiring treatment

    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 highly effective forms of contraception (oral, injected or implanted hormonal
    contraception and condom, have an intra-uterine device and condom, diaphragm with
    spermicidal gel and condom) during the trial and for six months afterwards are considered
    eligible.

    9. Male patients with partners of child-bearing potential (unless they agree to take
    measures not to father children by using one form of highly effective contraception
    [condom plus spermicide] during the trial and for six months afterwards). 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 active
    uncontrolled infection.

    12. Is a participant or plans to participate in another interventional clinical trial,
    whilst taking part in this Phase I study of DI-B4. Participation in an observational trial
    would be acceptable.

    13. Any other condition which in the Investigators opinion would not make the patient a
    good candidate for the clinical trial.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    To recommend a dose for future trials with a new drug called DI-B4 by finding the highest safe dose which can be given to patients

    Secondary Outcome Measures

    Measuring of PK parameter values for DI-B4 including AUC, Cmax, Tmax, and half life T1/2.

    To evaluate the effect of DI-B4 on the depletion of peripheral blood and bone marrow B-cells.

    To look for signs of anti-tumour activity of DI-B4 in patients with relapsed or refractory indolent B-cell malignancies.

    To assess immunogenicity of DI-B4 in patients with relapsed or refractory indolent B-cell malignancies

    To measure the time to disease progression and eighteen month survival

    Trial Keywords

    Phase I, Cancer, CD19 positive, B-Cell lymphoma, chronic lymphocytic leukaemia

    Waldenstrm Macroglobulinaemia