A Phase I Trial of DI-B4 in Patients With Advanced CD19 Positive Indolent B-cell Malignancies
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.
Indolent B-cell Lymphoma
Chronic Lymphocytic Leukaemia
|Study Design:||Primary Purpose: Treatment|
|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|
- 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 [ Time Frame: 38 Months ] [ Designated as safety issue: Yes ]
- Measuring of PK parameter values for DI-B4 including AUC, Cmax, Tmax, and half life T1/2. [ Time Frame: Samples taken during the four weeks of treatment and analysed in batches per cohort within 6 months of sampling ] [ Designated as safety issue: No ]
- To evaluate the effect of DI-B4 on the depletion of peripheral blood and bone marrow B-cells. [ Time Frame: Samples taken during the four weeks of treatment, and for 18 month follow-up and analysed in batches per cohort within 6 months of sampling ] [ Designated as safety issue: Yes ]
- To look for signs of anti-tumour activity of DI-B4 in patients with relapsed or refractory indolent B-cell malignancies. [ Time Frame: 38 months ] [ Designated as safety issue: No ]
- To assess immunogenicity of DI-B4 in patients with relapsed or refractory indolent B-cell malignancies [ Time Frame: 54 months ] [ Designated as safety issue: No ]
- To measure the time to disease progression and eighteen month survival [ Time Frame: 54 months ] [ Designated as safety issue: Yes ]
|Study Start Date:||April 2013|
|Estimated Primary Completion Date:||December 2017 (Final data collection date for primary outcome measure)|
Patients with relapsed or refractory CD19 positive indolent B-cell lymphoma, Waldenström 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01805375
|Royal Liverpool and Broadgreen University Hospital NHS Trust|
|Liverpool, United Kingdom, L7 8XP|
|The Christie NHS Foundation Trust|
|Manchester, United Kingdom, M20 4BX|
|The Churchill Hospital|
|Oxford, United Kingdom, OX3 7LE|
|Plymouth, United Kingdom, PL6 8DH|
|University Hospital Southampton NHS Foundation Trust|
|Southampton, United Kingdom, S016 6YD|