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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01805375
Recruitment Status : Completed
First Posted : March 6, 2013
Last Update Posted : February 5, 2018
Information provided by (Responsible Party):
Cancer Research UK

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Indolent B-cell Lymphoma Chronic Lymphocytic Leukaemia Waldenström Macroglobulinaemia Drug: DI-B4 Phase 1

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 28 participants
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
Study Start Date : April 2013
Actual Primary Completion Date : December 14, 2017
Actual Study Completion Date : December 14, 2017

Intervention Details:
  • Drug: DI-B4
    DI-B4 will be administered once weekly for up to a total of four weeks. The starting dose will be 0.02 mg given as an intravenous infusion. A cycle is 1 week in duration and patients should expect to receive a maximum of 4 cycles.

Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. To assess immunogenicity of DI-B4 in patients with relapsed or refractory indolent B-cell malignancies [ Time Frame: 54 months ]
  5. To measure the time to disease progression and eighteen month survival [ Time Frame: 54 months ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 Waldenström'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 Investigator‟s opinion would not make the patient a good candidate for the clinical trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01805375

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United Kingdom
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
Derriford Hospital
Plymouth, United Kingdom, PL6 8DH
University Hospital Southampton NHS Foundation Trust
Southampton, United Kingdom, S016 6YD
Sponsors and Collaborators
Cancer Research UK

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Responsible Party: Cancer Research UK Identifier: NCT01805375    
Other Study ID Numbers: CRUKD/12/003
First Posted: March 6, 2013    Key Record Dates
Last Update Posted: February 5, 2018
Last Verified: February 2018
Keywords provided by Cancer Research UK:
Phase I, Cancer, CD19 positive, B-Cell lymphoma, chronic lymphocytic leukaemia
Waldenström Macroglobulinaemia
Additional relevant MeSH terms:
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Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Waldenstrom Macroglobulinemia
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Lymphoma, Non-Hodgkin
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders