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

NCT01805375 | Completed Phase 1

• 1 other identifier: CRUKD/12/003
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 5

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.

Conditions

Indolent B-cell Lymphoma; Chronic Lymphocytic Leukaemia; Waldenström Macroglobulinaemia

Keywords

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

Outcome Measures

Primary Outcomes (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

  38 Months

Secondary Outcomes (5)

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

  Samples taken during the four weeks of treatment and analysed in batches per cohort within 6 months of sampling

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

  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

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

  38 months

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

  54 months

• To measure the time to disease progression and eighteen month survival

  54 months

Interventions

DI-B4 DRUG

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.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Histologically proven relapsed or refractory indolent B-cell lymphoma or chronic lymphocytic leukaemia. Patients must have received at least one line of previous therapy.
• \. CD19 positive malignancy as demonstrated by immunohistochemistry or flow cytometry
• \. Life expectancy of at least 12 weeks
• \. World Health Organisation (WHO) performance status of 0-1
• \. 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
• \. 18 years or over
• \. Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up
• \. 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.

You may not qualify if:

• \. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy, chemotherapy or investigational medicinal products during the previous 4 weeks before treatment.
• \. 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.
• \. Known to be serologically positive for hepatitis B (unless due to vaccination), hepatitis C or human immunodeficiency virus (HIV).
• \. Patients with clinically active leptomeningeal or central nervous system lymphoma/leukaemia.
• \. 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 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
• \. 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
• \. 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.
• \. 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.
• \. Major thoracic or abdominal surgery from which the patient has not yet recovered.
• \. At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
• \. 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.
• \. Any other condition which in the Investigator"s opinion would not make the patient a good candidate for the clinical trial.

Sponsors & Collaborators

• Cancer Research UK: lead

Study Sites (5)

Royal Liverpool and Broadgreen University Hospital NHS Trust

Liverpool, L7 8XP, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

The Churchill Hospital

Oxford, OX3 7LE, United Kingdom

Location

Derriford Hospital

Plymouth, PL6 8DH, United Kingdom

Location

University Hospital Southampton NHS Foundation Trust

Southampton, S016 6YD, United Kingdom

Location

MeSH Terms

Conditions

Leukemia, B-Cell; Waldenstrom Macroglobulinemia; Neoplasms; Lymphoma, B-Cell

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Lymphoma, Non-Hodgkin; Lymphoma

Study Design

• Study Type: interventional
• Phase: phase 1
• Purpose: TREATMENT
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 4, 2013
• First Posted: March 6, 2013
• Study Start: April 1, 2013
• Primary Completion: December 14, 2017
• Study Completion: December 14, 2017
• Last Updated: February 5, 2018

Record last verified: 2018-02

Locations

GB (5)