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Monoclonal Antibodies in Recurrent or Refractory B Cell Acute Lymphoblastic Leukaemia (ALL) (MARALL) (MARALL)

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ClinicalTrials.gov Identifier: NCT01279707
Recruitment Status : Unknown
Verified July 2014 by Queen Mary University of London.
Recruitment status was:  Active, not recruiting
First Posted : January 19, 2011
Last Update Posted : July 14, 2014
Sponsor:
Collaborator:
Immunomedics, Inc.
Information provided by (Responsible Party):
Queen Mary University of London

Study Description
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Brief Summary:

The treatment of adult B-cell acute lymphoblastic leukaemia (ALL) has progressed considerably in the past 3 decades, particularly due to intensification of chemotherapies, improved supportive care and the incorporation of stem cell transplantation. However, the maximum tolerability of standard chemotherapeutics has been reached in ALL. Using conventional chemotherapy, 80-85% of adults with ALL will achieve a complete remission (CR). Unfortunately treatment at relapse is generally unsuccessful and rarely results, in long-term survival (7% survival at 5 years). Therefore, the investigators are exploring novel treatment strategies through the use of monoclonal antibodies (MoAbs) directed at surface antigens on leukaemic blasts. Using MoAbs directed against surface proteins on B cells has had excellent results in other B-cell diseases such as low and high grade non-Hodgkin lymphomas, without additional toxicity. There has also been limited evidence from small studies and case reports of the efficacy of MoAbs in ALL.

This is a Phase I/II study to determine the safety and tolerability of the combination of veltuzumab and epratuzumab with intensive chemotherapy in patients with relapsed B-cell ALL. A maximum of 51 patients will be treated with a combination of UKALL XII induction chemotherapy and the monoclonal antibodies veltuzumab and epratuzumab. Veltuzumab and epratuzumab are humanised monoclonal antibodies that target CD20 and CD22 surface proteins, respectively. Both of these proteins are expressed on ALL tumour B cells.

One group of patients will receive modified UKALL XII chemotherapy + veltuzumab; a second, modified UKALL XII chemotherapy + epratuzumab and if limited toxicity is found in these first 2 groups, a third group will receive, modified UKALL XII chemotherapy + both veltuzumab and epratuzumab. Patients will be assessed for safety, tolerability and disease response. Safety and tolerability will be measured by the number of Dose Limiting Toxicities (DLTs) in each group. Disease response will be measured by the microscopic appearance of patient bone marrow samples at day 29, and by molecular tests for tumour cells in bone marrow.


Condition or disease Intervention/treatment Phase
Recurrent or Refractory B Cell Acute Lymphoblastic Leukaemia Biological: humanised monoclonal antibody, veltuzumab Biological: humanised monoclonal antibody epratuzumab Biological: humanised monoclonal antibodies veltuzumab and epratuzumab Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 55 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study Combining Humanised Anti-CD20 (Veltuzumab), Anti-CD22 (Epratuzumab) and Both Monoclonal Antibodies With Intensive Chemotherapy in Adults With Recurrent or Refractory B-precursor Acute Lymphoblastic Leukaemia (ALL)
Study Start Date : January 2010
Estimated Primary Completion Date : August 2014
Estimated Study Completion Date : August 2014

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Arms and Interventions
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Arm Intervention/treatment
Experimental: A: Veltuzumab and chemotherapy
Veltuzumab and modified UKALL XII chemotherapy
 Biological: humanised monoclonal antibody, veltuzumab
Veltuzumab with modified UKALL XII induction chemotherapy. Veltuzumab will be administered at 200 mg/m2 IV on Day 8 and subsequently, (if tolerated on Day 8), over 1 hour on Days 15, 22, 29.
Experimental: B: epratuzumab and chemotherapy
epratuzumab and modified UKALL XII chemotherapy
 Biological: humanised monoclonal antibody epratuzumab
Epratuzumab with modified UKALL XII induction chemotherapy. Epratuzumab will be administered at 360 mg/m2 IV over 1 hour on Days 8, 15, 22 and 29.
Experimental: C: veltuzumab and epratuzumab and chemotherapy
Veltuzumab and Epratuzumab and modified UKALL XII chemotherapy
 Biological: humanised monoclonal antibodies veltuzumab and epratuzumab
Epratuzumab + Veltuzumab with modified UKALL XII induction chemotherapy. Epratuzumab will be administered at 360 mg/m2 IV over 1 hour on Days 8, 15, 22 and 29. Veltuzumab will be administered at 200 mg/m2 IV over 2 hours on Day 8 and over 1 hour on Days 15, 22 and 29. Veltuzumab will be infused 1 hour after the infusion of epratuzumab.


Outcome Measures
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Primary Outcome Measures :
  1. The total number of dose limiting toxicity events (DLTs) to measure safety and tolerability [ Time Frame: Day 29 ]
    The primary objective is to assess the safety and tolerability of the combination of veltuzumab and/or epratuzumab with intensive chemotherapy for recurrent or refractory adult B-precursor ALL.


Secondary Outcome Measures :
  1. Morphological and molecular remission in bone marrow [ Time Frame: Day 29 ]

    Achievement of morphological complete remission on Day 29 bone marrow

    Efficacy of treatment to achieve MRD negativity, and investigate a possible association between the intensity of CD20 and CD22 antigen expression and treatment activity.



Eligibility Criteria
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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Aged 16 years or over
  2. Confirmed diagnosis of recurrent or refractory B-precursor ALL [according to the WHO classification].
  3. Greater than 5% blasts in the bone marrow
  4. WHO/ECOG performance status of 0-2 and well enough to receive intensive combination chemotherapy.
  5. Negative pregnancy test in women of childbearing potential. Women will not be considered of child bearing potential if they have undergone surgical removal of the uterus or are post menopausal and have been amenorrhoeic for at least 24 months.

  6. Patients must have adequate organ function:

    • Renal function - serum creatinine <2.5 x ULN or eGFR>50ml/min (measured EDTA or estimated creatinine clearance e.g Cockcroft & Gault)
    • Liver function (bilirubin/ALT <2.5 x ULN)
  7. Patients must be able to comply with the study schedule.

Exclusion Criteria:

  1. Patients should not have received chemotherapy for current episode of relapsed ALL (except corticosteroids for a maximum of 10 days, before joining the study).
  2. Patients with co-morbidities: e.g. uncontrolled hypertension and or poorly controlled diabetes which in the PI's opinion makes them unsuitable for the study.
  3. Patients with severe psychiatric disorders which in the PI's opinion makes them unsuitable for trial participation.
  4. Females of childbearing potential and all males must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) for the duration of the study and for up to 3 months after the last dose of study medication. Note: Subjects are not considered of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
  5. Females of childbearing potential must have a negative pregnancy test within 7 days prior to starting the study.
  6. Females must not be breastfeeding.
  7. Patients may not receive any other investigational agent during the study.
  8. Patients should not have received any antibody therapy within 3 months of joining this study.
Contacts and Locations
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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 ClinicalTrials.gov identifier (NCT number): NCT01279707


Locations
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United Kingdom
University Hospitals Birmingham NHS Foundation
Birmingham, United Kingdom, B15 2TH
University of Bristol Foundation Trust
Bristol, United Kingdom, BS2 8BJ
University Hospital of Wales
Cardiff, United Kingdom, CF14 4XN
Beatson West of Scotland Cancer Centre
Glasgow, United Kingdom, G12 0YN
Leeds Teaching Hospitals NHS Trust
Leeds, United Kingdom, LS9 7TF
Barts and the London NHS Trust
London, United Kingdom, EC1A 7BE
Royal Free Hampstead NHS Trust
London, United Kingdom, NW3 2QG
Newcastle University
Newcastle, United Kingdom, NE2 4HH
Nottingham City Hospital
Nottingham, United Kingdom, NG5 1PB
Plymouth Hospitals NHS Trust
Plymouth, United Kingdom, PL6 8DH
Sponsors and Collaborators
Queen Mary University of London
Immunomedics, Inc.
Investigators
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Principal Investigator: Matthew Smith, Doctor Barts and The London NHS Trust
More Information
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Responsible Party: Queen Mary University of London
ClinicalTrials.gov Identifier: NCT01279707    
Other Study ID Numbers: 6125
First Posted: January 19, 2011    Key Record Dates
Last Update Posted: July 14, 2014
Last Verified: July 2014
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
 Antineoplastic Agents, Immunological
Epratuzumab
Veltuzumab
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents