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

Sponsor

Queen Mary University of London (Other)

Overall Status

Unknown status

CT.gov ID

NCT01279707

Collaborator

Gilead Sciences (Industry)

Enrollment

Locations

Arms

Duration (Months)

5.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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

Study Type:

Interventional

Anticipated 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 :

Jan 1, 2010

Anticipated Primary Completion Date :

Aug 1, 2014

Anticipated Study Completion Date :

Aug 1, 2014

Arms and Interventions

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.

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

Primary Outcome Measures

The total number of dose limiting toxicity events (DLTs) to measure safety and tolerability [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

Morphological and molecular remission in bone marrow [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

Criteria

Ages Eligible for Study:

16 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Aged 16 years or over
Confirmed diagnosis of recurrent or refractory B-precursor ALL [according to the WHO classification].
Greater than 5% blasts in the bone marrow
WHO/ECOG performance status of 0-2 and well enough to receive intensive combination chemotherapy.
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.
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)

Patients must be able to comply with the study schedule.

Exclusion Criteria:

Patients should not have received chemotherapy for current episode of relapsed ALL (except corticosteroids for a maximum of 10 days, before joining the study).
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.
Patients with severe psychiatric disorders which in the PI's opinion makes them unsuitable for trial participation.
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.
Females of childbearing potential must have a negative pregnancy test within 7 days prior to starting the study.
Females must not be breastfeeding.
Patients may not receive any other investigational agent during the study.
Patients should not have received any antibody therapy within 3 months of joining this study.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	University Hospitals Birmingham NHS Foundation	Birmingham	United Kingdom	B15 2TH
2	University of Bristol Foundation Trust	Bristol	United Kingdom	BS2 8BJ
3	University Hospital of Wales	Cardiff	United Kingdom	CF14 4XN
4	Beatson West of Scotland Cancer Centre	Glasgow	United Kingdom	G12 0YN
5	Leeds Teaching Hospitals NHS Trust	Leeds	United Kingdom	LS9 7TF
6	Barts and the London NHS Trust	London	United Kingdom	EC1A 7BE
7	Royal Free Hampstead NHS Trust	London	United Kingdom	NW3 2QG
8	Newcastle University	Newcastle	United Kingdom	NE2 4HH
9	Nottingham City Hospital	Nottingham	United Kingdom	NG5 1PB
10	Plymouth Hospitals NHS Trust	Plymouth	United Kingdom	PL6 8DH