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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Recurrent or Refractory B Cell Acute Lymphoblastic Leukaemia

Intervention / Treatment
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* Biological: humanised monoclonal antibody, veltuzumab
* Biological: humanised monoclonal antibody epratuzumab
* Biological: humanised monoclonal antibodies veltuzumab and epratuzumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: Veltuzumab and chemotherapy<br>Veltuzumab and modified UKALL XII chemotherapy | Biological: humanised monoclonal antibody, veltuzumab<br>* 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.<br>|
| Experimental: B: epratuzumab and chemotherapy<br>epratuzumab and modified UKALL XII chemotherapy | Biological: humanised monoclonal antibody epratuzumab<br>* 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.<br>|
| Experimental: C: veltuzumab and epratuzumab and chemotherapy<br>Veltuzumab and Epratuzumab and modified UKALL XII chemotherapy | Biological: humanised monoclonal antibodies veltuzumab and epratuzumab<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The total number of dose limiting toxicity events (DLTs) to measure safety and tolerability | 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. | Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Morphological and molecular remission in bone marrow | 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. | Day 29 |