Targeted Radiotherapy in HSCT for Poor Risk Haematological Malignancy

Study Overview
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Brief Summary
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To determine whether a radiolabelled antibody that targets the bone marrow (the 'anti-CD66') can be administered safely to patients as part of the preparative treatment prior to haematopoietic stem cell transplantation ('a bone marrow transplant'). Can the radiolabelled antibody be shown to effectively target the bone marrow in these patients. If it can, could this result in better outcomes after transplantation.

Detailed Description
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The aim of this clinical research study is to establish whether a radiolabelled antibody can be used to safely deliver radiotherapy to the bone marrow prior to stem cell transplantation for haematological malignancies. With current chemotherapy regimens 60-90% of adult patients with acute leukaemia (AML and ALL) achieve a complete remission. However in a significant proportion of these patients the disease will recur. Although allogeneic and autologous bone marrow or peripheral blood haematopoietic stem cell transplantation (HSCT) are established as effective treatment options for haematological malignancies, resulting in long term disease free survival in a significant proportion of patients, the results of transplantation for patients with poor risk disease are disappointing. Further intensification of the treatment used prior to transplantation has been shown to reduce the risk of relapse, but the toxicity of the drugs or external beam radiotherapy causes an increase in transplant related deaths. The introduction of reduced intensity conditioning protocols allows the use of HSCT for older patients or those with significant additional medical problems but retrospective analysis indicates an increased rate of relapse. This is the 'Transplantation dilemma' - how to reduce the risk of disease relapse by intensifying therapy, but without an increase in toxicity to other organs causing an increase in transplant related deaths in remission. Normal haematopoietic tissue and the malignant cells arising from it are very radiosensitive. Theoretically intensification of the conditioning therapy, particularly total body irradiation (TBI), prior to transplantation could increase tumour reduction leading to improved disease free survival rates for patients with poor risk disease. Targeted radiotherapy could allow treatment intensification without the toxicity to non-haematological tissues. In addition, the continuous, low dose rate delivered by the natural decay of a targeted radionuclide may have a greater destructive effect upon tumour cells than single dose or fractionated external beam radiation.

Official Title
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Radiolabelled Anti-CD66 Monoclonal Antibody in the Conditioning Regimen Prior to Haematopoietic Stem Cell Transplantation: Phase I Study in Patients With Poor-risk Disease.

Conditions
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Acute Leukaemia, Chronic Leukaemia, Myeloma, Lymphoma

Intervention / Treatment
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* Radiation: Targeted radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: An underlying haematological malignancy including acute myeloid leukaemia in first complete remission (CR1) but with poor prognostic features or in >CR1 or in relapse; acute lymphoblastic leukaemia; transformed myelodysplasia, chronic myeloid leukaemia (accelerated phase or blast transformation, poor response or intolerance of tyrosine kinase inhibitors), myeloma. Patients may be in remission, partial remission or relapse. No concurrent or recent (within 3 weeks) chemotherapy for the underlying haematological condition For patients with relapsed leukaemia, bone marrow (BM) blasts must represent < 20% of BM nucleated cells. Although the BM remission status is not important, patients must have cellularity > 10%. As malignant plasma cells may or may not express CD66 antigens, patients with myeloma must have less than 30% plasma cells (as a percentage of total nucleated cells) in the BM at the time of the study. Age = or >18 yrs. WHO performance status of 0, 1 or 2 (Appendix 5). Predicted life-expectancy of greater than four months. Patients must be negative for human anti-mouse antibodies (HAMA). Peripheral blood counts: Wbc < 30 x 10e9/l (absolute neutrophil count >0.5 x 10e9/L) platelets > 50 x 10e9/l (platelet support is permitted) Biochemical indices: Plasma creatinine < 120 micromol/l (or creatinine clearance or Ethylene diamine tetra acetic acid (EDTA) clearance > 50 ml/min) Plasma bilirubin < 30 micromol/l Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) no more than 2.5 x upper limit of the normal range. Patient must be able to provide written informed consent. Exclusion Criteria: Any serious intercurrent disease. Patients with BM cellularity < 10%. History of atopic asthma, eczema or allergy to rodent protein, confirmed history of severe allergic reactions to penicillin or streptomycin. Positive Human anti-murine antibodies (HAMA). Patients unable to provide informed consent or who are unable to co-operate for reasons of poor mental or physical health. Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Targeted radiotherapy<br>Patients receive therapy with an yttrium-90 labelled anti-CD66 following favourable dosimetry with the same antibody radiolabelled with indium-111. | Radiation: Targeted radiotherapy<br>* Yttrium-90 labelled anti-CD66 monoclonal antibody.<br>* Other names: Y-90-anti-CD66;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicities related to radiolabelled antibody. | To determine the maximum tolerated dose (MTD) of targeted radiotherapy delivered by a murine anti-CD66 monoclonal antibody radiolabelled with yttrium-90 (Y-90) and determine the dose-limiting toxicity (DLT) in patients with haematological malignancies who are undergoing haematopoietic stem cell transplantation. Toxicities are assessed using WHO Toxicity Scale with 28 parameters. | Up to 1 year post transplant World Health Organisation (WHO) toxicity criteria | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dosimetry model | Dosimetry is determined by whole body and SPECT-CT of the thorax and abdomen on days 1, 2, 4 and 5 post infusion of an indium-111 radiolabelled anti-CD66. Dosimetry determines whether patients proceed to therapy with the yttrium-90 labelled anti-CD66. | 5 days post infusion of an Indium-111 radiolabelled anti-CD66 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radioimmunotherapy, Transplant, Bone Marrow Transplant (BMT), yttrium, indium