Targeted Radiotherapy in HSCT for Poor Risk Haematological Malignancy

Sponsor

University Hospital Southampton NHS Foundation Trust (Other)

Overall Status

Completed

CT.gov ID

NCT01521611

Collaborator

Royal Free and University College Medical School (Other)

Enrollment

Locations

Arm

197.9

Actual Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Leukaemia Chronic Leukaemia Myeloma Lymphoma	Radiation: Targeted radiotherapy	Phase 1/Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

62 participants

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jan 1, 2002

Actual Primary Completion Date :

Jul 1, 2017

Actual Study Completion Date :

Jul 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Targeted radiotherapy Patients receive therapy with an yttrium-90 labelled anti-CD66 following favourable dosimetry with the same antibody radiolabelled with indium-111.	Radiation: Targeted radiotherapy Yttrium-90 labelled anti-CD66 monoclonal antibody. Other Names: Y-90-anti-CD66

Arm

Intervention/Treatment

Experimental: Targeted radiotherapy

Patients receive therapy with an yttrium-90 labelled anti-CD66 following favourable dosimetry with the same antibody radiolabelled with indium-111.

Radiation: Targeted radiotherapy

Yttrium-90 labelled anti-CD66 monoclonal antibody.

Other Names:

Y-90-anti-CD66

Outcome Measures

Primary Outcome Measures

Toxicities related to radiolabelled antibody. [Up to 1 year post transplant World Health Organisation (WHO) toxicity criteria]
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.

Secondary Outcome Measures

Dosimetry model [5 days post infusion of an Indium-111 radiolabelled anti-CD66]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Southampton University Hospitals NHS Trust	Southampton	Hampshire	United Kingdom	SO16 6YD
2	Royal Free Hospital and University College London	London		United Kingdom