Clofarabine Pre-conditioning With Allogeneic Transplant for Acute Myeloid Leukaemia (AML)

Study Overview
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Brief Summary
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This study has been designed to investigate the safety and feasibility of using a chemotherapy drug, Clofarabine, to reduce the disease burden before a donor transplant, in patients with high risk Acute Myeloid Leukaemia or Myelodysplasia (MDS). In this study Clofarabine chemotherapy will be given a few days before a reduced or full intensity donor stem cell transplant and without waiting for normal blood counts to recover. It is hoped that this approach may improve the outcome for patients with high risk AML and MDS after their transplant.

Detailed Description
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This is a pilot study. Twenty patients in total will be treated in two cohorts of 10 patients each. Cohort One: Patients suitable for full intensity conditioning will receive Clofarabine pre-conditioning followed by a Cyclophosphamide and Total Body Irradiation conditioned allogeneic stem cell transplant. Cohort Two: Patients not suitable for a full intensity TBI-based transplant due to age or co-morbidity will receive Clofarabine pre-conditioning followed by a reduced intensity allogeneic stem cell transplant using Fludarabine, intravenous Busulphan and Campath 1H. The cohorts will be recruited concurrently. It is anticipated that recruitment of the 20 subjects will be achieved in 18 months to two years. The study will be conducted at a single centre (Southampton, UK) in the first instance. This design allows the use of a full intensity, TBI-based transplant conditioning schedule, for younger patients able to tolerate this approach but also the use of a reduced intensity transplant conditioning schedule in older or less fit patients who may still benefit from pre-conditioning with Clofarabine followed by an allogeneic stem cell transplant. This design, therefore, does not restrict potential recruitment to the study on age or performance status alone (within the limits set by ability to tolerate intensive chemotherapy and a transplant procedure).

Official Title
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A Pilot Study of Clofarabine Pre-conditioning Prior to Full or Reduced Intensity Allogeneic Transplantation in the Treatment of High Risk Acute Myeloid Leukaemia and Myelodysplasia.

Conditions
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Acute Myeloid Leukaemia, Myelodysplasia

Intervention / Treatment
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* Drug: Clofarabine
* Drug: Clofarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cytologically and immunophenotypically (or immunohistochemically) confirmed diagnosis of high risk AML or MDS Minimum age of 18 years Eligible for allogeneic stem cell transplant by local institutional guidelines Suitable matched-related/sibling or volunteer unrelated donor available, as determined by local institutional guidelines Negative pregnancy test for females of child-bearing potential within 7 days prior to the start of study treatment If sexually active, male and female subjects must agree that they will use an effective method of birth control throughout the active study period Written informed consent Capable of and willing to comply with scheduled visits, treatment plan and required laboratory tests Adequate renal and hepatic function Exclusion Criteria: Psychiatric, addictive or any disorder which compromises ability to give truly informed consent for participation in this study Previous Allogeneic Bone Marrow or Peripheral Blood Stem Cell Transplant. Pregnant or lactating women. All female subjects of child-bearing potential must have a negative pregnancy test within 7 days prior to the start of treatment. Any current active, invasive malignancy excluding AML or MDS

Ages Eligible for Study
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Minimum Age: 18 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: Clofarabine and Full intensity SCT<br>Cohort One: Patients suitable for full intensity conditioning will receive Clofarabine pre-conditioning followed by a Cyclophosphamide and Total Body Irradiation conditioned allogeneic stem cell transplant (SCT). | Drug: Clofarabine<br>* Clofarabine preconditioning (40mg/m2 daily for 5 days) prior to full intensity allogeneic stem cell transplant<br>|
| Experimental: Clofarabine and Reduced intensity SCT<br>Cohort 2: Patients not suitable for a full intensity TBI-based transplant due to age or co-morbidity will receive Clofarabine pre-conditioning followed by a reduced intensity allogeneic stem cell transplant using Fludarabine, intravenous Busulphan and Campath 1H. | Drug: Clofarabine<br>* Clofarabine preconditioning (40mg/m2 daily for 5 days) prior to reduced intensity allogeneic stem cell transplant<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment related mortality (TRM) | Treatment related mortality (TRM) measured at day 100 and 1 year post transplant and cause of mortality | day 100 and 1 year post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) |  | 1 year post transplant | 
| Event free survival (EFS) |  | 1 year post transplant | 
| Efficacy of Clofarabine as a leukaemia bulk-reducing agent prior to transplant conditioning | Efficacy of Clofarabine as a leukaemia bulk-reducing agent prior to transplant conditioning as determined by pre- and post-Clofarabine bone marrow biopsy examination | Within 4 weeks prior to Clofarabine and 1 to 5 days following Clofarabine | 
| Time to engraftment |  | by day 100 post transplant | 
| Donor/recipient chimerism |  | day 30, day 100 and 1 year post transplant | 
| Immune reconstitution parameters (T, B and NK cell subsets) |  | day 30, day 100 and 1 year post transplant | 
| Duration of hospital stay | Duration of in patient hospital stay for Clofarabine preconditioning chemotherapy and stem cell transplant | The duration of hospital stay will be measured, an expected average of 7 to 8 weeks | 
| Incidence of acute and chronic graft versus host disease |  | 1 year post transplant | 
| Grade of acute and chronic graft versus host disease |  | 1 year post transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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High risk, AML, MDS