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

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.

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.

Study Overview

• Status: Completed
• Conditions: Myelodysplasia; Acute Myeloid Leukaemia
• Intervention / Treatment: Drug: Clofarabine; Drug: Clofarabine

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Hampshire
    • Southampton, Hampshire, United Kingdom, SO16 6YD
      • Wessex Blood and Marrow Transplant Unit, Southampton University Hospitals NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clofarabine and Full intensity SCT; 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; Clofarabine preconditioning (40mg/m2 daily for 5 days) prior to full intensity allogeneic stem cell transplant; Drug: Clofarabine; Clofarabine preconditioning (40mg/m2 daily for 5 days) prior to reduced intensity allogeneic stem cell transplant
Experimental: Clofarabine and Reduced intensity SCT; 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; Clofarabine preconditioning (40mg/m2 daily for 5 days) prior to full intensity allogeneic stem cell transplant; Drug: Clofarabine; Clofarabine preconditioning (40mg/m2 daily for 5 days) prior to reduced intensity allogeneic stem cell transplant

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital Southampton NHS Foundation Trust
• Collaborators: Genzyme, a Sanofi Company
• Investigators: Principal Investigator: Deborah S Richardson, MA MB BChir MD FRCP FRCPath, University Hospital Southampton NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): March 31, 2015

Study Registration Dates

• First Submitted: August 22, 2011
• First Submitted That Met QC Criteria: August 23, 2011
• First Posted (Estimate): August 24, 2011

Study Record Updates

• Last Update Posted (Actual): September 7, 2018
• Last Update Submitted That Met QC Criteria: September 5, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: AML; MDS; High risk
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Clofarabine
• Other Study ID Numbers: RHM CAN0638; 2008-007043-14 (EudraCT Number)