Pilot Study of Unrelated Cord Blood Transplantation

Sponsor

King's College Hospital NHS Trust (Other)

Overall Status

Terminated

CT.gov ID

NCT00916045

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the safety and feasibility of unrelated double and single cord blood transplantation in patients with haematological malignancies using reduced-intensity or myeloablative conditioning regimens.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myeloid, Acute Myelodysplastic Syndromes Leukemia, Lymphoblastic, Acute Lymphoma, Non-Hodgkin Hodgkin Disease Chronic Lymphocytic Leukemia	Drug: Thiotepa Drug: Fludarabine Drug: Intravenous busulphan Drug: Thymoglobulin Drug: Ciclosporin Drug: Mycophenolate mofetil (MMF) Drug: Fludarabine Drug: Cyclophosphamide Radiation: Radiotherapy Drug: Thymoglobulin Drug: Ciclosporin Drug: Mycophenolate mofetil (MMF) Drug: Fludarabine Drug: Melphalan Drug: Thymoglobulin Drug: Ciclosporin Drug: Mycophenolate mofetil (MMF)	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Pilot Study of Unrelated Cord Blood Transplantation in Patients With Poor Risk Haematological Malignancies

Study Start Date :

Sep 1, 2009

Actual Primary Completion Date :

Mar 1, 2012

Actual Study Completion Date :

Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Other: Myeloblative conditioning regimen	Drug: Thiotepa Drug: Fludarabine Drug: Intravenous busulphan Other Names: Busilvex Drug: Thymoglobulin Drug: Ciclosporin Drug: Mycophenolate mofetil (MMF)
Other: Reduced intensity conditioning regimen - FluCyTBI	Drug: Fludarabine Drug: Cyclophosphamide Radiation: Radiotherapy Drug: Thymoglobulin Drug: Ciclosporin Drug: Mycophenolate mofetil (MMF)
Other: Reduced intensity conditioning regimen - FluMel	Drug: Fludarabine Drug: Melphalan Drug: Thymoglobulin Drug: Ciclosporin Drug: Mycophenolate mofetil (MMF)

Arm

Intervention/Treatment

Other: Myeloblative conditioning regimen

Drug: Thiotepa

Drug: Fludarabine

Drug: Intravenous busulphan

Other Names:

Busilvex

Drug: Thymoglobulin

Drug: Ciclosporin

Drug: Mycophenolate mofetil (MMF)

Other: Reduced intensity conditioning regimen - FluCyTBI

Drug: Fludarabine

Drug: Cyclophosphamide

Radiation: Radiotherapy

Drug: Thymoglobulin

Drug: Ciclosporin

Drug: Mycophenolate mofetil (MMF)

Other: Reduced intensity conditioning regimen - FluMel

Drug: Fludarabine

Drug: Melphalan

Drug: Thymoglobulin

Drug: Ciclosporin

Drug: Mycophenolate mofetil (MMF)

Outcome Measures

Primary Outcome Measures

Treatment related mortality at day 100 [Day 100]

Secondary Outcome Measures

Disease free survival at one year post-transplant for each cohort [1 year]
Chimerism [Days 14 (myeloblative conditioning only), 28, 56, 100 and months 6 and 12]
Incidence of neutrophil engraftment by day 42 [Days 14, 28 and 42]
Incidence of platelet engraftment by 6 months [Days 14, 28, 56, 100 and month 6]
Incidence of grade II-IV and III-IV acute GVHD [Days 28, 56, 100 and months 6, 9, 12, 18 and 24]
Incidence of chronic GVHD during the first year [Day 100 and months 6 and 12]
One year overall survival for each treatment cohort [1 year]
Incidence of systemic infections [Twice a week pre-transplant to day 100 then weekly or as clinically indicated]
Incidence of CMV, adenovirus and EBV activation [Twice a week pre-transplant to day 100 then weekly or as clinically indicated]
Immune reconstitution [Days 14, 28, 56, 100 and months 6, 9, 12, 18 and 24]
Dynamics of EBV infection and immunity following cord blood transplantation [Days 14, 28, 56, 100 and months 6, 9 and 12]
The development (if any) of transplant associated post transplant lymphoproliferative disease (PTLD) [Days 14, 28, 56, 100 and months 6, 9 and 12]
Identify any possible predictive markers for patients most at risk of PTLD development [Days 14, 28, 56, 100 and months 6, 9 and 12]
Quality of life [Pre-transplant and months 6, 12, 18 and 24]
Incidence of one year relapse or disease progression for each treatment cohort [1 year]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE INCLUSION CRITERIA:

In general this encompasses all haematological disorders where a volunteer unrelated donor transplant is clinically indicated.

Acute, chronic leukaemia or myelodysplastic syndrome for which allogeneic transplantation is considered as the best treatment option.
Acute myeloid leukaemia (AML) in first complete remission (CR1) with one of the following characteristics:

High risk cytogenetic or molecular alterations (e.g. t(9;22), deletion 7/7q-, monosomy 5 or del(5q), 3q26 alterations, complex karyotype [3 or more anomalies], p53 alterations, 11q23 especially t(6;11) abnormalities, FLT-3 ITD)
Leukocytes at diagnosis > 50 x109/l (except in cases with good prognosis molecular rearrangements for which leukocytes should be > 100 x 109/l)

Myelodysplastic syndromes

International Prognosis Index (IPSS) above 1 (intermediate group 2 or high risk)
IPSS 0 or 0.5 in the presence of cytopenias requiring treatment.

Therapy related AML or MDS in first CR
AML or MDS in second (CR2) or subsequent CR
Ph'-positive chronic myeloid leukaemia

In first chronic phase if refractory and/or intolerance to tyrosine kinase inhibitors is clearly demonstrated ii. In second chronic phase

Acute lymphoblastic leukaemia (ALL)

In CR1 with one of the following characteristics: i. Very high risk chromosome or molecular alterations (e.g. t(9;22), t(4;11), complex karyotype in adults, bcr/abl rearrangements, MLL rearrangements) ii. Slow response to induction treatment defined as the presence of >10% blasts in bone marrow at day 14 of induction treatment iii. Adults aged > 30 years iv. Adults with B ALL cell line with a number of leukocytes at diagnosis >25 x 109/L or T ALL cell line with a number of leukocytes at diagnosis

100X109/L

In CR2 or subsequent CR

Non-Hodgkin's lymphoma
Follicular NHL: in second or subsequent complete or partial remission
Mantle cell NHL: in second or subsequent complete or partial remission
High grade NHL: in second complete or very good partial remission
Hodgkin's disease

in second or subsequent complete or partial remission

Chronic lymphocytic leukaemia.
in second or subsequent remission
with adverse risk prognostic features in first remission
Acquired bone marrow failure syndromes
Other haematological malignancies for which UD bone marrow transplantation is indicated

PATIENT SELECTION

Inclusion criteria: myeloablative conditioning regimen

Aged under 35 years and greater than 18 years
Absence of HLA compatible related donor.
Need for an urgent transplantation or absence of HLA-compatible VUD after searching the international registries.
Patients with a HLA-compatible VUD but whose donor is considered by the transplantation centre as unsuitable will also be eligible.
Availability of suitable UD-UCB unit/s.
Informed consent.

Exclusion criteria: myeloablative conditioning regimen

Patients with an available 5-6/6 HLA-A, -B, -DRB1 matched sibling donor or 10/10 unrelated bone marrow donor
ECOG performance status worse than 2
Cardiac insufficiency requiring treatment, symptomatic coronary artery disease or LVEF less than 40%.
Hepatic disease, with total bilirubin above 20umol/l or AST > 3 times upper limit of normal.
Severe hypoxaemia, pO2 < 70 mm Hg, with decreased DLCO < 70% of predicted; or mild hypoxemia, pO2 < 80 mm Hg with severely decreased DLCO < 60% of predicted.
Impaired renal function (creatinine > 2 times upper limit of normal or creatinine clearance < 50% for age, gender, weight).
Patients who have received previous treatment with Thymoglobulin®
HIV or HTLV positive patients.
Female patients who are pregnant or breast feeding due to risks to foetus from conditioning regimen and potential risks to nursing infants.
Life expectancy severely limited by diseases other than the disease indication for transplant
Serious concurrent untreated infection e.g. active tuberculosis, mycoses or viral infection
Serious psychiatric/ psychological disorders
Absence of /inability to provide informed consent
Serious diseases that prevent treatments with chemotherapy
Myelofibrosis

Inclusion criteria: reduced-intensity conditioning regimen (For both FluMel & FluCyTBI regimens):

Age under 70 years and older than 18 years
Absence of HLA compatible related donor.
Need for an urgent transplantation or absence of HLA-compatible VUD after searching the international registries.
Patients with a HLA-compatible VUD but whose donor is considered by the transplantation centre as unsuitable will also be eligible.
Availability of suitable UD-UCB unit/s.
Informed consent.

Exclusion Criteria: reduced-intensity conditioning regimen (For both FluMel & FluCyTBI regimens):

Patients with an available 5-6/6 HLA-A, -B, -DRB1 matched sibling donor or 10/10 unrelated bone marrow donor
ECOG performance status worse than 2
Cardiac insufficiency requiring treatment, symptomatic coronary artery disease or LVEF less than 35%.
Hepatic disease, with total bilirubin greater than 2 times upper limit of normal or AST > 5 times upper limit of normal.
Severe hypoxaemia, pO2 < 70 mm Hg, with decreased DLCO < 50% of predicted; or mild hypoxemia, pO2 < 80 mm Hg with severely decreased DLCO < 50% of predicted.
Impaired renal function (creatinine > 2 times upper limit of normal or creatinine clearance < 50% for age, gender, weight).
Previous irradiation that precludes the safe administration of an additional dose of 200 cGy of total body irradiation (TBI).
Patients who have received previous treatment with Thymoglobulin®
HIV or HTLV positive patients.
Female patients who are pregnant or breast feeding due to risks to foetus from conditioning regimen and potential risks to nursing infants.
Life expectancy severely limited by diseases other than the disease indication for transplant
Serious concurrent uncontrolled infection e.g. active tuberculosis, mycoses or viral infection
Serious psychiatric/ psychological disorders
Absence of /inability to provide informed consent
Within 6 months of prior myeloablative transplant.
Patients with acute leukaemia in morphological relapse/ persistent/ progressive disease
Intermediate or high grade NHL, mantle cell NHL and Hodgkin's disease that is refractory or progressive on salvage therapy.
Myelofibrosis