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Pilot Study of Unrelated Cord Blood Transplantation

Primary Purpose

Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Leukemia, Lymphoblastic, Acute

Status
Terminated
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Thiotepa
Fludarabine
Intravenous busulphan
Thymoglobulin
Ciclosporin
Mycophenolate mofetil (MMF)
Fludarabine
Cyclophosphamide
Radiotherapy
Thymoglobulin
Ciclosporin
Mycophenolate mofetil (MMF)
Fludarabine
Melphalan
Thymoglobulin
Ciclosporin
Mycophenolate mofetil (MMF)
Sponsored by
King's College Hospital NHS Trust
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia, Myeloid, Acute

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

DISEASE INCLUSION CRITERIA:

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

  1. Acute, chronic leukaemia or myelodysplastic syndrome for which allogeneic transplantation is considered as the best treatment option.

    1. 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)
    2. 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.
    3. Therapy related AML or MDS in first CR
    4. AML or MDS in second (CR2) or subsequent CR
    5. Ph'-positive chronic myeloid leukaemia

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

  2. Acute lymphoblastic leukaemia (ALL)

    a. 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

    b. In CR2 or subsequent CR

  3. Non-Hodgkin's lymphoma

    1. Follicular NHL: in second or subsequent complete or partial remission
    2. Mantle cell NHL: in second or subsequent complete or partial remission
    3. High grade NHL: in second complete or very good partial remission
  4. Hodgkin's disease

    a. in second or subsequent complete or partial remission

  5. Chronic lymphocytic leukaemia.

    1. in second or subsequent remission
    2. with adverse risk prognostic features in first remission
  6. Acquired bone marrow failure syndromes
  7. Other haematological malignancies for which UD bone marrow transplantation is indicated

PATIENT SELECTION

Inclusion criteria: myeloablative conditioning regimen

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

Exclusion criteria: myeloablative conditioning regimen

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

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

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

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

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

Sites / Locations

  • King's College Hosptial NHS Foundation Trust

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Other

Other

Other

Arm Label

Myeloblative conditioning regimen

Reduced intensity conditioning regimen - FluCyTBI

Reduced intensity conditioning regimen - FluMel

Arm Description

Outcomes

Primary Outcome Measures

Treatment related mortality at day 100

Secondary Outcome Measures

Disease free survival at one year post-transplant for each cohort
Chimerism
Incidence of neutrophil engraftment by day 42
Incidence of platelet engraftment by 6 months
Incidence of grade II-IV and III-IV acute GVHD
Incidence of chronic GVHD during the first year
One year overall survival for each treatment cohort
Incidence of systemic infections
Incidence of CMV, adenovirus and EBV activation
Immune reconstitution
Dynamics of EBV infection and immunity following cord blood transplantation
The development (if any) of transplant associated post transplant lymphoproliferative disease (PTLD)
Identify any possible predictive markers for patients most at risk of PTLD development
Quality of life
Incidence of one year relapse or disease progression for each treatment cohort

Full Information

First Posted
June 5, 2009
Last Updated
February 10, 2015
Sponsor
King's College Hospital NHS Trust
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1. Study Identification

Unique Protocol Identification Number
NCT00916045
Brief Title
Pilot Study of Unrelated Cord Blood Transplantation
Official Title
Pilot Study of Unrelated Cord Blood Transplantation in Patients With Poor Risk Haematological Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
March 2012
Overall Recruitment Status
Terminated
Why Stopped
Recruitment issues
Study Start Date
September 2009 (undefined)
Primary Completion Date
March 2012 (Actual)
Study Completion Date
March 2012 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
King's College Hospital NHS Trust

4. Oversight

Data Monitoring Committee
No

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Leukemia, Lymphoblastic, Acute, Lymphoma, Non-Hodgkin, Hodgkin Disease, Chronic Lymphocytic Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Myeloblative conditioning regimen
Arm Type
Other
Arm Title
Reduced intensity conditioning regimen - FluCyTBI
Arm Type
Other
Arm Title
Reduced intensity conditioning regimen - FluMel
Arm Type
Other
Intervention Type
Drug
Intervention Name(s)
Thiotepa
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Intervention Type
Drug
Intervention Name(s)
Intravenous busulphan
Other Intervention Name(s)
Busilvex
Intervention Type
Drug
Intervention Name(s)
Thymoglobulin
Intervention Type
Drug
Intervention Name(s)
Ciclosporin
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil (MMF)
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Type
Radiation
Intervention Name(s)
Radiotherapy
Intervention Type
Drug
Intervention Name(s)
Thymoglobulin
Intervention Type
Drug
Intervention Name(s)
Ciclosporin
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil (MMF)
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Intervention Type
Drug
Intervention Name(s)
Melphalan
Intervention Type
Drug
Intervention Name(s)
Thymoglobulin
Intervention Type
Drug
Intervention Name(s)
Ciclosporin
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil (MMF)
Primary Outcome Measure Information:
Title
Treatment related mortality at day 100
Time Frame
Day 100
Secondary Outcome Measure Information:
Title
Disease free survival at one year post-transplant for each cohort
Time Frame
1 year
Title
Chimerism
Time Frame
Days 14 (myeloblative conditioning only), 28, 56, 100 and months 6 and 12
Title
Incidence of neutrophil engraftment by day 42
Time Frame
Days 14, 28 and 42
Title
Incidence of platelet engraftment by 6 months
Time Frame
Days 14, 28, 56, 100 and month 6
Title
Incidence of grade II-IV and III-IV acute GVHD
Time Frame
Days 28, 56, 100 and months 6, 9, 12, 18 and 24
Title
Incidence of chronic GVHD during the first year
Time Frame
Day 100 and months 6 and 12
Title
One year overall survival for each treatment cohort
Time Frame
1 year
Title
Incidence of systemic infections
Time Frame
Twice a week pre-transplant to day 100 then weekly or as clinically indicated
Title
Incidence of CMV, adenovirus and EBV activation
Time Frame
Twice a week pre-transplant to day 100 then weekly or as clinically indicated
Title
Immune reconstitution
Time Frame
Days 14, 28, 56, 100 and months 6, 9, 12, 18 and 24
Title
Dynamics of EBV infection and immunity following cord blood transplantation
Time Frame
Days 14, 28, 56, 100 and months 6, 9 and 12
Title
The development (if any) of transplant associated post transplant lymphoproliferative disease (PTLD)
Time Frame
Days 14, 28, 56, 100 and months 6, 9 and 12
Title
Identify any possible predictive markers for patients most at risk of PTLD development
Time Frame
Days 14, 28, 56, 100 and months 6, 9 and 12
Title
Quality of life
Time Frame
Pre-transplant and months 6, 12, 18 and 24
Title
Incidence of one year relapse or disease progression for each treatment cohort
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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 i. 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) a. 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 b. 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 a. 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Antonio Pagliuca, MBBS, MA, FRCP, FRCPath
Organizational Affiliation
King's College Hospital NHS Trust
Official's Role
Principal Investigator
Facility Information:
Facility Name
King's College Hosptial NHS Foundation Trust
City
London
ZIP/Postal Code
SE5 9RS
Country
United Kingdom

12. IPD Sharing Statement

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Pilot Study of Unrelated Cord Blood Transplantation

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