Pilot Study of Unrelated Cord Blood Transplantation

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

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.

Study Overview

• Status: Terminated
• Conditions: Lymphoma, Non-Hodgkin; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Hodgkin Disease; Chronic Lymphocytic Leukemia; Leukemia, Lymphoblastic, Acute
• Intervention / Treatment: Radiation: Radiotherapy; Drug: Cyclophosphamide; Drug: Thymoglobulin; Drug: Fludarabine; Drug: Melphalan; Drug: Thiotepa; Drug: Mycophenolate mofetil (MMF); Drug: Intravenous busulphan; Drug: Ciclosporin

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SE5 9RS
    • King's College Hosptial NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Treatment related mortality at day 100	Day 100

Secondary Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: King's College Hospital NHS Trust
• Investigators: Principal Investigator: Antonio Pagliuca, MBBS, MA, FRCP, FRCPath, King's College Hospital NHS Trust

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: June 5, 2009
• First Submitted That Met QC Criteria: June 5, 2009
• First Posted (Estimate): June 8, 2009

Study Record Updates

• Last Update Posted (Estimate): February 11, 2015
• Last Update Submitted That Met QC Criteria: February 10, 2015
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Leukemia, Lymphoid; Leukemia, B-Cell; Lymphoma; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Hodgkin Disease; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Melphalan; Fludarabine; Fludarabine phosphate; Mycophenolic Acid; Thiotepa; Busulfan; Thymoglobulin; Antilymphocyte Serum; Cyclosporine; Cyclosporins; Vidarabine
• Other Study ID Numbers: 07CC12; REC - 07/H0808/193; EudraCT - 2007-001657-26