Single Centre Phase II Pilot study of Unrelated Cord Blood Transplantation in Patients with Poor Risk Haematological Malignancies.

• Register: EUCTR
• Last refreshed on: 26 November 2018
• Main ID: EUCTR2007-001657-26-GB
• Date of registration: 07/11/2007
• Prospective Registration: Yes
• Primary sponsor: King's College Hospital NHS Foundation Trust
• Public title: Single Centre Phase II Pilot study of Unrelated Cord Blood Transplantation in Patients with Poor Risk Haematological Malignancies.
• Scientific title: Single Centre Phase II Pilot study of Unrelated Cord Blood Transplantation in Patients with Poor Risk Haematological Malignancies.
• Date of first enrolment: 29/02/2008
• Target sample size: 27
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-001657-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: Open: Single blind: Double blind: Parallel group: Cross over: Other: If controlled, specify comparator, Other Medicinial Product: Placebo: Other:
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
4.1 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.
a. Acute myeloid leukaemia (AML)
i. In first complete remission (CR1) with one of the following characteristics:
1. 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)
2. Leukocytes at diagnosis > 50 x109/l (except in cases with good prognosis molecular rearrangements for which leukocytes should be > 100 x 109/l)
b. Myelodysplastic syndromes
1. International Prognosis Index (IPSS) above 1 (intermediate group 2 or high risk)
2. IPSS 0 or 0.5 in the presence of cytopenias requiring treatment.
c. Therapy related AML or MDS in first CR
d. AML or MDS in second (CR2) or subsequent CR
e. 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
a. Follicular NHL: in second or subsequent complete or partial remission
b. Mantle cell NHL: in second or subsequent complete or partial remission
c. 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.
a. in second or subsequent remission
b. 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

4.2 Patient Selection
4.2.1 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.




4.2.3 Inclusion criteria: reduced-intensity conditioning regimen:

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.


Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 ye
Exclusion criteria:
4.2.2 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

4.2.4 Exclusion Criteria: reduced-intensity 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 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





Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

1. Acute, chronic leukaemia or myelodysplastic syndrome for which allogeneic transplantation is considered as the best treatment option. 2. Acute lymphoblastic leukaemia (ALL) 3. Non-Hodgkin’s lymphoma 4. Hodgkin’s disease 5. Chronic lymphocytic leukaemia. 6. Acquired bone marrow failure syndromes 7. Other haematological malignancies for which UD bone marrow transplantation is indicated
MedDRA version: 9.1 Level: LLT Classification code 10000880 Term: Acute myeloid leukaemia
MedDRA version: 9.1 Level: LLT Classification code 10028533 Term: Myelodysplastic syndrome
MedDRA version: 9.1 Level: LLT Classification code 10009013 Term: Chronic myeloid leukaemia
MedDRA version: 9.1 Level: LLT Classification code 10000844 Term: Acute lymphoblastic leukaemia
MedDRA version: 9.1 Level: LLT Classification code 10020328 Term: Hodgkin's lymphoma
MedDRA version: 9.1 Level: LLT Classification code 10029593 Term: Non-Hodgkin's lymphoma NOS
MedDRA version: 9.1 Level: LLT Classification code 10003892 Term: B-cell chronic lymphocytic leukaemia/prolymphocytic leukaemia/small lymphocytic lymphoma
MedDRA version: 9.1 Level: LLT Classification code 10002968 Term: Aplastic anaemia, unspecified

Intervention(s)

Trade Name: Fludarabine
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: FLUDARABINE PHOSPHATE
CAS Number: 75607-67-9
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Trade Name: Busilvex
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: BUSULFAN
CAS Number: 55-98-1
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 6-

Trade Name: Thymoglobulin
Pharmaceutical Form: Powder for solution for infusion
CAS Number: 0
Other descriptive name: RABBIT HUMAN T LYMPHOCYTE IMMUNOGLOBULIN
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-

Trade Name: Thiotepa
Pharmaceutical Form: Powder for injection*
INN or Proposed INN: THIOTEPA
CAS Number: 52244
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 15-

Trade Name: Cyclophosphamide
Pharmaceutical Form: Powder and solvent for solution for infusion
CAS Number: 6055192
Other descriptive name: CYCLOPHOSPHAMIDE MONOHYDRATE
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 1-

Trade Name: Alkeran
Pharmaceutical Form: Powder for infusion*
INN or Proposed INN: MELPHALAN
CAS Number: 148-82-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Primary Outcome(s)

Secondary Objective: Secondary endpoints:
1. Estimated Disease Free Survival at 1 year post-transplant for each cohort.
2. Chimerism at days 14 (myeloablative conditioning only), 28,56,100, 6 months and 12 months
3. Incidence of neutrophil engraftment by day 42
4. Incidence of platelet engraftment by six months
5. Incidence of grade II-IV and III-IV acute GVHD
6. Incidence of chronic GVHD during the first year
7. Probability of one year overall survival for each treatment cohort
8. Incidence of one year relapse or disease progression for each treatment cohort.
9. Incidence of systemic infections
10. Incidence of CMV, adenovirus and EBV activation as described
11. Immune reconstitution
12. The dynamics of EBV infection and immunity following cord blood transplantation.
13. The development (if any) of transplant associated post transplant lymphoproliferative disease
14. Identify any possible predictive markers for patients most at risk of PTLD development
15. Quality of Life

Main Objective: 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.

Primary endpoint:

1. Treatment related mortality at Day 100.

Primary end point(s): Primary endpoint:

1. Treatment related mortality at Day 100.

Secondary ID(s)

KCH-BMT-07-1.0