E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000880 |
E.1.2 | Term | Acute myeloid leukaemia |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028533 |
E.1.2 | Term | Myelodysplastic syndrome |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009013 |
E.1.2 | Term | Chronic myeloid leukaemia |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000844 |
E.1.2 | Term | Acute lymphoblastic leukaemia |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020328 |
E.1.2 | Term | Hodgkin's lymphoma |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029593 |
E.1.2 | Term | Non-Hodgkin's lymphoma NOS |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003892 |
E.1.2 | Term | B-cell chronic lymphocytic leukaemia/prolymphocytic leukaemia/small lymphocytic lymphoma |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10002968 |
E.1.2 | Term | Aplastic anaemia, unspecified |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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.
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E.2.2 | Secondary objectives of the trial |
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
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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.
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E.4 | Principal 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
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint:
1. Treatment related mortality at Day 100.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |