E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) considered ineligible to standard conditioning therapies prior to allogeneic stem cell transplantation. |
Patienten mit akuter myeloischer Leukämie (AML) oder myelodysplatischem Syndrom (MDS), die für eine Standard-Konditionierungstherapie vor allogener Stammzelltransplantation nicht in Frage kommen. |
|
E.1.1.1 | Medical condition in easily understood language |
Patients with haematopoietic tumors, who are ineligible to standard conditioning therapy (e.g. high dose chemotherapy or total body irradiation) prior to stem cell transplantation. |
Patienten mit Blutkrebs, die für eine Standard-Konditionierungsbehandlung (z. B. Hochdosis-Chemotherapie oder Ganzkörperbestrahlung) vor Stammzelltransplantation nicht geeignet sind. |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10000881 |
E.1.2 | Term | Acute myeloid leukaemia (in remission) |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028534 |
E.1.2 | Term | Myelodysplastic syndrome NOS |
E.1.2 | System Organ Class | 100000013034 |
|
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 show at least non-inferiority of treosulfan-based conditioning to reduced-intensity conditioning therapy based on i.v. busulfan and to compare the associated safety profiles.
The aim of the study is to compare event-free survival within 2 years after transplantation between treosulfan-based conditioning and busulfan-based conditioning. Events are defined as relapse of disease, graft failure or death (whatever occurs first). |
|
E.2.2 | Secondary objectives of the trial |
1. Comparative evaluation of incidence of CTC grade III/IV mucositis between day -6 and day +28.
2. Comparative evaluation of overall survival (OS) and cumulative incidence of relapse (RI), non-relapse mortality (NRM) and transplantation-related mortality (TRM) within 2 years after transplantation.
3. Comparative evaluation of day +28 conditional cumulative incidence of engraftment.
4. Comparative evaluation of day +28 and day +100 incidence of complete donor-type chimerism.
5. Comparative evaluation of cumulative incidence of acute and chronic GvHD within 2 years after transplantation.
6. Comparative evaluation of incidence of other CTC grade III/IV adverse events between day -6 and day +28.
|
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Evaluation of treosulfan pharmacokinetics (sub-study for patients randomised into the test-arm "treosulfan-based conditioning" of medac protocol MC-FludT.14/L).
Amendment 02, dated November 13, 2009 (country-specific for Germany) to study protocol MC-FludT.14/L (version: 02, dated September 23, 2009).
The objective of the sub-study is the pharmacokinetic (pk) evaluation of treosulfan (3 x 14 g/m2) if used in combination with fludarabine (5 x 30 mg/m2) as conditioning regimen. A subset of 24 patients (male or female) randomised in the treatment arm for treosulfan-based conditioning is intended to be included in the pk evaluation.
Individual pharmacokinetic parameters derived from treosulfan concentration in plasma and urine will be evaluated by standard model independent methods as well as two-compartment disposition modelling (e.g. AUC, Cmax, t1/2, CLtotal, Vss).
The objective of the new sub-study is the pharmacokinetic (pk) evaluation of treosulfan (3 x 10 g/m2) if used in combination with fludarabine (5 x 30 mg/m2) as conditioning regimen. A subset of 18 patients (male or female) randomised in the treatment arm for treosulfan-based conditioning is intended to be included in the pk evaluation. Individual pharmacokinetic parameters derived from treosulfan and its active epoxide concentration in plasma will be evaluated. |
|
E.3 | Principal inclusion criteria |
1. Patients with acute myeloid leukaemia acc. to WHO, 2008 (AML in complete remission at transplant, i.e. blast counts < 5 % in bone marrow) or myelodysplastic syndrome acc. to WHO, 2008 (MDS with blast counts < 20 % in bone marrow during disease history) indicated for allogeneic haematopoietic progenitor cell transplantation but considered to be at increased risk for standard conditioning therapies according to the following criteria:
- patients aged ≥ 50 years at transplant
and/or
- patients with a HCT-CI score > 2 [according to Sorror et al., 2005]
2. Availability of an HLA-identical sibling donor (MRD) or HLA-identical unrelated donor (MUD). Donor selection is based on molecular high resolution typing (4 digits) of class II alleles of the DRB1 and DQB1 gene loci and molecular (at least) low resolution typing (2 digits) of class I alleles (i.e., antigens) of the HLA- A, B, and C gene loci.
In case no class I and class II completely identical donor (10 out of 10 gene loci) can be identified, one antigen disparity (class I) and/or one allele disparity (class II) between patient and donor are acceptable. Conversely, disparity of two antigens (irrespective of the involved gene loci) cannot be accepted. These definitions for the required degree of histocompatibility apply to the selection of related as well as unrelated donors.
3. Adult patients of both gender, 18 – 70 years of age
4. Karnofsky Index ≥ 60 %
5. Written informed consent
6. Men capable of reproduction and women of childbearing potential must be willing to consent to using a highly effective method of birth control such as condoms, implants, injectables, combined oral contraceptives, IUDs, sexual abstinence or vasectomised partner while on treatment and for at least 6 months thereafter. |
|
E.4 | Principal exclusion criteria |
1. Patients with acute promyelocytic leukaemia with t(15;17)(q22;q12) and in CR1
2. Patients considered contra-indicated for allogeneic HSCT due to severe concomitant illness (within three weeks prior to scheduled day -6):
- patients with severe renal impairment like patients on dialysis or prior renal transplantation or S-creatinine > 3.0 x ULN or calculated creatinine-clearance < 60 ml/min
- patients with severe pulmonary impairment, DLCOSB
(Hb-adjusted)/or FEV1 < 50 % or severe dyspnoea at rest or requiring oxygen supply
- patients with severe cardiac impairment diagnosed by electrocardiogram and LVEF < 40 %
- patients with severe hepatic impairment indicated by hyperbilirubinaemia > 3 x ULN or ALT / AST > 5 x ULN
3. Active malignant involvement of the CNS
4. HIV-positivity, active non-controlled infectious disease under treatment (no decrease of CRP or PCT) including active viral liver infection
5. Previous allogeneic HSCT
6. Pleural effusion or ascites > 1.0 L
7. Pregnancy or lactation
8. Known hypersensitivity to treosulfan, busulfan and/or related ingredients
9. Participation in another experimental drug trial within 4 weeks prior to day –6 of the protocol
10. Non-cooperative behaviour or non-compliance
11. Psychiatric diseases or conditions that might compromise the ability to give informed consent
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Event-free survival (EFS) within 2 years after transplantation measured from time of start of HSCT (= day 0) to time of event. Events are defined as relapse of disease, graft failure or death (whatever occurs first). |
Ereignisfreies Überleben innerhalb von 2 Jahren nach Beginn der Transplantation (= Tag 0). Ereignisse sind definiert als Rezidiv der Erkrankung, Transplantatversagen oder Tod (was zuerst eintritt). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
2 years after start of transplantation. |
2 Jahre nach Beginn der Transplantation. |
|
E.5.2 | Secondary end point(s) |
CTC grade III/IV mucositis between day -6 and day +28.
Overall survival, relapse, non-relapse mortality and transplantation-related mortality within 2 years after transplantation.
Engraftment until day +28.
Complete donor-type chimerism of day +28 and day +100.
Acute and chronic GvHD within 2 years after transplantation.
|
CTC Grad III/IV Mukositis zwischen Tag -6 und Tag +28.
Gesamtüberleben, Rezidivrate, Nicht-rezidiv bedingte Mortalität und transplantationsbedingte Mortalität innerhalb von 2 Jahren nach Transplantation.
Transplantatanwachsen bis Tag +28.
Kompletter Donor-Typ Chimärismus an Tag +28 und Tag +100.
Akute und chronische GvHD innerhalb von 2 Jahren nach Transplantation. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to E.5.2 |
Siehe E.5.2 |
|
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 | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
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 | No |
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
|
According to study protocol chapter 5.4, the last patient will probably included in Q1-2017. Due to the follow-up of all study patients for 2 year after transplantation, the last patient out will expected in Q1-2019. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |