| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with high risk acute myeloid leukemia (AML) or advanced myelodysplastic syndrome (MDS) scheduled for allogeneic stem cell transplantation (SCT). |
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| E.1.1.1 | Medical condition in easily understood language |
| blood cancer and blood disorder |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028533 |
| E.1.2 | Term | Myelodysplastic syndrome |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate that event-free survival is improved by using ClAraC instead of the FLAMSA regimen. |
|
| E.2.2 | Secondary objectives of the trial |
1. Overall and relapse-free survival
2. Morbidity and mortality after allogeneic SCT with focus on cardiac toxicity
3. Rate of engraftment
4. Kinetics of chimerism after allogeneic SCT
Assessment of safety:
To evaluate the toxicity and safety of clofarabine in combination with ara-C and in comparison to FLAMSA in the setting of allogeneic SCT in patients with high risk AML or advanced MDS.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed written informed consent
2. Age ≥ 18 at the day of inclusion
3. Patients with high risk AML or advanced MDS (IPSS score ≥ intermediate 2) scheduled for an allogeneic SCT from HLA-matched related or unrelated donor
4. Amount of blasts < 60% (bone marrow)
5. Patients fulfilling at least one of the following risk factors:
• Contraindication for conventional conditioning therapy
• Relapsed or refractory to induction therapy
6. Adequate renal, hepatic and cardiac functions as indicated by the following values:
• Serum creatinine < = 1.0 mg/dL;
if serum creatinine > 1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be > 60 mL/min/1.73 m2
• Serum bilirubin < = 1.5 x upper limit of normal (ULN)
• Aspartate transaminase (AST) / alanine transaminase (ALT) < = 2.5 x ULN
• Alkaline phosphatase < = 5 x ULN
• Left ventricular ejection fraction ≥ 50 %
7. Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent
8. Female patients of childbearing potential must have a negative serum pregnancy test at the day of inclusion
9. Female patients must meet one of the following criteria:
• For female patients >= 50 years of age at the day of inclusion: Menopause since at least 1 year
• Female patients < 50 years of age at the day of inclusion who meet all of the following criteria:
- menopause since at least 1 year
- serum FSH levels > 40 MIU/mL
- serum estrogen levels < 30 pg/mL or negative estrogen test
• 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral ovariectomy with or without hysterectomy
• Correct use of two reliable contraception methods from the time of screening and during the study for a minimum of 90 days after the last administration of study medication. This includes every combination of a hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical ring) or of an intrauterine device (IUD) with a barrier method (diaphragm, cervical cap, Lea contraceptive, femidom or condom) or with a spermicide. In case the patient takes hormone preparations for suppression of menstruation during the period of aplasia, a suitable and effective method of contraception has to be discussed with the investigator and used by the patient
• General sexual abstinence from the time of screening, during the study until a minimum of 90 days after the last administration of study medication
• Having only female sexual partners
• Monogamous relationship with sterile male partner
10. Male patients must meet one of the following criteria:
• 6 weeks after surgical sterilization by vasectomy
• Correct use of two reliable contraception methods from the time of screening and during the study for a minimum of 90 days after the last administration of study medication. This includes every combination of a hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical ring) or of an intrauterine device (IUD) with a barrier method (diaphragm, cervical cap, Lea contraceptive, femidom or condom) or with a spermicide.
• General sexual abstinence from the time of screening, during the study until a minimum of 90 days after the last administration of study medication
• Having only male sexual partners
• Monogamous relationship with sterile female partner
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|
| E.4 | Principal exclusion criteria |
1. Patients with acute promyelocytic leukemia with t(15;17)
2. Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol
3. Any anticancer therapy within 2 weeks before study entry with the exception of hydroxyurea.
The patient must have recovered from all acute toxicities from any previous therapy
4. Current participation in any other clinical trial and/or participation in another clinical trial within 30 days before the trial begins (Exception: Parallel follow-up of any other trial at least 30 days after end of intervention)
5. Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart (heart insufficiency ≥ NYHA II), kidney (serum creatinine > 1.5 x normal serum level), liver (bilirubin > 1.5 x normal serum level, AST / ALT, AP > 5 x normal serum level), or other organ system that may place the patient at undue risk to undergo treatment
6. Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)
7. Human immunodeficiency virus (HIV) positivity
8. Pregnant or lactating patients
9. Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results
10. Have had a diagnosis of another malignancy, unless the patient has been disease-free for at least 3 years following the completion of curative intent therapy, with the following exceptions:
• Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed
• Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 18 months after stem cell Tx (last patient in) - approx. 72 months after stem cell Tx (first patient in). In case of death: timepoint of death. |
|
| E.5.2 | Secondary end point(s) |
1. Overall and relapse-free survival
2. Morbidity and mortality after allogeneic stem cell transplantation with focus on cardiac toxicity
3. Rate of engraftment
4. Kinetics of chimerism after allogeneic stem cell transplantation
Safety endpoints:
Toxicity and safety of clofarabine in combination with ara-C (ClAraC) and in comparison to FLAMSA |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary end points 1.-4.:
18 months after stem cell Tx (last patient in) - approx. 72 months after stem cell Tx (first patient in). In case of death: timepoint of death.
Safety endpoints:
30 days after stem cell Tx |
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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 | 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 | 3 |
| 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 | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| 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 |
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