E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
In Patients with High-Risk Myelodysplastic Syndrome who have failed Therapy with Azacitidine |
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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 | 10028533 |
E.1.2 | Term | Myelodysplastic syndrome |
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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 maximal tolerated dose (MTD) and dose limiting toxicities (DLTs) of increased doses of IV clofarabine administered either daily from D1 to D5 for a 28 to 56 day-course or every other day from D1 to D10 for a 28 to 56 day-course.
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E.2.2 | Secondary objectives of the trial |
To determine response rates, as defined by the 2006 modified IWG criteria, associated with the two different dosing and scheduling of clofarabine in patients with high-risk MDS or AML patients with less than 30% marrow blasts (RAEB-T in FAB MDS classification), previously treated by Azacitidine and without erythroid response after 6 cycles of azacitidine To evaluate response duration, time to IPSS progression, and loss of RBC transfusion independence in these patients. To evaluate hospitalization duration, rates of rehospitalization for non-hematological toxicities, severe bleeding or febrile neutropenia.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Patients aged 18 years or more with MDS according to FAB classification and intermediate-2 or high IPSS risk scores, or CMML (with WBC < 13 x 109/L and bone marrow blasts > 10%) according to WHO classification, or AML according to WHO classification if less than 30% bone marrow blasts (RAEB-T according to FAB MDS classification)
•Patients previously treated by azacitidine (Vidaza®) in proven progression, or stable after 6 courses with ongoing transfusion dependent anemia (> 4 RBC units in the 8 weeks preceding inclusion ( as erythroid response in IWG 2006 criteria is reduction of at least 4 RBC units in 8 weeks )
•Previous biological and or targeted therapies of MDS or AML are allowed if stopped more than 1 month before inclusion. 1.ECOG PS ≤ 2. 2.Adequate renal and liver function 3.Serum creatinine ≤ 110 microM/L in men or 90 microM/L in women. If plasma creatinine level >90- 110microM, then the estimated glomerular filtration rate (GFR) must be > 50 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease (MDRD) equation where Predicted GFR (ml/min/1.73 m2) = 32788x (plasma creatinine level (microM)-1.154 x (age in years)-0.023 x (0.742 if patient is female) x (1.212 if patient is African American) 4.Bilirubin < 1.5 x ULN, (except increased unconjugated bilirubin due to dyserythropoiesis) 5.Aspartate transaminase (AST)/alanine transaminase (ALT) 2.5 × ULN and Alkaline phosphatase 2.5 × ULN
•Absence of pregnancy or lactation in female patients (Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment)
•Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.
•Provided signed written informed consent
•Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent
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E.4 | Principal exclusion criteria |
•Patients with AML and bone marrow blasts count of 20-30% , if candidates to intensive AML type chemotherapy •Known hypersensitivity to clofarabine or excipients •Concomitant malignant disease. •Active uncontrolled infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment). •Concomitant severe cardiovascular disease, i.e. congestive heart failure (NYHA grade > 3) •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 •No affiliation to a national insurance scheme directly or to an equivalent system •Chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol. •Use of investigational agents within 30 days or 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
The MTD is defined as the dose at which no more than one of 6 patients experience a DLT with the next higher dose having at least 2 of 3 or 2 of 6 patients experiencing a DLT. The MTD or the target dose level, whichever is attained first, will be the RD. The RD will be further confirmed by the accrual of 3 new patients and the analysis of the tolerance of repeated cycles. Definitions of DLT The dose limiting toxicity will be defined as the occurrence during the first treatment course of any of the toxicities listed below which are attributed to study drug. Toxicity grades are based on the NCI Common Terminology Criteria for Adverse Events (version 3.0). - Fifty percent drop in the absolute neutrophil count (ANC) or platelet count, compared to baseline, or lower limits of normal range (if baseline counts were above normal range) and without recovery by D56 of cycle 1 of therapy - Other non-hematologic toxicity = any other drug-related grade ≥ 3 non-hematologic toxicity during cycle, excluding febrile neutropenia, grade 3 skin rash, ≥ grade 3 anorexia, transient isolated elevations in hepatic transaminases or alkaline phosphatase, and nausea/vomiting, diarrhea, or mucositis that resolves (with or without supportive care) to < grade 3 within 48 hours of onset of ≥ grade 3. Patients will be only evaluable for DLTs, if a complete first course of clofarabine (D1-5 or D1, 3, 5, 8, 10), has been administered during the phase I part of the study. From course 2 in the phase I part, and during any courses in phase II part of the study, patients may be evaluable for toxicity if related to clofarabine even after a administration of a single dose
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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 | Yes |
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) | Yes |
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 | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
The dosage of Clofarabine will be gradually augmented in a 3+3 design |
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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 | 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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |