| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| MYELODYSPLASTIC SYNDROMES |
|
| 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 | 10028534 |
| E.1.2 | Term | Myelodysplastic syndrome NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Phase I
To determine the safety of the deferasinox-vitaminD-azacitidine comination in the treatment of high-risk MDS
Phase II
To evaluate the response rate (CR, PR, marrow CR, according to IWG 2006 criteria) |
|
| E.2.2 | Secondary objectives of the trial |
Clinical part, to determine:
-the duration of the response
-overall survival
-the safety profile
Biological studies:
-Pre-treatment assessment; incidence of vitamin D deficiency and iron overload in MDS
-To monitor the safety of the combination iron work up; vitamin D level, renal function, phosphorus/calcium work up.
-To assess the correction of cytopenias and other effects on the complete blood count (elevation of circulating monocytes, blast counts)
-To establish pre-treatment tests that would predict the clinical response.
-To understand the mechanisms underlying efficacy, any resistance and secondary treatment failure. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Myelodysplastic Syndrome intermediate II and high risk according to the IPSS, non-proliferative chronic myelomonocytic leukemia (CMML) (leukocytes < 13 G/L), RAEB-T according to the FAB classification (< 30% blasts);
2.IPSS score ≥ 1.5 (risk categories intermediate-2 and high);
3.Age ≥ 18 years;
4.ECOG performance status ≤ 2 (cf. appendix 4);
5.Normal liver function, defined by total bilirubin and transaminases less than 1.5 times the upper limit of normal;
6.Normal renal function, defined by creatinine less than 1.2 times the upper limit of normal, creatinine clearance < 60 mL/min, and normal electrolytes (potassium > 4.0 mEq/L and magnesium > 75 mEq/L);
7.Patient ineligible for allogeneic hematopoietic stem cell transplantation;
8.Adherence to the study visit Schedule;
9.Women of childbearing potential must: Agree to use effective contraception without interruption throughout the study and for a further 3 months after the end of treatment;
10. Men must: Agree to not conceive during the treatment and to use effective contraception during the treatment period (including periods of dose reduction or temporary suspension) and for a further 3 months after the end of treatment if their partner is of childbearing potential. Agree to learn about the procedures for preservation of sperm.
|
|
| E.4 | Principal exclusion criteria |
1.Severe infection or any other uncontrolled severe condition
2.Less than 30 days since prior treatment with growth factors (EPO, G-CSF) or non-cytotoxic agents (including low-dose oral
chemotherapy)i in the event of prior treatment with cytotoxic or demethylating agents, an interval of 3 months is required;
3.Active cancer, or cancer during the year prior to trial entry other than
basal cell carcinoma or carcinoma in situ of the cervix or breast;
4.History of urinary calculi; 5.Uncontrolled primary hyperparathyroidis;
6.Hypercalcemia and/or hypophosphatemia, hypervitaminosis D; 7.Patient already enrolled in another therapeutic trial of an
investigational drug; 8.HIV infection or active hepatitis B or C;
9.Women who are or could become pregnant, or who are currently
breastfeeding;
10.Any medical or psychiatric contraindication that would prevent the patient from understanding and signing the informed consent form; 11.Ferritin < 300 ng/mL.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I: Safety of the deferasirox-vitamin D combination and of azacitidine. It will be analyzed after 2 cycles, and the decision to continue to the dose level above and to enroll 20 phase II patients (10 patients per group) will be taken after assessment of the first patients enrolled by an independent data monitoring committee (IDMC), in association with the investigators.
-Phase II: number of complete responses (CR) + partial responses (PR) according to IWG 2006 criteria . |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I: Toxicity, evaluated using NCI-CTCAE V3.0 criteria. All patients who have received at least one cycle will be considered evaluable for response.
Phase II: response, according to IWG 2006 criteria. |
|
| E.5.2 | Secondary end point(s) |
Total percentage of responses, including all patients achieving CR, PR, marrow CR or hematologic improvement, evaluated according to IWG 2006 criteria after 3 and 6 treatment cycles.
-Duration of response, measured from the date an objective response was achieved to the date of relapse or progression or the date of last contact if no event occurred.
-Overall survival measured from the date of enrollment to death or the date of last contact.
-Biological assessment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
to determine
-the duration of the response
-overall survival
-the safety profile |
|
| 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 | Yes |
| E.7.1.3.1 | Other trial type description |
| Testing three levels of doses of Exjade |
|
| 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 | 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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
|
- Frequency and / or severity of an unexpected toxicity,
- Inadequate patient recruitment,
- Insufficient quality data collection. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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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