| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Myelodysplastic Syndrome (MDS) or secondary Acute Myeloid Leukemia after MDS |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the safety and tolerability of eltrombopag when administered to subjects with advanced MDS, sAML/MDS or de novo AML with 10-50% bone marrow blasts. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of eltrombopag on platelet counts.
To evaluate the effect of eltrombopag on the need for platelet transfusions.
To evaluate the effect of eltrombopag on the duration of platelet transfusion independence.
To evaluate the effect of eltrombopag on bleeding events.
To evaluate the effect of eltrombopag on overall survival (OS).
To evaluate eltrombopag population pharmacokinetics.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult subjects (18 years of age or older) with advanced MDS, sAML/MDS, or de novo AML with >=10% and <=50% blasts in bone marrow. Peripheral blood blast change over time should not be suggestive of highly proliferative disease (as judged by the investigator).
2. Subjects must be dependent on regular platelet transfusions or have a platelet count taken within the 4 weeks prior to randomization that is <30 Gi/L.
3. Subjects must be relapsed, refractory or ineligible to receive standard treatment
options of azacitidine and decitabine and must be relapsed, refractory or ineligible to
receive intensive chemotherapy or autologous/allogeneic stem cell transplantation. A subject may be considered relapsed/refractory to a standard treatment if it is discontinued due to lack of efficacy. For subjects ineligible for standard treatments, it is permissible to start one of these standard treatments while on study medication if the Investigator considers that the subject becomes eligible during the course of the study.
4. Prior therapy with demethylating agents (azacitidine or decitabine), lenalidomide or IL-11(oprelvekin) must have been completed at least 4 weeks before Day 1;
antithymocyte/antilymphocyte globulin, intensive chemotherapy, or autologous/allogeneic stem cell transplantation must have been completed at least 2
months before Day 1. If a subject must discontinue a course of therapy due to lack of efficacy, the washout periods listed above do not apply (and the patient may be screened and randomized immediately if other eligibility criteria are met).
5. Subjects must have platelet count and platelet transfusion data available over a
period of 4 weeks prior to randomization.
6. Subjects with advanced MDS, sAML/MDS or de novo AML must have stable disease indicated by a doubling time of peripheral blast counts >7 days during screening.
7. During the 4 weeks prior to randomization, subjects must have a baseline bone
marrow examination including the following:
a. cytomorphology to confirm bone marrow blasts between 10-50%,
b. cytogenetics (provide only most prevalent abnormal clone),
The results of the above tests are required prior to subject randomization
8. Supportive/palliative therapies such as cytokines (except for IL-11; oprelvekin), valproic acid, all-trans retinoic acid or mild chemotherapy are allowed if part of the local SOC, provided those therapies have been at a stable dose for 4 weeks. If the subject chooses to discontinue these therapies prior to study entry, they must be completed 4 weeks prior to enrollment into this study, unless the therapy is discontinued due to lack of efficacy. Erythropoiesis-timulatingagents (ESAs) in anemic subjects or granulocyte colony-stimulating factor (G-CSF) in subjects with severe neutropenia and recurrent infections are allowed during the study as per accepted standards. Subjects who enter the study on ESAs or G-CSF should continue at the same dose schedule until the optimal dose of study medication has been established.
9. ECOG Status 0-3.
10. Subject is able to understand and comply with protocol requirements and
instructions.
11. Subject has signed and dated informed consent.
12. Prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) must
be within 80 to 120% of the normal range at baseline.
13. Adequate baseline organ function defined by the criteria below:
• total bilirubin (except for Gilbert’s Syndrome) <=1.5xULN
• ALT and AST <=3xULN
• creatinine <=2xULN
• albumin must not be below the lower limit of normal (LLN) by more than 20%.
14. Subject is practicing an acceptable method of contraception (documented in chart). Female subjects (or female partners of male subjects) must either be of nonchildbearing potential (hysterectomy, bilateral oophorectomy, bilateral tubal ligation or post-menopausal >1 year), or of childbearing potential and use 1 of the following highly effective methods of contraception (i.e., Pearl Index <1.0%) from 2 weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study:
a. Complete abstinence from intercourse;
b. Intrauterine device (IUD);
c. Two forms of barrier contraception (diaphragm plus spermicide, and for males
condom plus spermicide);
d. Male partner is sterile prior to entry into the study and is the only partner of the
female;
e. Systemic contraceptives (combined or progesterone only). |
|
| E.4 | Principal exclusion criteria |
1. Subjects with a diagnosis of acute promyelocytic leukemia.
2. History of treatment for cancer (other than MDS, sAML/MDS or or de novo AML) with systemic chemotherapy and/or radiotherapy within the last 2 years.
3. History of treatment with romiplostim or other TPO-R agonists.
4. Pre-existing cardiovascular disease (including congestive heart failure, New York
Heart Association [NYHA] Grade III/IV), or arrhythmia known to increase the risk
of thromboembolic events (e.g. atrial fibrillation), or subjects with a QTc >450 msec
(QTc >480 msec for subjects with Bundle Branch Block).
5. Bone marrow fibrosis that leads to an inability to aspirate marrow for assessment.
6. Spleen size >14 cm (length as per ultrasound examination).
7. Leukocytosis ≥25,000/uL prior to Day 1 of study medication.
8. Female subjects who are nursing or pregnant (positive serum or urine β-human
chorionic gonadotropin [β-hCG] pregnancy test) at screening or pre-dose on Day 1.
9. Current alcohol or drug abuse.
10. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is
longer) preceding the first dose of study medication.
11. Active and uncontrolled infections.
12. Subjects infected with Hepatitis B, C or Human Immunodeficiency Virus (HIV).
13. Subjects with liver cirrhosis. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety and tolerability parameters including non-hematological laboratory Grade 3/Grade 4 toxicities, change in bone marrow blast counts from baseline and adverse events reporting. |
|
| 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 | No |
| 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 | 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) | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
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