Study PMA112509, a Phase I/II Study of Eltrombopag in Thrombocytopenic Subjects With Advanced Myelodysplastic Syndrome (MDS) or Secondary Acute Myeloid Leukemia After MDS (sAML/MDS)
- 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
- 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.
- 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.
- 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).
- Subjects must have platelet count and platelet transfusion data available over a
period of 4 weeks prior to randomization.
- 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.
- During the 4 weeks prior to randomization, subjects must have a baseline bone marrow
examination including the following:
- cytomorphology to confirm bone marrow blasts between 10-50%,
- cytogenetics (provide only most prevalent abnormal clone),
The results of the above tests are required prior to subject randomization.
- 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-stimulating agents (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
- ECOG Status 0-3.
- Subject is able to understand and comply with protocol requirements and instructions.
- Subject has signed and dated informed consent.
- Prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) must be
within 80 to 120% of the normal range at baseline.
- 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%.
- Subject is practicing an acceptable method of contraception (documented in chart).
Female subjects (or female partners of male subjects) must either be of
non-childbearing 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:
- Complete abstinence from intercourse;
- Intrauterine device (IUD);
- Two forms of barrier contraception (diaphragm plus spermicide, and for males condom
- Male partner is sterile prior to entry into the study and is the only partner of the
- Systemic contraceptives (combined or progesterone only).
- Subjects with a diagnosis of acute promyelocytic leukemia.
- History of treatment for cancer (other than MDS, sAML/MDS, or de novo AML) with
systemic chemotherapy and/or radiotherapy within the last 2 years.
- History of treatment with romiplostim or other TPO-R agonists.
- 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).
- Bone marrow fibrosis that leads to an inability to aspirate marrow for assessment.
- Spleen size >14 cm (length as per ultrasound examination).
- Leukocytosis >=25,000/uL prior to Day 1 of study medication.
- Female subjects who are nursing or pregnant (positive serum or urine Beta-human
chorionic gonadotropin [B-hCG] pregnancy test) at screening or pre-dose on Day 1.
- Current alcohol or drug abuse.
- Treatment with an investigational drug within 30 days or 5 half-lives (whichever is
longer) preceding the first dose of study medication.
- Active and uncontrolled infections.
- Subjects infected with Hepatitis B, C or Human Immunodeficiency Virus (HIV).
- Subjects with liver cirrhosis.