Brief Summary
This was a worldwide, three-part (Part 1: open-label, Part 2: randomized, double-blind, Part 3: extension), multi-center study to evaluate the effect of eltrombopag in subjects with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have thrombocytopenia due to bone marrow insufficiency from their underlying disease or prior chemotherapy. This objective was assessed by a composite primary endpoint that consists of the following: the proportion of ≥Grade 3 hemorrhagic adverse events, or platelet counts \<10 Gi/L, or platelet transfusions. Patients with MDS or AML and Grade 4 thrombocytopenia due to bone marrow insufficiency from their underlying disease or prior chemotherapy were enrolled in the study. No low or intermediate-1 risk MDS subjects were enrolled in the study. Subjects must have had at least one of the following during the 4 weeks prior to enrolment: platelet count \<10 Gi/L, platelet transfusion, or symptomatic hemorrhagic event. Supportive standard of care (SOC), including hydroxyurea, was allowed as indicated by local practice throughout the study. The study had 3 sequential parts. Subjects who were enrolled in Part 1 (open-label) cannot be enrolled in Part 2 of the study (randomized, double-blind); however, subjects who completed the treatment period for Part 1 or Part 2 (8 and 12 weeks, respectively) continued in Part 3 (extension) if the investigator determined that the subject was receiving clinical benefit on treatment.
Brief Title
A Three-part Study of Eltrombopag in Thrombocytopenic Subjects With Myelodysplastic Syndromes or Acute Myeloid Leukemia
Categories
Completion Date
Completion Date Type
Actual
Conditions
Thrombocytopaenia
Eligibility Criteria
Inclusion Criteria:
* Adult subjects (18 years of age or older) with MDS or AML (bone marrow blasts ≤50%) with thrombocytopenia due to bone marrow insufficiency from the disease or prior treatment. Subjects with transient thrombocytopenia due to active treatment with disease modifying agents or chemotherapy (except for hydroxyurea) are excluded.
* Subjects must have Grade 4 thrombocytopenia (platelet counts \<25 Gi/L) due to bone marrow insufficiency (or Grade 4 thrombocytopenia, but platelet count greater than or equal to 25 Gi/L due to platelet transfusion). In addition, subjects must have had at least one of the following during the 4 week screening period: platelet transfusion, or symptomatic bleeding or platelet count \<10 Gi/L. Subjects whose thrombocytopenia below 10 Gi/L is due to causes other than bone marrow insufficiency (e.g., fever, infection, autoimmune disease) are not eligible.
* Subjects must have platelet count, bleeding and platelet transfusion data available over a period of at least 4 weeks prior to randomization.
* Prior systemic treatment for malignancy, with the exception of hydroxyurea, must have been discontinued prior to entry into the study: at least 4 weeks before Day 1 for the following: chemotherapy, demethylating agents (azacitidine or decitabine), lenalidomide, thalidomide, clofarabine and IL-11(oprelvekin); at least 8 weeks before Day 1 for antithymocyte/antilymphocyte globulin.
* Subjects with a prior stem cell transplant (SCT) must have relapsed after the SCT.
* Subjects must be stable and, in the opinion of the investigator, be expected to complete a 12 week treatment period.
* ECOG Status 0-2.
* Subject must be able to understand and comply with protocol requirements and instructions.
* Subject has signed and dated an informed consent form.
* Adequate baseline organ function defined by the criteria below: total bilirubin ≤ 1.5xULN except for Gilbert's syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect (hemolytic) bilirubin in the absence of ALT abnormality), ALT ≤ 3xULN, creatinine ≤ 2.5xULN
* Women must be either of non-child bearing potential or women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to the first dose of study treatment.
* In France, a subject eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.
Exclusion Criteria:
* Subjects with MDS and an IPSS of low or intermediate-1 risk at screening.
* Subjects with a diagnosis of acute promyelocytic or megakaryocytic leukemia or AML secondary to a myeloproliferative neoplasm.
* History of treatment with romiplostim or other TPO-R agonists.
* Subjects with a QTc \>480 msec (QTc \>510 msec for subjects with Bundle Branch Block).
* Leukocytosis ≥25,000/uL on Day 1 of treatment with study medication.
* Subjects with known thrombophilic risk factors. Exception: Subjects for whom the potential benefits of participating in the study outweigh the potential risks of thromboembolic events, as determined by the investigator.
* 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.
* 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 (e.g. sepsis, hepatitis B, hepatitis C).
* Subjects infected with Human Immunodeficiency Virus (HIV).
* Subjects with liver cirrhosis (as determined by the investigator).
* Subjects receiving or planned to receive any prohibited medication.
* Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or excipient (microcrystalline cellulose, mannitol, polyvinylpyrrolidone, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol 400 and polysorbate 80) that contraindicates the subjects' participation.
* In France, subjects who have participated in any study using an investigational drug during the previous 30 days.
* Adult subjects (18 years of age or older) with MDS or AML (bone marrow blasts ≤50%) with thrombocytopenia due to bone marrow insufficiency from the disease or prior treatment. Subjects with transient thrombocytopenia due to active treatment with disease modifying agents or chemotherapy (except for hydroxyurea) are excluded.
* Subjects must have Grade 4 thrombocytopenia (platelet counts \<25 Gi/L) due to bone marrow insufficiency (or Grade 4 thrombocytopenia, but platelet count greater than or equal to 25 Gi/L due to platelet transfusion). In addition, subjects must have had at least one of the following during the 4 week screening period: platelet transfusion, or symptomatic bleeding or platelet count \<10 Gi/L. Subjects whose thrombocytopenia below 10 Gi/L is due to causes other than bone marrow insufficiency (e.g., fever, infection, autoimmune disease) are not eligible.
* Subjects must have platelet count, bleeding and platelet transfusion data available over a period of at least 4 weeks prior to randomization.
* Prior systemic treatment for malignancy, with the exception of hydroxyurea, must have been discontinued prior to entry into the study: at least 4 weeks before Day 1 for the following: chemotherapy, demethylating agents (azacitidine or decitabine), lenalidomide, thalidomide, clofarabine and IL-11(oprelvekin); at least 8 weeks before Day 1 for antithymocyte/antilymphocyte globulin.
* Subjects with a prior stem cell transplant (SCT) must have relapsed after the SCT.
* Subjects must be stable and, in the opinion of the investigator, be expected to complete a 12 week treatment period.
* ECOG Status 0-2.
* Subject must be able to understand and comply with protocol requirements and instructions.
* Subject has signed and dated an informed consent form.
* Adequate baseline organ function defined by the criteria below: total bilirubin ≤ 1.5xULN except for Gilbert's syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect (hemolytic) bilirubin in the absence of ALT abnormality), ALT ≤ 3xULN, creatinine ≤ 2.5xULN
* Women must be either of non-child bearing potential or women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to the first dose of study treatment.
* In France, a subject eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.
Exclusion Criteria:
* Subjects with MDS and an IPSS of low or intermediate-1 risk at screening.
* Subjects with a diagnosis of acute promyelocytic or megakaryocytic leukemia or AML secondary to a myeloproliferative neoplasm.
* History of treatment with romiplostim or other TPO-R agonists.
* Subjects with a QTc \>480 msec (QTc \>510 msec for subjects with Bundle Branch Block).
* Leukocytosis ≥25,000/uL on Day 1 of treatment with study medication.
* Subjects with known thrombophilic risk factors. Exception: Subjects for whom the potential benefits of participating in the study outweigh the potential risks of thromboembolic events, as determined by the investigator.
* 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.
* 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 (e.g. sepsis, hepatitis B, hepatitis C).
* Subjects infected with Human Immunodeficiency Virus (HIV).
* Subjects with liver cirrhosis (as determined by the investigator).
* Subjects receiving or planned to receive any prohibited medication.
* Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or excipient (microcrystalline cellulose, mannitol, polyvinylpyrrolidone, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol 400 and polysorbate 80) that contraindicates the subjects' participation.
* In France, subjects who have participated in any study using an investigational drug during the previous 30 days.
Inclusion Criteria
Inclusion Criteria:
* Adult subjects (18 years of age or older) with MDS or AML (bone marrow blasts ≤50%) with thrombocytopenia due to bone marrow insufficiency from the disease or prior treatment. Subjects with transient thrombocytopenia due to active treatment with disease modifying agents or chemotherapy (except for hydroxyurea) are excluded.
* Subjects must have Grade 4 thrombocytopenia (platelet counts \<25 Gi/L) due to bone marrow insufficiency (or Grade 4 thrombocytopenia, but platelet count greater than or equal to 25 Gi/L due to platelet transfusion). In addition, subjects must have had at least one of the following during the 4 week screening period: platelet transfusion, or symptomatic bleeding or platelet count \<10 Gi/L. Subjects whose thrombocytopenia below 10 Gi/L is due to causes other than bone marrow insufficiency (e.g., fever, infection, autoimmune disease) are not eligible.
* Subjects must have platelet count, bleeding and platelet transfusion data available over a period of at least 4 weeks prior to randomization.
* Prior systemic treatment for malignancy, with the exception of hydroxyurea, must have been discontinued prior to entry into the study: at least 4 weeks before Day 1 for the following: chemotherapy, demethylating agents (azacitidine or decitabine), lenalidomide, thalidomide, clofarabine and IL-11(oprelvekin); at least 8 weeks before Day 1 for antithymocyte/antilymphocyte globulin.
* Subjects with a prior stem cell transplant (SCT) must have relapsed after the SCT.
* Subjects must be stable and, in the opinion of the investigator, be expected to complete a 12 week treatment period.
* ECOG Status 0-2.
* Subject must be able to understand and comply with protocol requirements and instructions.
* Subject has signed and dated an informed consent form.
* Adequate baseline organ function defined by the criteria below: total bilirubin ≤ 1.5xULN except for Gilbert's syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect (hemolytic) bilirubin in the absence of ALT abnormality), ALT ≤ 3xULN, creatinine ≤ 2.5xULN
* Women must be either of non-child bearing potential or women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to the first dose of study treatment.
* In France, a subject eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.
* Adult subjects (18 years of age or older) with MDS or AML (bone marrow blasts ≤50%) with thrombocytopenia due to bone marrow insufficiency from the disease or prior treatment. Subjects with transient thrombocytopenia due to active treatment with disease modifying agents or chemotherapy (except for hydroxyurea) are excluded.
* Subjects must have Grade 4 thrombocytopenia (platelet counts \<25 Gi/L) due to bone marrow insufficiency (or Grade 4 thrombocytopenia, but platelet count greater than or equal to 25 Gi/L due to platelet transfusion). In addition, subjects must have had at least one of the following during the 4 week screening period: platelet transfusion, or symptomatic bleeding or platelet count \<10 Gi/L. Subjects whose thrombocytopenia below 10 Gi/L is due to causes other than bone marrow insufficiency (e.g., fever, infection, autoimmune disease) are not eligible.
* Subjects must have platelet count, bleeding and platelet transfusion data available over a period of at least 4 weeks prior to randomization.
* Prior systemic treatment for malignancy, with the exception of hydroxyurea, must have been discontinued prior to entry into the study: at least 4 weeks before Day 1 for the following: chemotherapy, demethylating agents (azacitidine or decitabine), lenalidomide, thalidomide, clofarabine and IL-11(oprelvekin); at least 8 weeks before Day 1 for antithymocyte/antilymphocyte globulin.
* Subjects with a prior stem cell transplant (SCT) must have relapsed after the SCT.
* Subjects must be stable and, in the opinion of the investigator, be expected to complete a 12 week treatment period.
* ECOG Status 0-2.
* Subject must be able to understand and comply with protocol requirements and instructions.
* Subject has signed and dated an informed consent form.
* Adequate baseline organ function defined by the criteria below: total bilirubin ≤ 1.5xULN except for Gilbert's syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect (hemolytic) bilirubin in the absence of ALT abnormality), ALT ≤ 3xULN, creatinine ≤ 2.5xULN
* Women must be either of non-child bearing potential or women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to the first dose of study treatment.
* In France, a subject eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.
Gender
All
Gender Based
false
Keywords
acute myeloid leukemia (AML)
acute myelogenous leukemia (AML)
acute non lymphocytic leukemia (ANLL)
myeloproliferative disease (MDS)
myelodysplastic syndrome ( secondary acute myeloid leukemia)
refractory acute myeloid leukemia
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
110 Years
Minimum Age
18 Years
NCT Id
NCT01440374
Org Class
Industry
Org Full Name
Novartis
Org Study Id
114968
Overall Status
Completed
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Three-part Study of Eltrombopag in Thrombocytopenic Subjects With Myelodysplastic Syndromes or Acute Myeloid Leukemia (Part 1: Open-label, Part 2: Randomized, Double-blind, Part 3: Extension)
Primary Outcomes
Outcome Description
A participant was considered as a responder if he/she met the following response criteria: a Baseline platelet count \<20 Giga cells per liter (Gi/L) and a post-Baseline increased to \>20 Gi/L and at least 2 times the Baseline value; or a Baseline platelet count \>=20 Gi/L and a post-Baseline absolute platelet count increased to \>=50 Gi/L and at least 2 times the Baseline value. The response criteria was evaluated at each visit. Increase in platelet count observed up to 3 days after a platelet transfusion was not considered as a platelet response. The Part 1 Population was comprised of all participants enrolled into Part 1.
Outcome Measure
Number of Participants With Platelet Response up to Week 8 During Part 1
Outcome Time Frame
From Baseline up to Week 8 during Part 1
Outcome Description
A participant was considered to have a CRTE at a given assessment if he/she had platelet counts \<10 Gi/L, or platelet transfusions, or \>=Grade 3 hemorrhagic adverse events. CRTEs during Weeks 5 to 12 were compared between treatments using a generalized linear mixed model. Average of weekly proportion of subjects with CRTE during Week 5 to 12 was estimated for each treatment. Intent to Treat (ITT) Population was comprised of all randomized participants during Part 2.
Outcome Measure
Clinically Relevant Thrombocytopenic Events (CRTE) From Week 5 up to Week 12 During Part 2
Outcome Time Frame
From Week 5 up to Week 12 during Part 2
Secondary Ids
Secondary Id
2011-000114-19
Secondary Outcomes
Outcome Time Frame
Day 1 to week 8
Outcome Measure
Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 1 Subjects)
Outcome Time Frame
Day 1 to week 12
Outcome Measure
Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 2 Subjects)
Outcome Time Frame
Weeks 5 to 12
Outcome Measure
Mean Number of Platelet Transfusions
Outcome Description
Definitions of hematologic improvement for platelets, neutrophils, and hemoglobin were based on modified International Working Group (IWG) consensus criteria.
Outcome Time Frame
Weeks 5 to 12
Outcome Measure
Hematologic Improvement
Outcome Time Frame
Baseline to Week 12
Outcome Measure
Change in Mean Platelet Count
Outcome Time Frame
Weeks 5 to 12
Outcome Measure
Maximum Duration of Platelet Transfusion Independence
Outcome Description
Occurrence and severity of bleeding, measured using the WHO Bleeding Scale Grade 0=no bleeding; Grade 1=petechiae; Grade 2=mild blood loss; Grade 3=gross blood loss; Grade 4=debilitating blood loss.
Outcome Time Frame
Weeks 5 to 12
Outcome Measure
Number of Participants With Maximum Bleeding Grade According to World Health Organization on Bleeding Scale
Outcome Description
Participants were evaluated in accordance with the modified International Working Group (Cheson, 2006). CR: Bone marrow blasts \<5%, Hgb ≥11g/dL, Hematologic Improvement - Platelets (Baseline \<20Gi/L: \>20 Gi/L and 2x baseline; Baseline ≥20 Gi/L: ≥50 Gi/L and 2x baseline), Neutrophils ≥1.0 Gi/L, Peripheral blasts 0%. PR: Bone marrow blasts decreased by ≥50% but \>5%, Peripheral blood as in CR. Marrow CR: Bone marrow blasts \<5% and decrease by ≥50%, Note any Hematologic Improvements, Stable disease: Failure to achieve PR, but no evidence of progression for \>8w, Cytogenetic response: Complete: disappearance of chromosomal abnormality; no new abnormalities Partial: ≥50% reduction of chromosomal abnormality.
Outcome Time Frame
up to week 12
Outcome Measure
Independent Reviewer-Assessed Best Response
Outcome Time Frame
Up to week 12
Outcome Measure
Independent Reviewer Assessed Disease Progression
Outcome Time Frame
Up to 13 months
Outcome Measure
Median Overall Survival
Outcome Description
The number of subject with medical resource utilization (MRU) data are reported in this table.
MRU included number of emergency room visits, number of home healthcare visits, number of hospitalization days, number of medication or surgery specialist visits, number of procedures inpatient, number of procedures outpatient, number of non-study radiology visits, number of non-study laboratory visits, number of nurse practitioner/physician assistance/nurse visits, number of primary care physician visits, number of telephone consultations.
MRU included number of emergency room visits, number of home healthcare visits, number of hospitalization days, number of medication or surgery specialist visits, number of procedures inpatient, number of procedures outpatient, number of non-study radiology visits, number of non-study laboratory visits, number of nurse practitioner/physician assistance/nurse visits, number of primary care physician visits, number of telephone consultations.
Outcome Time Frame
week 12
Outcome Measure
Summary of Health Outcomes
Outcome Description
The FACT-Th-18 is the most widely used and accepted tool evaluating health-related quality-of-life outcomes in cancer patients with chronically low platelets (where Th designates thrombocytopenia). The entire FACT-Th-18 was used in this trial, which includes the 18-item thrombocytopenia subscale used to assess the impact of symptoms, signs, and functional consequences of thrombocytopenia in MDS and AML subjects. The FACT-Th-18 is a validated and reliable instrument with known psychometric properties. FACT-ThS is an 18 item questionnaire specific to assessing the impact of symptoms, signs, and functional consequences of Thrombocytopenia. ThS score ranges from 0 to 72 with higher the score, the better the QoL. FACT G total score moves from 0 to 108 where higher the score, the better the HRQL.
FACT-Th Total Score is calculated by adding the FACT-ThS and FACT-G score. Total score ranges from 0 to 180 and again, higher the score, the better the HRQL.
FACT-Th Total Score is calculated by adding the FACT-ThS and FACT-G score. Total score ranges from 0 to 180 and again, higher the score, the better the HRQL.
Outcome Time Frame
Change from baseline, up to week 12
Outcome Measure
Functional Assessment of Cancer Therapy (FACT)
Outcome Description
EuroQoL Five Dimensions Questionnaire (EQ-5D) is a standardized generic preference based health related quality of life instrument. It records how one's health is "today" and consists of a descriptive system. The Descriptive system is Comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension on the EQ-5D involves a 3-point response scale which indicates the level of impairment (level 1 = no problem; level 2 = some or moderate problem(s) and level 3 = unable, or extreme problems). Level of problem reported in each EQ-5D dimension determines a unique health state which is converted into a weighted health state index by applying scores from EQ-5D preference weights elicited from general population samples. This generates a unique description of the subjects' health status, which is valued between 0 (representing death) and 1 (representing perfect health). Higher the score, the better the quality of life.
EQ-ED is a score.
EQ-ED is a score.
Outcome Time Frame
Change from baseline, up to week 12
Outcome Measure
EQ-5D Utility Score Analysis
Start Date
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
110
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Amit Verma
Investigator Email
amit.verma@einsteinmed.org
Investigator Phone
718-405-8505 / 718-904-2900
Categories Mesh Debug
Blood & Bone Marrow Cancers --- LEUKEMIA, MYELOID, ACUTE
Blood & Bone Marrow Cancers --- MYELOPROLIFERATIVE DISORDERS
Blood & Bone Marrow Cancers --- MYELODYSPLASTIC SYNDROMES
Blood Disorders --- BLOOD PLATELET DISORDERS
Blood Disorders --- HEMATOLOGIC DISEASES
Blood & Bone Marrow Cancers --- HEMATOLOGIC DISEASES
Blood & Bone Marrow Cancers --- LEUKEMIA, MYELOID
Cancer --- LEUKEMIA
Blood & Bone Marrow Cancers --- LEUKEMIA
Cancer --- NEOPLASMS
Blood & Bone Marrow Cancers --- BONE MARROW DISEASES
MeSH Terms
THROMBOCYTOPENIA
LEUKEMIA, MYELOID, ACUTE
MYELOPROLIFERATIVE DISORDERS
MYELODYSPLASTIC SYNDROMES
BLOOD PLATELET DISORDERS
HEMATOLOGIC DISEASES
HEMIC AND LYMPHATIC DISEASES
CYTOPENIA
LEUKEMIA, MYELOID
LEUKEMIA
NEOPLASMS BY HISTOLOGIC TYPE
NEOPLASMS
BONE MARROW DISEASES
ELTROMBOPAG
COUNTERFEIT DRUGS
SUBSTANDARD DRUGS
PHARMACEUTICAL PREPARATIONS