Blood and Lymph Conditions

All Conditions

Neoplasms

Symptoms and General Pathology

Rare Diseases

Thrombocytopenia

Neoplasm Metastasis

Syndrome

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Myeloproliferative Disorders

Preleukemia

Myelodysplastic Syndromes

Neoplasms by Histologic Type

Hematologic Diseases

Bone Marrow Diseases

Precancerous Conditions

Blood Platelet Disorders

Cytopenia

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Chronic Myeloproliferative Disorders

100 mg daily (50 mg for subjects of East Asian heritage), intrasubject dose escalations to a maximum dose 300 mg (150 mg for subjects of East Asian heritage) are allowed.

100 mg daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg (150 mg for subjects of East Asian heritage)

100 mg matching placebo daily (50 mg for subjects of East Asian heritage), intra-subject dose escalations to a maximum dose of 300 mg matching placebo (150 mg for subjects of East Asian heritage)

eltrombopag

placebo

Novartis Pharmaceuticals

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.

A Three-part Study of Eltrombopag in Thrombocytopenic Subjects With Myelodysplastic Syndromes or Acute Myeloid Leukemia

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)

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.

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.

Definitions of hematologic improvement for platelets, neutrophils, and hemoglobin were based on modified International Working Group (IWG) consensus criteria.

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.

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.

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.

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.

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.

Eltrombopag, Part 1 Subjects

Eltrombopag, Part 2 plus 1 day from Part 2 subjects

Eltrombopag, Part 2 Plus 1 Day From Part 2 Subjects

Placebo, Part 2 plus 1 day from Part 2 subjects

Placebo, Part 2 Plus 1 Day From Part 2 Subjects

Eltrombopag, Part 3 plus 30 Days from Part 2 subjects

Eltrombopag, Part 3 Plus 30 Days From Part 2 Subjects

The eltrombopag starting dose the participants received was 100 mg daily (50 mg for participants of East Asian heritage). The dose of eltrombopag was escalated from 100 mg to 200 mg (50 mg to 100 mg for East Asians) and further from 200 mg to 300 mg once daily (100 mg to 150 mg for East Asians) based on the platelet response and safety data after two weeks of current dose level. After all participants finished the 8 week treatment period, platelet response and safety were analyzed before initiating Part 2 of the study. Supportive standard of care was allowed as needed. The duration of Part 1 was 8 weeks.

Part 1: Eltrombopag

Participants received eltrombopag matching placebo once daily (3 tablets). Supportive standard of care was allowed as needed throughout the study.

Part 2: Placebo

The eltrombopag starting dose the participants received was 100 mg daily (50 mg for participants of East Asian heritage). The duration of treatment with the initial dose level prior to first dose escalation was determined based on the platelet response and toxicity observed in Part 1. The dose of eltrombopag was escalated from 100 mg to 200 mg (50 mg to 100 mg for East Asians) and further from 200 mg to 300 mg once daily (100 mg to 150 mg for East Asians) based on the platelet response and safety data after two weeks of current dose level. Supportive standard of care was allowed as needed throughout the study.

Part 2: Eltrombopag

Total

Age, Continuous

Sex: Female, Male

African American/African Heritage

Asian - East Asian Heritage

Asian - South East Asian Heritage

White - Arabic/North African Heritage

White - White/Caucasian/European Heritage

Race/Ethnicity, Customized

Part 3, 59 subjects from Part 2 entered Part 3 (23 of 47 subjects in the placebo group in Part 2 and 36 of 98 subjects in the eltrombopag group in Part 2). All subjects who entered Part 3 received treatment with eltrombopag. SOC was allowed as needed throughout the study. Subjects could receive disease-modifying therapy as needed.

Study Director

Part 1 Population: all subjects who enrolled in Part 1.

Number of Participants With Platelet Response up to Week 8 During Part 1

Part 2 Population (Intent-To-Treat (ITT) Population: all randomized subjects in part 2)

Clinically Relevant Thrombocytopenic Events (CRTE) From Week 5 up to Week 12 During Part 2

Baseline/day 1 (Pre-dose PK)

Day8 week 1 (Pre-dose PK)

Day15 week 2 (Pre-dose PK)

Day22 week 3 (Pre-dose PK)

Day29 week 3 (2-6hrs post-dose PK)

Day36 week 5 (Pre-dose PK)

Day43 week6 (2-6hrs post-dose PK)

Day50 week 7 (Pre-dose PK)

Day57 week 8 (2-6hrs post-dose PK)

Pharmacokinetic population: all subjects in All Subjects Population who had a PK blood sample obtained/analyzed.

Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 1 Subjects)

Day22 week 3 (2-6hrs post-dose PK)

Day29 week 4 (Pre-dose PK)

Day43 week 6 (Pre-dose PK)

Day50 week 7 (2-6hrs post-dose PK)

Day57 week8 (Pre-dose PK)

Day71 week 10 (Pre-dose PK)

Day78 week 11 (2-6hrs post-dose PK)

Day85 week12 (Pre-dose PK)

Plasma Eltrombopag Pharmacokinetic Concentration-Time Data - by Visit (Part 2 Subjects)

Part 2: Eltrombopag The eltrombopag starting dose the participants received was 100 mg daily (50 mg for participants of East Asian heritage). The duration of treatment with the initial dose level prior to first dose escalation was determined based on the platelet response and toxicity observed in Part 1. The dose of eltrombopag was escalated from 100 mg to 200 mg (50 mg to 100 mg for East Asians) and further from 200 mg to 300 mg once daily (100 mg to 150 mg for East Asians) based on the platelet response and safety data after two weeks of current dose level. Supportive standard of care was allowed as needed throughout the study.

Part 2 Population (Intent-to-Treat population)

Mean Number of Platelet Transfusions

Any Improvement

Platelets

Neutrophils

Hemoglobin

Platelets and neutrophils

Platelets and hemoglobin

Platelets, hemoglobin and neutrophils

Neutrophils and hemoglobin

Hematologic Improvement

Day8 week1

Day15 week2

Day22 week3

Day29 week4

Day36 week5

Day43 week6

Day50 week7

Day57 week8

Day64 week9

Day71 week10

Day78 week11

Day 85 week12

Change in Mean Platelet Count

Maximum Duration of Platelet Transfusion Independence

Grade 0 (no bleeding)

Grade 1 (petechiae)

Grade 2 (mild blood loss)

Grade 3 (gross blood loss)

Grade 4 (debilitating blood loss)

Grades 0 - 1

Grades 1 - 4

Grades 2 - 4

Number of Participants With Maximum Bleeding Grade According to World Health Organization on Bleeding Scale

Responder

Complete response (CR)

Morphologic CR

Morphologic leukemia-free state

Marrow CR

Cytogenetic CR

Molecular CR

Non-responder

Partial response

Stable disease (non-responder)

Progressive disease (non-responder)

Not evaluable (non-responder)

Missing (non-responder)

Independent Reviewer-Assessed Best Response

Disease progression

No disease progression

Not evaluable

Missing

Independent Reviewer Assessed Disease Progression

Median Overall Survival

Number of emergency room visits (n=17, n=10)

Number of home healthcare visits (n=17, n=10)

Number of hospitalization days (n=17, n=10)

Number of med/surg specialist visits (n=17, n=10)

Number of procedures inpatient (n=17, n=10)

Number of procedures outpatient (n=17, n=10)

Number of non-study radiology visits (n=2, n=2)

Number of nurse prac/pa/nurse visits (n=17, n=10)

Number of primary care physician visits (n=17,10)

Number of telephone consultations (n=17, n=10)

Number of non-study laboratory visits (n=17, n=10)

Summary of Health Outcomes

FACTG week 5 (n=61. n=34)

FACTG week 9 (n=46. n=28)

FACTG week12 (n=37. n=26)

FACTHTOI week 5 (n=61, n=34)

FACTHTOI week 9 (n=46, n=28)

FACTHTOI week 12 (n=37, n=26)

Functional Assessment of Cancer Therapy (FACT)

Week 5 (n=55. n=34)

Week 9 (n=43. n=27)

Week 12 (n=36. n=26)

EQ-5D Utility Score Analysis

The eltrombopag starting dose the participants received was 100 milligrams (mg) daily (50 mg for participants of East Asian heritage). The dose of eltrombopag was escalated from 100 mg to 200 mg (50 mg to 100 mg for East Asians) and further from 200 mg to 300 mg once daily (100 mg to 150 mg for East Asians) based on the platelet response and safety data after two weeks of current dose level. After all participants finished the 8 week treatment period, platelet response and safety were analyzed before initiating Part 2 of the study. Supportive standard of care was allowed as needed. The duration of Part 1 was 8 weeks.

23 subjects of the 47 randomized to the placebo group in Part 2 entered part 3. 36 subjects of the 98 randomized to the Etrombopag group in Part 2 entered part 3.

All subjects received eltrombopag. Part 3 subjects could also have received treatment for their disease per local SOC, including azacitidine, decitabine, lenalidomide, and chemotherapy. The duration of Part 3 was to be 10 months for subjects from Part 1and 9 months for subjects from Part 2.

Part 3: Eltrombopag

Part 1: Open-label Phase

Part 2; Double-blind Phase

Part 3: Extension

Spots Global Cancer Trial Database for myelodysplastic syndrome ( secondary acute myeloid leukemia)