Clinical trial NCT02158936: A Study of Eltrombopag or Placebo in Combination With Azacitidine in Subjects With International Prognostic Scoring System (IPSS) Intermediate-1, Intermediate-2 or High-risk Myelodysplastic Syndromes (MDS)
Official title: A Randomized, Double-blind, Placebo-controlled, Phase III, Multi-centre Study of Eltrombopag or Placebo in Combination With Azacitidine in Subjects With IPSS Intermediate-1, Intermediate 2 and High-risk Myelodysplastic Syndromes (MDS) SUPPORT: A StUdy of eltromboPag in myelodysPlastic SyndrOmes Receiving azaciTidine
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Thrombocytopaenia
Keywords: thrombocytopenia
myelodysplastic syndromes
MDS
thrombopoietin
azacitidine
Eltrombopag
myelodysplastic syndromes (MDS)
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2014-06-09
Enrollment: 356
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Eltrombopag olamine (SB-497115-GR) is an orally bioavailable, small molecule thrombopoietin receptor agonist that may be beneficial in medical disorders associated with thrombocytopenia. Eltrombopag has been shown to increase platelet counts in patients with thrombocytopenia from various etiologies (Idiopathic thrombocytopenic purpura \[ITP\], liver disease, aplastic anemia and chemotherapy induced thrombocytopenia). Approximately 350 subjects will be randomized in a 1:1 ratio (175 into the eltrombopag arm and 175 into the placebo arm). Approximately 55 subjects will be enrolled into the azacitidine. Subjects with intermediate-1, intermediate-2 or high risk MDS by IPSS, and baseline platelet count of \<75 Giga (10\^9) per liter (Gi/L) will only be enrolled. This is a randomized, double-blind, parallel group, placebo-controlled study designed to explore the platelet supportive care effects of eltrombopag versus placebo in combination with the standard of care hypomethylating agent, azacitidine. The primary objective of this study is to determine the effect of eltrombopag versus placebo on the proportion of subjects who are platelet transfusion free during the first 4 cycles of azacitidine therapy. Key secondary endpoints include overall survival, disease response, and disease progression.


Eligibility criteria: Inclusion Criteria:

* Age \>=18 years (For subjects in Taiwan, Age \>= 20 years)
* MDS by World Health Organization (WHO) or French-American-British (FAB) classification
* Intermediate 1, intermediate 2 or high risk MDS by IPSS
* At least one platelet count \< 75 Gi/L
* Eastern Cooperative Oncology Group (ECOG) Status 0-2
* Adequate baseline organ function defined by the criteria below: total bilirubin =\< 1.5x the upper limit of normal (ULN) except for Gilbert's syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect \[haemolytic\] bilirubin in the absence of alanine aminotransferase \[ALT\] abnormality); ALT =\< 2.5xULN; creatinine =\< 2.5xULN
* Subjects with a corrected QT interval (QTc) \<450 milliseconds (msec) or \<480msec for subjects with bundle branch block. The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF), machine or manual overread. For subject eligibility and withdrawal, QTcF will be used. For purposes of data analysis, QTcF will be used. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period
* Subject is able to understand and comply with protocol requirements and instructions
* Subject has signed and dated informed consent
* 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 of first dose of study treatment and agree to use effective contraception during the study and for 3 months following the last dose of study treatment
* Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from time of randomization until 16 weeks after the last dose of study treatment
* French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category

Exclusion Criteria:

* Previous treatment with hypomethylating agent or induction chemotherapy for MDS
* Proliferative type chronic myelomonocytic leukemia with white blood cell count \>12 Gi/L at any time during the 28 days before Day 1
* History of treatment with eltrombopag, romiplostim or other thrombopoietin receptor (TPO-R) agonists
* Previous allogeneic stem-cell transplantation
* 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
* Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of investigational product (eltrombopag/placebo)
* Active and uncontrolled infections, including hepatitis B or C
* Human Immunodeficiency Virus (HIV) infection
* Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or its excipient, or azacitidine, that contraindicates the subjects' participation
* Pregnant or lactating female
* Any serious and/or unstable pre-existing medical condition (including any advanced malignancy other than the disease under study), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance with the study procedures
* French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days

Primary outcomes:
measure: Number of Participants Who Were Platelet Transfusion Independent During Cycles 1-4 of Azacitidine Therapy
timeFrame: 4 cycles (Cycle = 28 days)
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Randomization until death or end of study, approximately 2 years
measure: Summary of Progression Free Survival From Investigator Assessment (ITT)
timeFrame: First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years
measure: Summary of Progression Free Survival From Central Review (ITT)
timeFrame: First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years
measure: Summary of AML Progression From Investigator Assessment and Central Review (ITT)
timeFrame: First day of each cycle (Cycles 3+), at the end of therapy visit and every 3 months in follow-up for approximately 2 years
measure: Best Disease Response From Investigator Assessment (ITT)
timeFrame: At end of Cycle 6 (cycle=28 days) or end of therapy, whichever came first
measure: Best Disease Response From Central Review (ITT)
timeFrame: At end of Cycle 6 (cycle=28 days) or end of therapy, whichever came first
measure: Hematologic Improvement (HI) in Platelets, Neutrophils, and Hemoglobin Based on the Modified IWG Criteria for MDS (ITT)
timeFrame: From Day 1 to 4-week follow-up (samples collected weekly in Cycle 1, Days 1 and 15 in Cycles 2-6 and Day 1 of Cycles >=7)
measure: Number of Participants Who Were Platelet Transfusion Independent (ITT Set)
timeFrame: From Day 1 to end of study treatment up to approximately 2 years
measure: Bleeding Adverse Events (AEs) >= Grade 3
timeFrame: From Day 1 to 4-week follow-up up to approximately 2 years
measure: Number of of Subjects With Azacitidine Dose Delays, Dose Reductions, Interruptions
timeFrame: From Day 1 to 4-week follow-up up to approximately 2 years
measure: Response Levels in All Domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™)
timeFrame: From Day 1 to 4-week follow-up up to approximately 2 years
measure: Functional Assessment of Chronic Disease Therapy-fatigue Subscale (FACIT-Fatigue) (ITT)
timeFrame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years
measure: Medical Resource Utilization (MRU): Event -Hospitalizations Inpatient and Outpatient
timeFrame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years
measure: Medical Resource Utilization (MRU): Event and Use of Site Specific Medical Resources - Non-study Laboratory Tests
timeFrame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years
measure: Medical Resource Utilization (MRU): Use of Site Specific Medical Resources
timeFrame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up) up to approximately 2 years
measure: Summary of Post-Hoc Estimates of Steady-state Eltrombopag Cmax and Cmin Pharmacokinetic Parameters for a 50 mg Dose
timeFrame: Cycle 1, Week 2: Pre-dose, 1.5 and 3 hour post dose; Cycle 1, Week 3: 4, 5.5, and 7 hours post dose
measure: Summary of Post-Hoc Estimates of Steady-state Eltrombopag AUC0 Infinity Pharmacokinetic Parameters for a 50 mg Dose
timeFrame: Cycle 1, Week 2: Pre-dose, 1.5 and 3 hour post dose; Cycle 1, Week 3: 4, 5.5, and 7 hours post dose
measure: AUC0-infinity -Pharmacokinetic(s) Parameter of Azacitidine
timeFrame: Cycle 2 Day 1: Pre-dose, 15 min, 0.5, 1, 2 and 4 hr post dose
measure: Cmax -Pharmacokinetic Parameter of Azacitidine
timeFrame: Cycle 2 Day 1: Pre-dose, 15 min, 0.5, 1, 2 and 4 hr post dose
Other outcomes:
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Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Dickinson M, Cherif H, Fenaux P, Mittelman M, Verma A, Portella MSO, Burgess P, Ramos PM, Choi J, Platzbecker U; SUPPORT study investigators. Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia. Blood. 2018 Dec 20;132(25):2629-2638. doi: 10.1182/blood-2018-06-855221. Epub 2018 Oct 10.