A Study of Galunisertib in Participants With Myelodysplastic Syndromes

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effect of the study drug known as galunisertib in participants with myelodysplastic syndromes (MDS). Participants with different degrees of disease (very low, low, and intermediate risk) will be studied. The study treatment is expected to last about 6 months for each participant.

Official Title
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Phase 2/3 Study of Monotherapy LY2157299 Monohydrate in Very Low-, Low-, and Intermediate-Risk Patients With Myelodysplastic Syndromes

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Galunisertib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of MDS based on the World Health Organization (WHO) criteria Participants with 5q deletions are allowed only if they have failed or are intolerant of lenalidomide treatment Participants must have a Revised International Prognostic Scoring System (IPSS-R) category of very low-, low-, or intermediate-risk disease In the 8 weeks prior to registration, participants in phase 2 should have anemia with Hb ≤10.0 g/dL (based on the average of 2 baseline measurements and untransfused for at least 1 week) with or without red blood cell (RBC) transfusion dependence confirmed for a minimum of 8 weeks before enrollment For phase 3, participants should have anemia with RBC transfusion dependence confirmed within 8 weeks before enrollment Performance status ≤2 on the Eastern Cooperative Oncology Group (ECOG) scale Exclusion Criteria: No history of moderate or severe cardiac disease No prior history of acute myeloid leukemia (AML)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase (ph) 2: Galunisertib + BSC<br>Ph 2. 150 milligrams Galunisertib given orally twice daily (BID) for 14 days followed by 14 days with no study drug (28 day cycles). Participants will receive best supportive care (BSC) according to institutional guidelines. Treatment is expected to last for 6 cycles. Participants may receive additional cycles if they are deriving clinical benefit. | Drug: Galunisertib<br>* Administered orally<br>* Other names: LY2157299;|
| Placebo Comparator: Ph 3: Placebo + BSC<br>Placebo administered orally BID for 14 days followed by 14 days with no study drug (28 day cycles). Participants will receive BSC according to institutional guidelines. Treatment is expected to last for 6 cycles. Participants may receive additional cycles if they are deriving clinical benefit. This arm is contingent on the data from the phase 2 arm. | Drug: Placebo<br>* Administered orally<br>|
| Experimental: Ph 3: Galunisertib + BSC<br>150 milligrams Galunisertib given orally twice daily (BID) for 14 days followed by 14 days with no study drug (28 day cycles). Participants will receive best supportive care (BSC) according to institutional guidelines. Treatment is expected to last for 6 cycles. Participants may receive additional cycles if they are deriving clinical benefit. This arm is contingent on the data from the phase 2 arm. | Drug: Galunisertib<br>* Administered orally<br>* Other names: LY2157299;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Hematological Improvement (HI) | Percentage of participants with hematological improvement (HI) based on International Working Group (IWG) 2006 criteria in participants with very low, low, and intermediate-risk myelodysplastic syndromes treated with Galunisertib plus best supportive care, as assessed by the International Prognostic Scoring System (IPSS-R). To be classified as an HI responder, the HI response must have lasted at least 8 weeks (56 days). | Baseline through end of study treatment (24 weeks) | 
| Percentage of Participants Who Are Transfusion-free or Have Hemoglobin (Hb) Increase ≥1.5 Grams/Deciliter Maintained for 8 Weeks During Phase 3 | Comparison of the percentage of participants with very low-, low-,and intermediate-risk MDS who were transfusion-free or had an increase ≥1.5 g/dL in hemoglobin (Hb) maintained for at least 8 weeks within the first 24 weeks of treatment with galunisertib plus best supportive care or placebo plus best supportive care and assessed by IPSS-R. The Phase 3 portion of this study was not conducted because efficacy level required in phase 2 to move forward to phase 3 was not achieved. | Baseline through end of study treatment (24 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Brief Fatigue Inventory (BFI) | The Brief Fatigue Inventory (BFI) is a brief participant-reported questionnaire that measures the severity of fatigue based on the worst fatigue experienced during the past 24-hours. The severity of fatigue is assessed using an 11-point numeric scale, with 0 = no fatigue and 10 = fatigue as bad as you can imagine. | Baseline, Follow up (final visit up to 24 months) | 
| Change From Baseline in EuroQol 5-Dimension 5 Level Instrument | EuroQol 5-Dimension 5 Level Instrument (EQ-5D-5L) was not conducted, trial terminated prior to Phase 3. No data collected. | Phase 3: Baseline, Cycle 2, Cycle 4, Cycle 6 (Cycle = 28 days) | 
| Percentage of Participants With Cytogenetic Response | Percentage of Participants with Cytogenetic Response with either complete or partial response. Complete cytogenetic response is the disappearance of the chromosomal abnormality without appearance of new ones. Partial cytogenetic response is at least 50% reduction of the chromosomal abnormality. | Baseline through end of study treatment (24 weeks) | 
| Percentage of Participants Who Are Hospitalized (Resource Utilization) | Percentage of any participant with a hospitalization admission and discharge date on the same day are counted as a half-day in the duration of hospitalization. | Baseline through end of study treatment (24 weeks) | 
| Population Pharmacokinetics (PK): Mean Population Clearance of Galunisertib | Population mean (between-participant coefficient variation [CV%]) apparent clearance. | Day 1 pre-dose & between 0.5 to 2 hours post dose; Day 14 pre-dose, between 0.5 to 2 & between 3 to 5 hours post dose; Days 15 & 16 (if logistically possible) between 0.5 to 2 hours post dose | 
| Overall Survival (OS) | Overall survival is defined as the time from the date of first dose to the date of death from any cause. | Baseline to date of death from any cause (Up to 2 years) | 
| Number of Participants With a Change in Bone Marrow Fibrosis Grading | Change from baseline in bone marrow fibrosis measured the number of participants with a change in bone marrow fibrosis grading (negative, mild, moderate, and severe). | Baseline, Cycle 6 (Cycle = 28 days) |