Myelodysplastic Syndromes
Conditions
Brief summary
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.
Interventions
DRUGGalunisertib
Administered orally
DRUGPlacebo
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Hematological Improvement (HI) | Baseline through end of study treatment (24 weeks) | 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). |
| Percentage of Participants Who Are Transfusion-free or Have Hemoglobin (Hb) Increase ≥1.5 Grams/Deciliter Maintained for 8 Weeks During Phase 3 | Baseline through end of study treatment (24 weeks) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Cytogenetic Response | Baseline through end of study treatment (24 weeks) | 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. |
| Percentage of Participants Who Are Hospitalized (Resource Utilization) | Baseline through end of study treatment (24 weeks) | 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. |
| Change From Baseline in Brief Fatigue Inventory (BFI) | Baseline, Follow up (final visit up to 24 months) | 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. |
| Overall Survival (OS) | Baseline to date of death from any cause (Up to 2 years) | Overall survival is defined as the time from the date of first dose to the date of death from any cause. |
| Number of Participants With a Change in Bone Marrow Fibrosis Grading | Baseline, Cycle 6 (Cycle = 28 days) | 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). |
| Population Pharmacokinetics (PK): Mean Population Clearance of Galunisertib | 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 | Population mean (between-participant coefficient variation \[CV%\]) apparent clearance. |
| Change From Baseline in EuroQol 5-Dimension 5 Level Instrument | Phase 3: Baseline, Cycle 2, Cycle 4, Cycle 6 (Cycle = 28 days) | EuroQol 5-Dimension 5 Level Instrument (EQ-5D-5L) was not conducted, trial terminated prior to Phase 3. No data collected. |
Countries
Germany, Italy, Spain
Participant flow
Pre-assignment details
This is a single-arm study (Galunisertib at 150 milligram \[mg\]); the Galunisertib at 80 mg was considered exploratory and only conducted in parallel with the main study, at one site in Spain.
Participants by arm
| Arm | Count |
|---|---|
| Galunisertib at 150 mg Galunisertib at 150 mg 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. | 41 |
| Galunisertib at 80 mg Exploratory arm: Galunisertib at 80 mg 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. | 2 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 0 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Progressive Disease | 2 | 0 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Galunisertib at 150 mg | Galunisertib at 80 mg | Total |
|---|---|---|---|
| Age, Continuous | 70.49 years STANDARD_DEVIATION 7.65 | 62.50 years STANDARD_DEVIATION 10.61 | 70.12 years STANDARD_DEVIATION 7.83 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 0 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 2 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 4 Participants |
| IPSS-R Prognostic Risk Score Intermediate= (>3 - 4.5) | 9 Participants | 1 Participants | 10 Participants |
| IPSS-R Prognostic Risk Score Low= (>1.5 - 3) | 30 Participants | 1 Participants | 31 Participants |
| IPSS-R Prognostic Risk Score Very Low= (≤1.5) | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 41 Participants | 2 Participants | 43 Participants |
| Region of Enrollment Germany | 23 Participants | 0 Participants | 23 Participants |
| Region of Enrollment Italy | 8 Participants | 0 Participants | 8 Participants |
| Region of Enrollment Spain | 10 Participants | 2 Participants | 12 Participants |
| Sex: Female, Male Female | 15 Participants | 1 Participants | 16 Participants |
| Sex: Female, Male Male | 26 Participants | 1 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 33 / 41 | 2 / 2 |
| serious Total, serious adverse events | 8 / 41 | 0 / 2 |
Outcome results
Primary
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.
Time frame: Baseline through end of study treatment (24 weeks)
Population: Participants who received at least one dose of study drug during Phase 3.
Primary
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).
Time frame: Baseline through end of study treatment (24 weeks)
Population: Participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Galunisertib at 150 mg | Percentage of Participants With Hematological Improvement (HI) | 31.7 percentage of participants |
| Arm: Galunisertib at 80 mg | Percentage of Participants With Hematological Improvement (HI) | 0.0 percentage of participants |
Secondary
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.
Time frame: Baseline, Follow up (final visit up to 24 months)
Population: Participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Galunisertib at 150 mg | Change From Baseline in Brief Fatigue Inventory (BFI) | Current Fatigue at Follow-up | 0.818 units on a scale | Standard Error 0.42 |
| Galunisertib at 150 mg | Change From Baseline in Brief Fatigue Inventory (BFI) | Usual Fatigue at Follow-up | -0.017 units on a scale | Standard Error 0.37 |
| Galunisertib at 150 mg | Change From Baseline in Brief Fatigue Inventory (BFI) | Worst Fatigue at Follow-up | -0.191 units on a scale | Standard Error 0.38 |
| Arm: Galunisertib at 80 mg | Change From Baseline in Brief Fatigue Inventory (BFI) | Current Fatigue at Follow-up | -1.005 units on a scale | Standard Error 2.08 |
| Arm: Galunisertib at 80 mg | Change From Baseline in Brief Fatigue Inventory (BFI) | Usual Fatigue at Follow-up | -0.157 units on a scale | Standard Error 1.87 |
| Arm: Galunisertib at 80 mg | Change From Baseline in Brief Fatigue Inventory (BFI) | Worst Fatigue at Follow-up | -0.063 units on a scale | Standard Error 1.93 |
Secondary
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.
Time frame: Phase 3: Baseline, Cycle 2, Cycle 4, Cycle 6 (Cycle = 28 days)
Population: Participants who received at least one dose of study drug during Phase 3.
Secondary
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).
Time frame: Baseline, Cycle 6 (Cycle = 28 days)
Population: Participants who received at least one dose of study drug and had both a baseline and postbaseline assessment excluding the exploratory participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Galunisertib at 150 mg | Number of Participants With a Change in Bone Marrow Fibrosis Grading | 11 participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the time from the date of first dose to the date of death from any cause.
Time frame: Baseline to date of death from any cause (Up to 2 years)
Population: Participants who received at least one dose of study drug excluding the exploratory participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Galunisertib at 150 mg | Overall Survival (OS) | 679 days |
Secondary
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.
Time frame: Baseline through end of study treatment (24 weeks)
Population: Participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Galunisertib at 150 mg | Percentage of Participants Who Are Hospitalized (Resource Utilization) | 24.3 percentage of participants |
| Arm: Galunisertib at 80 mg | Percentage of Participants Who Are Hospitalized (Resource Utilization) | 0 percentage of participants |
Secondary
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.
Time frame: Baseline through end of study treatment (24 weeks)
Population: Participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Galunisertib at 150 mg | Percentage of Participants With Cytogenetic Response | 2.4 percentage of participants |
| Arm: Galunisertib at 80 mg | Percentage of Participants With Cytogenetic Response | 0 percentage of participants |
Secondary
Population Pharmacokinetics (PK): Mean Population Clearance of Galunisertib
Population mean (between-participant coefficient variation \[CV%\]) apparent clearance.
Time frame: 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
Population: All participants who received at least one dose of study drug, regardless of dose, with evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Galunisertib at 150 mg | Population Pharmacokinetics (PK): Mean Population Clearance of Galunisertib | 32 Liter per hour (L/h) | Geometric Coefficient of Variation 52 |