MDS, Myelodysplastic Syndromes, Thrombocytopenia
Conditions
Keywords
MDS, Myelodysplastic Syndromes, Refractory Cytopenias, Thrombocytopenia
Brief summary
The purpose of this study is to evaluate the effect of Romiplostim (AMG 531) on the incidence of clinically significant thrombocytopenic events (grade 3 or 4 and/or receipt of platelet transfusions) in subjects with low or intermediate risk Myelodysplastic Syndrome (MDS) receiving hypomethylating agents. It is hypothesized that Romiplostim administration, at the appropriate dose and schedule, will result in reduction in the incidence of clinically significant thrombocytopenic events in low or intermediate risk MDS subjects receiving hypomethylating agents.
Interventions
DRUGPlacebo
Subjects in the control group will receive a placebo subcutaneous injection on a weekly basis during the 4 cycle treatment period.
BIOLOGICALAMG 531 (Romiplostim)
AMG 531 (Romiplostim) will be administered weekly by subcutaneous injection at a dose of 500 or 750 μg during Part A and 750 μg during Part B for the 4 cycle treatment period, depending on randomization.
DRUGAzacitidine
hypomethylating agent
DRUGDecitabine
hypomethylating agent
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- Diagnosis of MDS by bone marrow biopsy based on the World Health Organization (WHO) classification - Low, Intermediate-1 or Intermediate-2 risk category MDS using the IPSS (International Prognostic Scoring System) - Planned to receive either azacytidine 75 mg/m2 by subcutaneous administration each day for 7 days or decitabine 20 mg/m2 by intravenous administration each day for 5 days for at least 4 cycles
Exclusion criteria
* Prior exposure to \>3 cycles hypomethylating agents * Prior history of leukemia or aplastic anemia * Prior history of bone marrow transplantation * Prior malignancy (other than in situ cervical cancer or basal cell cancer of the skin) unless treated with curative intent and without evidence of disease for ³ 3 years before randomization * Active or uncontrolled infections * Unstable angina, congestive heart failure \[NYHA (New York Heart Association) \> class II\], uncontrolled hypertension \[diastolic \> 100 mmHg\], uncontrolled cardiac arrhythmia, or recent (within 1 year) myocardial infarction * History of arterial thrombosis ( eg, stroke or transient ischemic attack) in the past year * History of venous thrombosis that currently requires anti-coagulation therapy * Received IL-11 within 4 weeks of screening * Less than 4 weeks since receipt of any therapeutic drug or device that is not FDA approved for any indication * Have previously received any other thrombopoietic growth factor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of a Clinically Significant Thrombocytopenic Event | Treatment period (up to 20 weeks) | Occurrence of a clinically significant thrombocytopenic event within the participant, defined as any platelet count obtained from day 15 of cycle 1 through the end of the interim follow-up visit that was less than 50 x 10\^9/L or receipt of platelet transfusions at any time through the interim follow-up visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hypomethylating Agent Dose Reduction and Delay Due to Thrombocytopenia | Treatment period (up to 20 weeks) | Occurrence of hypomethylating agent dose reduction and delay due to thrombocytopenia |
| Achieving an Overall Response (Complete or Partial Response, CR or PR) at the End of the Treatment Period | Treatment period (up to 20 weeks) | CR = decrease in bone marrow blast (≤5%) and improvement in peripheral blood counts (Hgb ≥ 11 g/dL, platelets ≥ 100x10\^9/L, neutrophils ≥ 1x10\^9/L, peripheral blasts=0%). PR = improvement in peripheral blood counts plus a decrease in bone marrow blasts ≥50% but not ≤5, or decrease in International Prognostic Scoring System score. |
| Platelet Transfusion | Study day 1 through the interim follow-up visit (up to 20 weeks) | Occurrence of one or more platelet transfusions from study day 1 through the interim follow-up visit (16 weeks) |
Participant flow
Recruitment details
Participants in Part A were enrolled from 9 November 2006 through 31 August 2007; participants in Part B were enrolled from 26 March 2008 through 3 November 2008. Participants who enrolled in Part A were not eligible for enrollment in Part B.
Participants by arm
| Arm | Count |
|---|---|
| Romiplostim (AMG 531) Placebo Plus Azacitidine Romiplostim (AMG 531) placebo weekly via subcutaneous injection plus 75 mg/m\^2 azacitidine daily for 7 days during each of four 28-day cycles (Part A) | 13 |
| Romiplostim (AMG 531) 500 mcg Plus Azacitidine 500 mcg romiplostim (AMG 531) weekly via subcutaneous injection plus 75 mg/m\^2 azacitidine daily for 7 days during each of four 28-day cycles (Part A) | 13 |
| Romiplostim (AMG 531) 750 mcg Plus Azacitidine 750 mcg romiplostim (AMG 531) weekly via subcutaneous injection plus 75 mg/m\^2 azacitidine daily for 7 days during each of four 28-day cycles (Part A) | 14 |
| Romiplostim (AMG 531) Placebo Plus Decitabine Romiplostim (AMG 531) placebo weekly via subcutaneous injection plus 20 mg/m\^2 decitabine daily for 5 days during each of four 28-day cycles (Part B) | 14 |
| Romiplostim (AMG 531) 750 mcg Plus Decitabine 750 mcg romiplostim (AMG 531) weekly via subcutaneous injection plus 20 mg/m\^2 decitabine daily for 5 days during each of four 28-day cycles (Part B) | 15 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Part A | Adverse Event | 3 | 3 | 2 | 0 | 0 |
| Part A | Disease progression | 0 | 1 | 0 | 0 | 0 |
| Part A | Other | 1 | 2 | 3 | 0 | 0 |
| Part A | Physician Decision | 0 | 1 | 3 | 0 | 0 |
| Part A | Protocol deviation | 0 | 0 | 1 | 0 | 0 |
| Part A | Requirement for alternative therapy | 0 | 2 | 1 | 0 | 0 |
| Part A | Withdrawal by Subject | 1 | 1 | 1 | 0 | 0 |
| Part B | Adverse Event | 0 | 0 | 0 | 2 | 1 |
| Part B | Death | 0 | 0 | 0 | 2 | 1 |
| Part B | Disease progression | 0 | 0 | 0 | 1 | 0 |
| Part B | Noncompliance | 0 | 0 | 0 | 0 | 1 |
| Part B | Physician Decision | 0 | 0 | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Romiplostim (AMG 531) Placebo Plus Azacitidine | Romiplostim (AMG 531) 500 mcg Plus Azacitidine | Romiplostim (AMG 531) 750 mcg Plus Azacitidine | Romiplostim (AMG 531) Placebo Plus Decitabine | Romiplostim (AMG 531) 750 mcg Plus Decitabine | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 67.3 Years | 71.9 Years | 71.4 Years | 70.5 Years | 68.2 Years | 69.8 Years |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized White or Caucasian | 13 Participants | 10 Participants | 14 Participants | 9 Participants | 11 Participants | 57 Participants |
| Sex: Female, Male Female | 6 Participants | 3 Participants | 7 Participants | 3 Participants | 7 Participants | 26 Participants |
| Sex: Female, Male Male | 7 Participants | 10 Participants | 7 Participants | 11 Participants | 8 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 13 | 13 / 13 | 14 / 14 | 14 / 14 | 14 / 15 |
| serious Total, serious adverse events | 9 / 13 | 4 / 13 | 10 / 14 | 8 / 14 | 8 / 15 |
Outcome results
Primary
Occurrence of a Clinically Significant Thrombocytopenic Event
Occurrence of a clinically significant thrombocytopenic event within the participant, defined as any platelet count obtained from day 15 of cycle 1 through the end of the interim follow-up visit that was less than 50 x 10\^9/L or receipt of platelet transfusions at any time through the interim follow-up visit.
Time frame: Treatment period (up to 20 weeks)
Population: Full Analysis Set, composed of all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Romiplostim (AMG 531) Placebo Plus Azacitidine | Occurrence of a Clinically Significant Thrombocytopenic Event | 11 Participants |
| Romiplostim (AMG 531) 500 mcg Plus Azacitidine | Occurrence of a Clinically Significant Thrombocytopenic Event | 8 Participants |
| Romiplostim (AMG 531) 750 mcg Plus Azacitidine | Occurrence of a Clinically Significant Thrombocytopenic Event | 10 Participants |
| Romiplostim (AMG 531) Placebo Plus Decitabine | Occurrence of a Clinically Significant Thrombocytopenic Event | 11 Participants |
| Romiplostim (AMG 531) 750 mcg Plus Decitabine | Occurrence of a Clinically Significant Thrombocytopenic Event | 12 Participants |
95% CI: [0.153, 6.95]
95% CI: [0.028, 3.926]
95% CI: [0.007, 1.882]
Secondary
Achieving an Overall Response (Complete or Partial Response, CR or PR) at the End of the Treatment Period
CR = decrease in bone marrow blast (≤5%) and improvement in peripheral blood counts (Hgb ≥ 11 g/dL, platelets ≥ 100x10\^9/L, neutrophils ≥ 1x10\^9/L, peripheral blasts=0%). PR = improvement in peripheral blood counts plus a decrease in bone marrow blasts ≥50% but not ≤5, or decrease in International Prognostic Scoring System score.
Time frame: Treatment period (up to 20 weeks)
Population: Full Analysis Set, composed of all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Romiplostim (AMG 531) Placebo Plus Azacitidine | Achieving an Overall Response (Complete or Partial Response, CR or PR) at the End of the Treatment Period | 2 Participants |
| Romiplostim (AMG 531) 500 mcg Plus Azacitidine | Achieving an Overall Response (Complete or Partial Response, CR or PR) at the End of the Treatment Period | 1 Participants |
| Romiplostim (AMG 531) 750 mcg Plus Azacitidine | Achieving an Overall Response (Complete or Partial Response, CR or PR) at the End of the Treatment Period | 1 Participants |
| Romiplostim (AMG 531) Placebo Plus Decitabine | Achieving an Overall Response (Complete or Partial Response, CR or PR) at the End of the Treatment Period | 3 Participants |
| Romiplostim (AMG 531) 750 mcg Plus Decitabine | Achieving an Overall Response (Complete or Partial Response, CR or PR) at the End of the Treatment Period | 5 Participants |
95% CI: [0.347, 9.618]
95% CI: [0.037, 5.325]
95% CI: [0.032, 6.08]
Secondary
Hypomethylating Agent Dose Reduction and Delay Due to Thrombocytopenia
Occurrence of hypomethylating agent dose reduction and delay due to thrombocytopenia
Time frame: Treatment period (up to 20 weeks)
Population: Full Analysis Set, composed of all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Romiplostim (AMG 531) Placebo Plus Azacitidine | Hypomethylating Agent Dose Reduction and Delay Due to Thrombocytopenia | 1 Participants |
| Romiplostim (AMG 531) 500 mcg Plus Azacitidine | Hypomethylating Agent Dose Reduction and Delay Due to Thrombocytopenia | 1 Participants |
| Romiplostim (AMG 531) 750 mcg Plus Azacitidine | Hypomethylating Agent Dose Reduction and Delay Due to Thrombocytopenia | 0 Participants |
| Romiplostim (AMG 531) Placebo Plus Decitabine | Hypomethylating Agent Dose Reduction and Delay Due to Thrombocytopenia | 0 Participants |
| Romiplostim (AMG 531) 750 mcg Plus Decitabine | Hypomethylating Agent Dose Reduction and Delay Due to Thrombocytopenia | 0 Participants |
95% CI: [0.063, 15.988]
Secondary
Platelet Transfusion
Occurrence of one or more platelet transfusions from study day 1 through the interim follow-up visit (16 weeks)
Time frame: Study day 1 through the interim follow-up visit (up to 20 weeks)
Population: Full Analysis Set, composed of all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Romiplostim (AMG 531) Placebo Plus Azacitidine | Platelet Transfusion | 9 Participants |
| Romiplostim (AMG 531) 500 mcg Plus Azacitidine | Platelet Transfusion | 6 Participants |
| Romiplostim (AMG 531) 750 mcg Plus Azacitidine | Platelet Transfusion | 5 Participants |
| Romiplostim (AMG 531) Placebo Plus Decitabine | Platelet Transfusion | 8 Participants |
| Romiplostim (AMG 531) 750 mcg Plus Decitabine | Platelet Transfusion | 7 Participants |
95% CI: [-69, 2]
95% CI: [0.029, 3.412]
95% CI: [0.021, 2.082]