Myelodysplastic Syndromes, Thrombocytopenia
Conditions
Keywords
Revlimid, Lenalidomide, Low Platelet Count, Low Risk Myelodysplastic Syndrome, Intermediate 1 Myelodysplastic Syndrome, MDS, Myelodysplastic Syndrome
Brief summary
This is a dose and schedule finding study of AMG 531 designed to assess the activity of AMG 531 to reduce the rate of clinically significant bleeding and blood transfusions in subjects with myelodysplastic syndrome (MDS) receiving lenalidomide. Subjects with MDS that are planned to receive at least four cycles of lenalidomide for treatment of their disease are appropriate to screen for this study. All subjects meeting the eligibility criteria will receive lenalidomide 10 mg capsule by mouth daily every day of each 28-day cycle. Subjects will receive AMG 531 or placebo once a week by subcutaneous injection for 16 weeks.
Interventions
BIOLOGICALAMG 531
AMG 531 will be administered by subcutaneous injection at a dose of 500 or 750 μg.
DRUGPlacebo
Subjects in the control group will receive placebo via subcutaneous injection.
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 or Intermediate-1 risk category MDS using the IPSS * Planned to receive lenalidomide 10 mg capsule by mouth daily for all 28 days of each cycle for at least 4 cycles * Eastern Cooperative Oncology (ECOG) performance status of 0-2 * Subjects must be at least 18 years of age or older
Exclusion criteria
* Prior exposure to \>3 cycles of lenalidomide * Exposure to lenalidomide within the last 30 days * Prior history of leukemia or aplastic anemia * Prior history of stem cell 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 years before randomization * Active or uncontrolled infections * Unstable angina, congestive heart failure \[NYHA \> class II\], 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 in the past year * Received IL-11 within 4 weeks of screening * Less than 4 weeks since receipt of any investigational drug or device * Have previously received any other thrombopoietic growth factor * Pregnant or breast feeding * Subjects of reproductive potential who are not using adequate contraceptive precautions, in the judgment of the investigator * Known hypersensitivity to any recombinant E coli-derived product
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of a Clinically Significant Thrombocytopenic Event | Treatment period through interim follow-up visit (up to 16 weeks) | Occurrence of one or more clinically significant thrombocytopenic events, defined as either Common Terminology Criteria for Adverse Events (CTCAE) v. 3 grade 3 or 4 thrombocytopenia starting from week 3 of cycle 1 or receipt of platelet transfusions starting from week 1 of cycle 1 and continuing through the end of treatment visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lenalidomide Dose Reduction and Delay Due to Thrombocytopenia | Treatment period (up to 16 weeks) | Occurrence of lenalidomide dose reduction and delay due to thrombocytopenia |
| Achieving an Overall Response (Complete Response (CR) or Partial Response (PR)) Determined by the Investigator Based on Modified International Working Group 2006 Response Criteria Guidelines | Treatment period and post-treatment follow-up (up to 21 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 | Treatment period (up to 16 weeks) | Occurrence of one or more platelet transfusions during the treatment period |
Participant flow
Recruitment details
Participants were enrolled from 14 March 2007 through 24 July 2008
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo weekly via subcutaneous injection plus lenalidomide 10 mg orally once per day for 16 weeks | 12 |
| Romiplostim 500 μg Romiplostim (AMG 531) 500 μg weekly by subcutaneous injection plus lenalidomide 10 mg orally once per day for 16 weeks | 14 |
| Romiplostim 750 μg Romiplostim (AMG 531) 750 μg weekly by subcutaneous injection plus lenalidomide 10 mg orally once per day for 16 weeks | 13 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Treatment Extension | Adverse Event | 1 | 0 | 0 |
| Treatment Extension | Death | 0 | 0 | 1 |
| Treatment Extension | Physician Decision | 2 | 2 | 1 |
| Treatment Extension | Requirement for alternative therapy | 2 | 2 | 0 |
| Treatment Extension | Withdrawal by Subject | 1 | 0 | 0 |
| Treatment Period | Adverse Event | 2 | 2 | 0 |
| Treatment Period | Ineligibility determined | 1 | 1 | 0 |
| Treatment Period | Physician Decision | 1 | 0 | 3 |
| Treatment Period | Requirement for alternative therapy | 1 | 0 | 0 |
| Treatment Period | Withdrawal by Subject | 0 | 3 | 1 |
Baseline characteristics
| Characteristic | Romiplostim 500 μg | Total | Romiplostim 750 μg | Placebo |
|---|---|---|---|---|
| Age Continuous | 72.9 Years STANDARD_DEVIATION 11.4 | 70.9 Years STANDARD_DEVIATION 12.1 | 66.7 Years STANDARD_DEVIATION 9.4 | 73.2 Years STANDARD_DEVIATION 15 |
| International Prognostic Scoring System (IPSS) Score 0 | 4 Participants | 14 Participants | 6 Participants | 4 Participants |
| International Prognostic Scoring System (IPSS) Score 0.5 | 6 Participants | 13 Participants | 4 Participants | 3 Participants |
| International Prognostic Scoring System (IPSS) Score >1.0 | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| International Prognostic Scoring System (IPSS) Score 1.0 | 2 Participants | 8 Participants | 3 Participants | 3 Participants |
| International Prognostic Scoring System (IPSS) Score Missing | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White or Caucasian | 13 Participants | 36 Participants | 12 Participants | 11 Participants |
| Sex: Female, Male Female | 6 Participants | 15 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 8 Participants | 24 Participants | 8 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 9 | 14 / 14 | 14 / 14 |
| serious Total, serious adverse events | 6 / 9 | 5 / 14 | 4 / 14 |
Outcome results
Primary
Occurrence of a Clinically Significant Thrombocytopenic Event
Occurrence of one or more clinically significant thrombocytopenic events, defined as either Common Terminology Criteria for Adverse Events (CTCAE) v. 3 grade 3 or 4 thrombocytopenia starting from week 3 of cycle 1 or receipt of platelet transfusions starting from week 1 of cycle 1 and continuing through the end of treatment visit.
Time frame: Treatment period through interim follow-up visit (up to 16 weeks)
Population: Full Analysis Set, composed of all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Occurrence of a Clinically Significant Thrombocytopenic Event | 8 Participants |
| Romiplostim 500 μg | Occurrence of a Clinically Significant Thrombocytopenic Event | 4 Participants |
| Romiplostim 750 μg | Occurrence of a Clinically Significant Thrombocytopenic Event | 8 Participants |
95% CI: [0.07, 5.136]
95% CI: [0.022, 1.071]
Secondary
Achieving an Overall Response (Complete Response (CR) or Partial Response (PR)) Determined by the Investigator Based on Modified International Working Group 2006 Response Criteria Guidelines
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 and post-treatment follow-up (up to 21 weeks)
Population: Full Analysis Set, composed of all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Achieving an Overall Response (Complete Response (CR) or Partial Response (PR)) Determined by the Investigator Based on Modified International Working Group 2006 Response Criteria Guidelines | 1 Participants |
| Romiplostim 500 μg | Achieving an Overall Response (Complete Response (CR) or Partial Response (PR)) Determined by the Investigator Based on Modified International Working Group 2006 Response Criteria Guidelines | 2 Participants |
| Romiplostim 750 μg | Achieving an Overall Response (Complete Response (CR) or Partial Response (PR)) Determined by the Investigator Based on Modified International Working Group 2006 Response Criteria Guidelines | 3 Participants |
95% CI: [0.227, 39.608]
95% CI: [0.144, 20.473]
Secondary
Lenalidomide Dose Reduction and Delay Due to Thrombocytopenia
Occurrence of lenalidomide dose reduction and delay due to thrombocytopenia
Time frame: Treatment period (up to 16 weeks)
Population: Full Analysis Set, composed of all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Lenalidomide Dose Reduction and Delay Due to Thrombocytopenia | 6 Participants |
| Romiplostim 500 μg | Lenalidomide Dose Reduction and Delay Due to Thrombocytopenia | 5 Participants |
| Romiplostim 750 μg | Lenalidomide Dose Reduction and Delay Due to Thrombocytopenia | 2 Participants |
95% CI: [0.022, 1.071]
95% CI: [0.102, 2.589]
Secondary
Platelet Transfusion
Occurrence of one or more platelet transfusions during the treatment period
Time frame: Treatment period (up to 16 weeks)
Population: Full Analysis Set, composed of all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Platelet Transfusion | 4 Participants |
| Romiplostim 500 μg | Platelet Transfusion | 4 Participants |
| Romiplostim 750 μg | Platelet Transfusion | 4 Participants |
95% CI: [0.097, 8.529]
95% CI: [0.175, 4.278]