Cancer, Chemotherapy-Induced Thrombocytopenia, Lung Cancer, Lung Neoplasms, Non-Small Cell Lung Cancer, Oncology, Solid Tumors, Thrombocytopenia
Conditions
Keywords
Advanced Non-Small Cell Lung Cancer, Chemotherapy Induced Thrombocytopenia, CIT, NSCLC, Stage IIIB NSCLC, Stage IV NSCLC, Gemcitabine, Carboplatin, Cisplatin
Brief summary
The purpose of this study is to identify an effective, well tolerated dose and schedule of romiplostim that is appropriate for the treatment of chemotherapy induced thrombocytopenia (CIT) in patients with non-small cell lung cancer receiving gemcitabine and platinum.
Interventions
BIOLOGICALRomiplostim
Romiplostim is a thrombopoiesis recombinant protein that targets the thrombopoietin (TPO) receptor which results in increased platelet production.
DRUGPlacebo
Placebo subcutaneous injection.
DRUGGemcitabine
Intravenous infusion
DRUGCarboplatin
Intravenous infusion
DRUGCisplatin
Intravenous infusion
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
* Histologically or cytologically confirmed locally advanced or metastatic stage IIIB or stage IV NSCLC receiving 21-day cycles of gemcitabine/carboplatin or gemcitabine/cisplatin * Life expectancy ≥ 12 weeks at the time of screening * Thrombocytopenia as evidenced by a platelet count ≤ 50 x 10\^9/L during the qualifying cycle of chemotherapy, OR platelet count \< 100 x 10\^9/L on Day 22 of the qualifying cycle (for eligibility inclusion: ability to receive the same dose of chemotherapy on study), this criteria ensures that the patient must be dose delayed for platelet recovery * Ability to receive the same dose and schedule of chemotherapy during the first on-study treatment cycle as was given in the qualifying cycle (except Day 8 gemcitabine) * Absolute neutrophil count (ANC) ≥ 1,000/µL, hemoglobin ≥ 9.5 g/dL, and platelet count ≥ 100 x 10 \^9/L on Day 1 of the first on study chemotherapy treatment cycle * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 at the time of screening * Adequate Liver function; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3.0 x upper limit of normal (ULN) (except for patients with a confirmed diagnosis of Gilbert's Syndrome) * Adequate renal function; serum creatinine \< 1.5 x ULN
Exclusion criteria
* Receipt of \> 1 prior systemic chemotherapy regimen * Sepsis, disseminated coagulation or any other condition (i.e. immune \[idiopathic\] thrombocytopenic purpura \[ITP\], thrombotic thrombocytopenic purpura \[TTP\], hemolytic uremic syndrome \[HUS\]) that may exacerbate thrombocytopenia * History of unstable angina, congestive heart failure, uncontrolled hypertension (diastolic \> 100 mmHg), uncontrolled cardiac arrhythmia, or recent (within 1 year of screening ) myocardial infarction * History of arterial thrombosis (e.g., stroke or transient ischemic attack) within 1 year of screening * History of pulmonary embolism or other venous thrombosis within 1 year of screening (except for catheter-related clots) * Use of any nitrosourea or mitomycin-C within 6 weeks of screening * Have received any thrombopoietic growth factor or related substance * Have received granulocyte macrophage colony stimulating factor (GM-CSF) within the last 4 weeks prior to screening * Have received any experimental therapy within 4 weeks prior to screening * Have ever received a bone marrow or peripheral blood stem cell infusion (within 1 year of screening) * Known hypersensitivity to any recombinant E. coli-derived product.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | 4 months | This summary includes all treatment-emergent adverse events recorded from the start of investigational product on this study, or any worsening of adverse events initially experienced before initiation of this study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Grade 3 or 4 Thrombocytopenia | 3 weeks | The duration of grade 3 or 4 thrombocytopenia (defined as platelet count \<50 x 10\^9/L) experienced during the first on study chemotherapy cycle by treatment group. |
| Number of Participants Experiencing Grade 3 or 4 Thrombocytopenia During the First Treatment Cycle. | 3 weeks | The number of participants in each treatment group with grade 3 or 4 thrombocytopenia during the first on study treatment cycle. Per the Common Terminology Criteria for Adverse Events (CTCAE) v3.0, participants with a platelet count \< 50 x 10\^9/L, but ≥ 25 x 10\^9/L are considered to have Grade 3 thrombocytopenia and participants with a platelet count \< 25 x 10\^9/L are considered to have Grade 4 thrombocytopenia. Additionally, participants with a platelet transfusion during the first on-study treatment cycle were classified as having Grade 3/4 thrombocytopenia. |
| Number of Participants With Platelet Transfusions | 3 weeks | Number of participants who were administered platelet transfusions during first on study treatment cycle. |
| Platelet Count on Day 22 | Day 22 | Platelet count on Day 22 of the first on study chemotherapy treatment cycle (planned Day 1 of next cycle) by treatment group |
| Gemcitabine Dose Reduction on Day 8 of the First Chemotherapy Cycle | 8 days | Number of participants who required a gemcitabine dose reduction on Day 8 of the first on study chemotherapy cycle. |
Countries
Austria, Canada, Germany, Hungary, Ireland, Italy, Portugal, United States
Participant flow
Recruitment details
Participants were enrolled from 28 December 2006 through 11 August 2008.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received a placebo subcutaneous injection on Day 2 of each chemotherapy cycle. Chemotherapy consisted of 21-day cycles of gemcitabine/carboplatin (gemcitabine and carboplatin on Day 1 and gemcitabine again on Day 8) or 21-day cycles of gemcitabine/cisplatin (gemcitabine and cisplatin on Day 1 and gemcitabine again on Day 8), up to a maximum of 5 cycles administered according to standard institutional practice. | 12 |
| Romiplostim 250 µg Participants received romiplostim 250 μg administered subcutaneously on Day 2 of each chemotherapy cycle. Chemotherapy consisted of 21-day cycles of gemcitabine/carboplatin (gemcitabine and carboplatin on Day 1 and gemcitabine again on Day 8) or 21-day cycles of gemcitabine/cisplatin (gemcitabine and cisplatin on Day 1 and gemcitabine again on Day 8), up to a maximum of 5 cycles administered according to standard institutional practice. | 16 |
| Romiplostim 500 µg Participants received romiplostim 500 μg administered subcutaneously on Day 2 of each chemotherapy cycle. Chemotherapy consisted of 21-day cycles of gemcitabine/carboplatin (gemcitabine and carboplatin on Day 1 and gemcitabine again on Day 8) or 21-day cycles of gemcitabine/cisplatin (gemcitabine and cisplatin on Day 1 and gemcitabine again on Day 8), up to a maximum of 5 cycles administered according to standard institutional practice. | 18 |
| Romiplostim 750 µg Participants received romiplostim 750 μg administered subcutaneously on Day 2 of each chemotherapy cycle. Chemotherapy consisted of 21-day cycles of gemcitabine/carboplatin (gemcitabine and carboplatin on Day 1 and gemcitabine again on Day 8) or 21-day cycles of gemcitabine/cisplatin (gemcitabine and cisplatin on Day 1 and gemcitabine again on Day 8), up to a maximum of 5 cycles administered according to standard institutional practice. | 17 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Death | 0 | 0 | 1 | 1 |
| Overall Study | Ineligibility determined | 0 | 0 | 0 | 1 |
| Overall Study | Other | 0 | 0 | 1 | 0 |
| Overall Study | Protocol deviation | 0 | 1 | 0 | 0 |
| Overall Study | Requirement for alternative therapy | 0 | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Romiplostim 750 µg | Total | Placebo | Romiplostim 250 µg | Romiplostim 500 µg |
|---|---|---|---|---|---|
| Age Continuous | 65.4 Years STANDARD_DEVIATION 8.2 | 63.1 Years STANDARD_DEVIATION 8.5 | 59.8 Years STANDARD_DEVIATION 6.6 | 63.8 Years STANDARD_DEVIATION 10.8 | 62.5 Years STANDARD_DEVIATION 7.7 |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White or Caucasian | 17 Participants | 62 Participants | 12 Participants | 15 Participants | 18 Participants |
| Sex: Female, Male Female | 2 Participants | 18 Participants | 6 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 15 Participants | 45 Participants | 6 Participants | 12 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 12 | 16 / 16 | 17 / 18 | 14 / 16 |
| serious Total, serious adverse events | 1 / 12 | 7 / 16 | 5 / 18 | 5 / 16 |
Outcome results
Primary
Number of Participants With Adverse Events
This summary includes all treatment-emergent adverse events recorded from the start of investigational product on this study, or any worsening of adverse events initially experienced before initiation of this study.
Time frame: 4 months
Population: Safety Analysis Set, composed of all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Adverse Events | 12 Participants |
| Romiplostim 250 µg | Number of Participants With Adverse Events | 16 Participants |
| Romiplostim 500 µg | Number of Participants With Adverse Events | 18 Participants |
| Romiplostim 750 µg | Number of Participants With Adverse Events | 14 Participants |
Secondary
Duration of Grade 3 or 4 Thrombocytopenia
The duration of grade 3 or 4 thrombocytopenia (defined as platelet count \<50 x 10\^9/L) experienced during the first on study chemotherapy cycle by treatment group.
Time frame: 3 weeks
Population: Efficacy Analysis Set, composed of all randomized participants except those who were replaced (participants who discontinued prior to the completion of at least 1 romiplostim treatment cycle for non-platelet-related reasons).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Duration of Grade 3 or 4 Thrombocytopenia | 2.1 days | Standard Deviation 3.3 |
| Romiplostim 250 µg | Duration of Grade 3 or 4 Thrombocytopenia | 3.6 days | Standard Deviation 4.3 |
| Romiplostim 500 µg | Duration of Grade 3 or 4 Thrombocytopenia | 2.6 days | Standard Deviation 3.9 |
| Romiplostim 750 µg | Duration of Grade 3 or 4 Thrombocytopenia | 2.1 days | Standard Deviation 2.7 |
p-value: 0.972Satterthwaite t-test
p-value: 0.725Satterthwaite t-test
p-value: 0.312Satterthwaite t-test
Secondary
Gemcitabine Dose Reduction on Day 8 of the First Chemotherapy Cycle
Number of participants who required a gemcitabine dose reduction on Day 8 of the first on study chemotherapy cycle.
Time frame: 8 days
Population: Efficacy Analysis Set, composed of all randomized participants except those who were replaced.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Gemcitabine Dose Reduction on Day 8 of the First Chemotherapy Cycle | 2 Participants |
| Romiplostim 250 µg | Gemcitabine Dose Reduction on Day 8 of the First Chemotherapy Cycle | 4 Participants |
| Romiplostim 500 µg | Gemcitabine Dose Reduction on Day 8 of the First Chemotherapy Cycle | 4 Participants |
| Romiplostim 750 µg | Gemcitabine Dose Reduction on Day 8 of the First Chemotherapy Cycle | 5 Participants |
p-value: 0.662Fisher Exact
p-value: 1Fisher Exact
p-value: 0.662Fisher Exact
Secondary
Number of Participants Experiencing Grade 3 or 4 Thrombocytopenia During the First Treatment Cycle.
The number of participants in each treatment group with grade 3 or 4 thrombocytopenia during the first on study treatment cycle. Per the Common Terminology Criteria for Adverse Events (CTCAE) v3.0, participants with a platelet count \< 50 x 10\^9/L, but ≥ 25 x 10\^9/L are considered to have Grade 3 thrombocytopenia and participants with a platelet count \< 25 x 10\^9/L are considered to have Grade 4 thrombocytopenia. Additionally, participants with a platelet transfusion during the first on-study treatment cycle were classified as having Grade 3/4 thrombocytopenia.
Time frame: 3 weeks
Population: Efficacy Analysis Set, composed of all randomized participants except those who were replaced.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants Experiencing Grade 3 or 4 Thrombocytopenia During the First Treatment Cycle. | 5 Participants |
| Romiplostim 250 µg | Number of Participants Experiencing Grade 3 or 4 Thrombocytopenia During the First Treatment Cycle. | 7 Participants |
| Romiplostim 500 µg | Number of Participants Experiencing Grade 3 or 4 Thrombocytopenia During the First Treatment Cycle. | 7 Participants |
| Romiplostim 750 µg | Number of Participants Experiencing Grade 3 or 4 Thrombocytopenia During the First Treatment Cycle. | 7 Participants |
p-value: 1Fisher Exact
p-value: 1Fisher Exact
p-value: 1Fisher Exact
Secondary
Number of Participants With Platelet Transfusions
Number of participants who were administered platelet transfusions during first on study treatment cycle.
Time frame: 3 weeks
Population: Efficacy Analysis Set, composed of all randomized participants except those who were replaced.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Platelet Transfusions | 1 Participants |
| Romiplostim 250 µg | Number of Participants With Platelet Transfusions | 4 Participants |
| Romiplostim 500 µg | Number of Participants With Platelet Transfusions | 1 Participants |
| Romiplostim 750 µg | Number of Participants With Platelet Transfusions | 1 Participants |
p-value: 1Fisher Exact
p-value: 1Fisher Exact
p-value: 0.342Fisher Exact
Secondary
Platelet Count on Day 22
Platelet count on Day 22 of the first on study chemotherapy treatment cycle (planned Day 1 of next cycle) by treatment group
Time frame: Day 22
Population: Efficacy Analysis Set, composed of all randomized participants except those who were replaced
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Platelet Count on Day 22 | 281.2 10^9/L | Standard Deviation 116 |
| Romiplostim 250 µg | Platelet Count on Day 22 | 222.6 10^9/L | Standard Deviation 112 |
| Romiplostim 500 µg | Platelet Count on Day 22 | 412.8 10^9/L | Standard Deviation 295.2 |
| Romiplostim 750 µg | Platelet Count on Day 22 | 336.0 10^9/L | Standard Deviation 254.9 |
p-value: 0.454Satterthwaite t-test
p-value: 0.101Satterthwaite t-test
p-value: 0.199Satterthwaite t-test