Anemia, Cancer, Lung Cancer, Non-Small Cell Lung Cancer
Conditions
Keywords
darbepoetin alfa, non-small cell lung cancer, Aranesp, chemotherapy, chemotherapy induce anemia, advanced lung cancer, malignant pleural effusion, metastatic lung cancer, NSCLC, anemia, lung cancer, pleural effusion, Stage IIIB lung cancer, Stage IV lung cancer
Brief summary
This is a study in patients with chemotherapy induced anemia receiving multi-cycle chemotherapy for the treatment of stage IV non-small cell lung cancer (NSCLC). The primary objective of the study is to demonstrate that overall survival (OS) is not worse in participants on darbepoetin alfa treated to a hemoglobin ceiling of 12.0 g/dL compared to participants treated with placebo.
Detailed description
Oversight Authorities continued: Colombia
Interventions
DRUGDarbepoetin alfa
Administered subcutaneously once every 3 weeks
DRUGPlacebo
Administered subcutaneously once every 3 weeks
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects with stage IV NSCLC (not recurrent or re-staged). * Expected to receive at least 2 additional cycles (at least 6 total weeks) of first line myelosuppressive cyclic chemotherapy after randomization. Subjects should not be expected to receive only maintenance chemotherapy. * Eastern Cooperative Oncology Group performance status of 0 or 1 as assessed within 21 days prior to randomization. * 18 years of age or older at screening. * Life expectancy greater than 6 months based on the judgment of the investigator and documented during screening. * Hemoglobin level less than or equal to 11.0 g/dL as assessed by the local laboratory; sample obtained within 7 days prior to randomization (retest in screening is acceptable). * Adequate serum folate (greater than or equal to 2 ng/mL) and vitamin B12 (greater than or equal to 200 pg/mL) levels assessed by central laboratory (supplementation and retest acceptable) during screening. * Subjects must have had a baseline scan (computed tomography \[CT\], magnetic resonance imaging \[MRI\], or positron emission tomography-computer tomography \[PET/CT\]) of the chest to assess disease burden before starting on first line chemotherapy for NSCLC and those images must have been reviewed by the investigator prior to randomization. If the scan was performed more than 28 days prior to randomization, an additional scan must be performed and reviewed by the investigator to confirm that the patient has not progressed before randomization. * Before any study-specific procedure, the appropriate written informed consent must be obtained from the subject or a legally accepted representative.
Exclusion criteria
* Known primary benign or malignant hematologic disorder which can cause anemia. * History of, or current active cancer other than NSCLC, with the exception of curatively resected non-melanomatous skin cancer, curatively treated cervical carcinoma in situ, or other primary solid tumors curatively treated with no known active disease present and no curative treatment administered for the last 3 years. * Received any prior adjuvant or neoadjuvant therapy for NSCLC. * Subjects with a history of brain metastasis. * Uncontrolled hypertension (systolic blood pressure \[BP\] \> 160 mmHg or diastolic BP \> 100 mmHg), or as determined by the investigator during screening. * History of neutralizing antibody activity to recombinant human erythropoietin (rHuEPO) or darbepoetin alfa. * Uncontrolled angina, uncontrolled heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator at screening. Subjects with known myocardial infarction within 6 months prior to randomization. * Subjects with a history of seizure disorder taking anti-seizure medication within 30 days prior to randomization. * Clinically significant systemic infection or uncontrolled chronic inflammatory disease (eg, rheumatoid arthritis, inflammatory bowel disease) as determined by the investigator during screening. * Known seropositivity for human immunodeficiency virus (HIV) or diagnosis of acquired immunodeficiency syndrome (AIDS), positive for hepatitis B surface antigen, or seropositive for hepatitis C virus * History of pure red cell aplasia * History of deep venous thrombosis or embolic event (eg, pulmonary embolism) within 6 months prior to randomization. * Transferrin saturation \< 20% and ferritin \< 50 ng/mL as assessed by the central laboratory during screening. Subjects must have both to be excluded (supplementation and retest acceptable). * Abnormal renal function (serum creatinine level \> 2X upper limit of normal \[ULN\]) as assessed by the central laboratory during screening. * Abnormal liver function (total bilirubin \> 2X ULN or liver enzymes alanine aminotransferase \[ALT\] or aspartate aminotransferase \[AST\] \> 2.5X ULN for subjects without liver metastasis or ≥ 5X ULN for subjects with liver metastasis) as assessed by the central laboratory during screening. Subjects with documented Gilbert's Disease may be eligible. * Received any red blood cell (RBC) transfusion within 28 days prior to randomization. * Plan to receive any RBC transfusion between randomization and study day 1. * Known previous treatment failure to erythropoiesis stimulating agents (ESAs) (eg, rHuEPO, darbepoetin alfa). * ESA therapy within the 28 days prior to randomization. * Known hypersensitivity to recombinant ESAs or the excipients contained within the investigational product. * Less than 30 days since receipt of any investigational product or device. Investigational use/receipt of a medicinal product or device that has been approved by the country's local regulatory authority for any indication is permitted. * Subjects of reproductive potential who are pregnant, breast feeding or not willing to use effective contraceptive precautions during the study and for at least one month after the last dose of investigational product in the judgment of the investigator (including females of childbearing potential who are partners of male subjects). * Previously randomized to this study. * Investigator has concerns regarding the ability of the subject to give written informed consent and/or to comply with study procedures (including availability for follow up visits).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization until death or end of study; maximum time on follow-up was 93.6 months. | Overall survival (OS) was defined as the time from randomization to the date of death due to any cause. Participants were censored on the date of last contact (ie, the date the participant was last known to be alive) if they were not known to have died. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Red Blood Cell Transfusion or Hemoglobin ≤ 8.0 g/dL From Week 5 to End of the Efficacy Treatment Period | Week 5 (day 29) to end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later); median (range) duration of dosing was 10 (1 to 106) weeks in both groups. | Any red blood cell (RBC) transfusion (packed RBCs or whole blood) given or a hemoglobin ≤ 8.0 g/dL on or after study day 29 until the EOETP, inclusive. |
| Number of Participants With Adverse Events of Special Interest | From first dose of study drug until 30 days after last dose; the median (range) duration of treatment was 10 (1 to 106) weeks in both groups. | Adverse events of interest for darbepoetin alfa, based on clinical data in anemic patients with cancer to date, included the following categories: antibody-mediated pure red cell aplasia (PRCA), cardiac failure, central nervous system vascular disorders, convulsions, embolic and thrombotic events, hypersensitivity, hypertension, ischemic heart disease, malignancies, and severe cutaneous adverse reactions. Lack of efficacy and medication errors were also evaluated. |
| Percentage of Participants With an Objective Tumor Response | Day 1 to end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later); median (range) duration of dosing was 10 (1 to 106) weeks in both groups. | Objective response was defined as the incidence of a complete or partial response at any time during the study. Response was determined by the investigator's assessment of the scans using RECIST version 1.0 or 1.1 depending on the timing of enrollment. |
| Progression-free Survival (PFS) | From randomization until disease progression or death; maximum time on follow-up was 87.23 months. | Progression-free survival was defined as the time from randomization to the date of radiographic disease progression or death from any cause, whichever event occurred first. Participants without either event were censored on the date of their last disease assessment. Disease progression was based on the investigator's assessment of scans using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 or 1.1 depending on the timing of enrollment. |
| Percentage of Participants With a Red Blood Cell Transfusion or Hemoglobin ≤ 8.0 g/dL From Week 1 to End of the Efficacy Treatment Period | Week 1 to end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later); the median (range) duration of treatment was 10 (1 to 106) weeks in both groups. | Any red blood cell (RBC) transfusion (packed RBCs or whole blood) given or a hemoglobin ≤ 8.0 g/dL on or after study day 1 until the EOETP, inclusive. |
| Change From Baseline in Hemoglobin to End of Efficacy Treatment Period | Baseline and end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later); the median (range) duration of treatment was 10 (1 to 106) weeks in both groups. | Post-baseline hemoglobin values within 28 days after a RBC transfusion were not be used in the calculation of change. |
| Number of Participants Who Developed Neutralizing Antibodies to Darbepoetin Alfa | Baseline and end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later. the median (range) duration of treatment was 10 (1 to 106) weeks in both groups. | Developing antibody incidence was defined as neutralizing antibody positive postbaseline with a negative or no result at baseline. |
Countries
Argentina, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Croatia, Czechia, Germany, Greece, Hong Kong, India, Ireland, Israel, Italy, Japan, Luxembourg, Malaysia, Mexico, Netherlands, Philippines, Poland, Puerto Rico, Romania, Russia, Serbia, Slovenia, South Africa, South Korea, Spain, Switzerland, Taiwan, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 371 centers in Europe, Latin America, Asia, India, North America, Israel, and South Africa.
Pre-assignment details
Eligible participants were randomized to darbepoetin alfa or placebo in a 2:1 ratio. Randomization was stratified by histology (squamous vs other), screening hemoglobin (\< 10.0 g/dL vs ≥ 10.0 g/dL), and geographic region.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first. | 846 |
| Darbepoetin Alfa Participants received darbepoetin alfa 500 µg once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first. | 1,703 |
| Total | 2,549 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative Decision | 3 | 2 |
| Overall Study | Adverse Event | 5 | 2 |
| Overall Study | Ineligibility Determined | 1 | 10 |
| Overall Study | Lost to Follow-up | 24 | 54 |
| Overall Study | Missing | 1 | 1 |
| Overall Study | Noncompliance | 3 | 4 |
| Overall Study | Other | 9 | 17 |
| Overall Study | Protocol Deviation | 0 | 2 |
| Overall Study | Still on-study | 114 | 247 |
| Overall Study | Withdrawal by Subject | 44 | 118 |
Baseline characteristics
| Characteristic | Placebo | Darbepoetin Alfa | Total |
|---|---|---|---|
| Age, Continuous | 62.2 years STANDARD_DEVIATION 9.9 | 61.6 years STANDARD_DEVIATION 9.8 | 61.8 years STANDARD_DEVIATION 9.8 |
| Age, Customized 18 - 64 years | 482 Participants | 1014 Participants | 1496 Participants |
| Age, Customized 65 - 74 years | 287 Participants | 547 Participants | 834 Participants |
| Age, Customized 75 - 84 years | 71 Participants | 134 Participants | 205 Participants |
| Age, Customized ≥ 85 years | 6 Participants | 8 Participants | 14 Participants |
| Geographic Region Central and Eastern Europe | 220 Participants | 451 Participants | 671 Participants |
| Geographic Region China | 123 Participants | 243 Participants | 366 Participants |
| Geographic Region India | 168 Participants | 339 Participants | 507 Participants |
| Geographic Region Japan | 6 Participants | 10 Participants | 16 Participants |
| Geographic Region Latin America and Asia | 166 Participants | 337 Participants | 503 Participants |
| Geographic Region North America | 99 Participants | 192 Participants | 291 Participants |
| Geographic Region Western Europe, Israel and South Africa | 54 Participants | 108 Participants | 162 Participants |
| Histology Non-squamous | 547 Participants | 1091 Participants | 1638 Participants |
| Histology Squamous | 289 Participants | 589 Participants | 878 Participants |
| Race/Ethnicity, Customized Aborigine | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 357 Participants | 741 Participants | 1098 Participants |
| Race/Ethnicity, Customized Black or African American | 27 Participants | 46 Participants | 73 Participants |
| Race/Ethnicity, Customized Hispanic | 45 Participants | 81 Participants | 126 Participants |
| Race/Ethnicity, Customized Japanese | 7 Participants | 12 Participants | 19 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 14 Participants | 19 Participants |
| Race/Ethnicity, Customized White or Caucasian | 404 Participants | 808 Participants | 1212 Participants |
| Screening Hemoglobin < 10 g/dL | 433 Participants | 870 Participants | 1303 Participants |
| Screening Hemoglobin ≥ 10 g/dL | 403 Participants | 810 Participants | 1213 Participants |
| Sex: Female, Male Female | 281 Participants | 585 Participants | 866 Participants |
| Sex: Female, Male Male | 565 Participants | 1118 Participants | 1683 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 657 / 833 | 1,273 / 1,685 |
| other Total, other adverse events | 674 / 833 | 1,319 / 1,685 |
| serious Total, serious adverse events | 259 / 833 | 524 / 1,685 |
Outcome results
Primary
Overall Survival (OS)
Overall survival (OS) was defined as the time from randomization to the date of death due to any cause. Participants were censored on the date of last contact (ie, the date the participant was last known to be alive) if they were not known to have died.
Time frame: From randomization until death or end of study; maximum time on follow-up was 93.6 months.
Population: Primary analysis set (all randomized and consented participants with non-small cell lung cancer who received at least one dose of study drug)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Overall Survival (OS) | 9.260 months |
| Darbepoetin Alfa | Overall Survival (OS) | 9.460 months |
Comparison: The primary analysis used the Cox Proportional Hazard Model stratified by the randomization stratification factors (geographic region, histology, and screening hemoglobin), with treatment group as the only covariate.95% CI: [0.83, 1.01]
Comparison: As a sensitivity analysis, an unstratified Cox Proportional Hazard Model with treatment group as the only covariate was conducted.95% CI: [0.83, 1]
p-value: 0.07Stratified log-rank test
p-value: 0.047Log Rank
Comparison: To evaluate the potential effect of cross-in (participants in the placebo group who began treatment with an erythropoiesis-stimulating agent (ESA) at any point after randomization), a sensitivity analysis was conducted that included ESA use as a time-dependent covariate in a Cox regression model stratified by the randomization stratification factors (geographic region, histology, and screening hemoglobin).95% CI: [0.84, 1.02]
Secondary
Change From Baseline in Hemoglobin to End of Efficacy Treatment Period
Post-baseline hemoglobin values within 28 days after a RBC transfusion were not be used in the calculation of change.
Time frame: Baseline and end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later); the median (range) duration of treatment was 10 (1 to 106) weeks in both groups.
Population: Primary analysis set with available baseline and at least 1 postbaseline value; if the EOETP value was missing, the last available postbaseline value was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hemoglobin to End of Efficacy Treatment Period | -0.11 g/dL | Standard Deviation 1.71 |
| Darbepoetin Alfa | Change From Baseline in Hemoglobin to End of Efficacy Treatment Period | 0.50 g/dL | Standard Deviation 1.81 |
Secondary
Number of Participants Who Developed Neutralizing Antibodies to Darbepoetin Alfa
Developing antibody incidence was defined as neutralizing antibody positive postbaseline with a negative or no result at baseline.
Time frame: Baseline and end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later. the median (range) duration of treatment was 10 (1 to 106) weeks in both groups.
Population: Randomized and consented participants who received at least one dose of study drug and with a postbaseline result.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Developed Neutralizing Antibodies to Darbepoetin Alfa | 0 Participants |
| Darbepoetin Alfa | Number of Participants Who Developed Neutralizing Antibodies to Darbepoetin Alfa | 0 Participants |
Secondary
Number of Participants With Adverse Events of Special Interest
Adverse events of interest for darbepoetin alfa, based on clinical data in anemic patients with cancer to date, included the following categories: antibody-mediated pure red cell aplasia (PRCA), cardiac failure, central nervous system vascular disorders, convulsions, embolic and thrombotic events, hypersensitivity, hypertension, ischemic heart disease, malignancies, and severe cutaneous adverse reactions. Lack of efficacy and medication errors were also evaluated.
Time frame: From first dose of study drug until 30 days after last dose; the median (range) duration of treatment was 10 (1 to 106) weeks in both groups.
Population: All randomized and consented participants who received at least 1 dose of study drug. Four participants in the placebo group received at least 1 dose of darbepoetin alfa during the study and were included in the darbepoetin alfa group for safety analyses.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events of Special Interest | Hypertension | 26 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Cardiac failure | 7 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Ischaemic heart disease | 9 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Embolic and thrombotic events, arterial | 6 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Lack of efficacy/effect | 0 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Convulsions | 8 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Malignancies | 16 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Embolic and thrombotic events, venous | 23 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Medication errors | 0 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Central nervous system vascular disorders | 8 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Severe cutaneous adverse reactions | 11 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Embolic and thrombotic events | 34 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Any adverse events of interest | 157 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Antibody-mediated pure red cell aplasia | 20 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Embolic and thrombotic events, unspecified/mixed | 10 Participants |
| Placebo | Number of Participants With Adverse Events of Special Interest | Hypersensitivity | 75 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Hypersensitivity | 178 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Antibody-mediated pure red cell aplasia | 51 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Cardiac failure | 12 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Central nervous system vascular disorders | 25 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Convulsions | 9 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Embolic and thrombotic events | 89 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Embolic and thrombotic events, arterial | 19 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Embolic and thrombotic events, venous | 51 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Embolic and thrombotic events, unspecified/mixed | 26 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Hypertension | 41 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Ischaemic heart disease | 23 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Lack of efficacy/effect | 0 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Malignancies | 38 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Medication errors | 1 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Severe cutaneous adverse reactions | 35 Participants |
| Darbepoetin Alfa | Number of Participants With Adverse Events of Special Interest | Any adverse events of interest | 369 Participants |
Secondary
Percentage of Participants With an Objective Tumor Response
Objective response was defined as the incidence of a complete or partial response at any time during the study. Response was determined by the investigator's assessment of the scans using RECIST version 1.0 or 1.1 depending on the timing of enrollment.
Time frame: Day 1 to end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later); median (range) duration of dosing was 10 (1 to 106) weeks in both groups.
Population: The radiographic endpoint primary analysis set includes all participants in the primary analysis set who did not have disease progression prior to randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With an Objective Tumor Response | 32.6 percentage of participants |
| Darbepoetin Alfa | Percentage of Participants With an Objective Tumor Response | 36.2 percentage of participants |
p-value: 0.07695% CI: [0.983, 1.401]Cochran-Mantel-Haenszel
p-value: 0.07895% CI: [0.982, 1.401]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With a Red Blood Cell Transfusion or Hemoglobin ≤ 8.0 g/dL From Week 1 to End of the Efficacy Treatment Period
Any red blood cell (RBC) transfusion (packed RBCs or whole blood) given or a hemoglobin ≤ 8.0 g/dL on or after study day 1 until the EOETP, inclusive.
Time frame: Week 1 to end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later); the median (range) duration of treatment was 10 (1 to 106) weeks in both groups.
Population: Primary analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a Red Blood Cell Transfusion or Hemoglobin ≤ 8.0 g/dL From Week 1 to End of the Efficacy Treatment Period | 29.7 percentage of participants |
| Darbepoetin Alfa | Percentage of Participants With a Red Blood Cell Transfusion or Hemoglobin ≤ 8.0 g/dL From Week 1 to End of the Efficacy Treatment Period | 24.2 percentage of participants |
p-value: 0.00395% CI: [0.61, 0.901]Cochran-Mantel-Haenszel
p-value: 0.00395% CI: [0.63, 0.913]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With a Red Blood Cell Transfusion or Hemoglobin ≤ 8.0 g/dL From Week 5 to End of the Efficacy Treatment Period
Any red blood cell (RBC) transfusion (packed RBCs or whole blood) given or a hemoglobin ≤ 8.0 g/dL on or after study day 29 until the EOETP, inclusive.
Time frame: Week 5 (day 29) to end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later); median (range) duration of dosing was 10 (1 to 106) weeks in both groups.
Population: Primary analysis set participants who were on study as of day 29
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a Red Blood Cell Transfusion or Hemoglobin ≤ 8.0 g/dL From Week 5 to End of the Efficacy Treatment Period | 29.2 percentage of participants |
| Darbepoetin Alfa | Percentage of Participants With a Red Blood Cell Transfusion or Hemoglobin ≤ 8.0 g/dL From Week 5 to End of the Efficacy Treatment Period | 22.5 percentage of participants |
Comparison: The primary analysis of the incidence of a transfusion or hemoglobin ≤ 8.0 g/dL from day 29 to EOETP was based on the Cochran-Mantel-Haenszel method to test for treatment group differences while adjusting for the randomization stratification factors (geographic region, histology, and screening hemoglobin).p-value: <0.00195% CI: [0.573, 0.864]Cochran-Mantel-Haenszel
Comparison: As a sensitivity analysis a logistic regression analysis was conducted, stratified by the randomization stratification factors (geographic region, histology, screening hemoglobin).p-value: <0.00195% CI: [0.574, 0.866]Regression, Logistic
Secondary
Progression-free Survival (PFS)
Progression-free survival was defined as the time from randomization to the date of radiographic disease progression or death from any cause, whichever event occurred first. Participants without either event were censored on the date of their last disease assessment. Disease progression was based on the investigator's assessment of scans using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 or 1.1 depending on the timing of enrollment.
Time frame: From randomization until disease progression or death; maximum time on follow-up was 87.23 months.
Population: The radiographic endpoint primary analysis set includes all participants in the primary analysis set who did not have disease progression prior to randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Progression-free Survival (PFS) | 4.340 months |
| Darbepoetin Alfa | Progression-free Survival (PFS) | 4.800 months |
Comparison: The primary analysis of PFS used a Cox Proportional Hazard Model stratified by the randomization stratification factors (geographic region, histology, and screening hemoglobin), with treatment group as the only covariate.95% CI: [0.87, 1.04]
Comparison: As a sensitivity analysis, an unstratified Cox Proportional Hazard Model with treatment group as the only covariate was conducted.95% CI: [0.87, 1.04]
p-value: 0.31Stratified log-rank test
p-value: 0.27Log Rank
Comparison: To evaluate the potential effect of cross-in (participants in the placebo group who began treatment with an erythropoiesis-stimulating agent (ESA) at any point after randomization), a sensitivity analysis was conducted that included ESA use as a time-dependent covariate in a Cox regression model stratified by the randomization stratification factors (geographic region, histology, and screening hemoglobin).95% CI: [0.88, 1.05]