Anemia Treatment for Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Receiving Chemotherapy

Study Overview
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Brief Summary
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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
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Oversight Authorities continued: Colombia

Official Title
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A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Long-term Safety and Efficacy of Darbepoetin Alfa Administered at 500 µg Once-Every-3-Weeks in Anemic Subjects With Advanced Stage Non-small Cell Lung Cancer Receiving Multi-cycle Chemotherapy

Conditions
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Non-Small Cell Lung Cancer, Anemia, Cancer, Lung Cancer

Intervention / Treatment
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* Drug: Darbepoetin alfa
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* Administered subcutaneously once every 3 weeks<br>|
| Experimental: Darbepoetin alfa<br>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. | Drug: Darbepoetin alfa<br>* Administered subcutaneously once every 3 weeks<br>* Other names: Aranesp®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From randomization until death or end of study; maximum time on follow-up was 93.6 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From randomization until disease progression or death; maximum time on follow-up was 87.23 months. | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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