Non Small Cell Lung Cancer
Conditions
Keywords
Non Small Cell Lung Cancer, Lung, NSCLC
Brief summary
The purpose of this study is to evaluate the progression-free survival (PFS) rate at 6 months of ramucirumab administered in combination with paclitaxel and carboplatin as first-line therapy for Stage IIIB or IV non-small cell lung cancer
Detailed description
Non-small cell lung cancer (NSCLC) accounts for 75-80% of all lung cancers. The advanced stages are associated with poor survival rates, a median survival rate of approximately 3.9 months if left untreated. Angiogenesis is a process for wound healing and restoring blood flow to tissues after injury. It is the physiological process involving the growth of new blood vessels from pre-existing vessels. Angiogenesis may be promoted by growth factors and in diseases such as cancer, where growth factors are over expressed, the body loses the ability to maintain a balanced angiogenesis. This may embellish the existing supplies of blood; potentially increasing the delivery of oxygen and nutrients supplies for cancer growth and survival. Ramucirumab is an angiogenesis inhibitor; and is believed to block the promotion of the growth factor to form new blood vessels, thus reducing the blood supply to the cancer cells.
Interventions
BIOLOGICALRamucirumab
10 milligrams per kilogram (mg/kg), intravenous (IV) infusion, on Day 1 of each 21-day cycle.
DRUGPaclitaxel
200 milligrams per meter squared (mg/m\^2), administered intravenously (IV) following the ramucirumab infusion, on day 1 of each 21-day cycle, for up to six cycles.
DRUGCarboplatin
Administered after paclitaxel, as an intravenous infusion (IV), over 30 minutes on day 1 of each 21-day cycle, for up to six cycles. The dose to be administered is calculated based on the participant's actual body weight at time of treatment and the area under the curve (AUC) dosing. The target AUC for carboplatin treatment is AUC=6.
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed NSCLC * Advanced NSCLC * Measurable disease (as defined by Response Evaluation Criteria in Solid Tumors \[RECIST 1.0\]) * Eastern Cooperative Oncology Group (ECOG) Performance Status is ≤ 1 * Age ≥ 18 years * Adequate hematologic function = an absolute neutrophil count (ANC) ≥ 1500/μL, hemoglobin ≥ 9 g/dL, and a platelet count ≥ 100,000/microliter (μL) * Adequate hepatic function = a total bilirubin ≤ 1.5 mg/dL transaminases and alkaline phosphatase ≤ 5 x the upper limit of normal (ULN) * Adequate renal function serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance (CrCl) \> 60 mL/minute, and urine dipstick for protein \< 1+ (ie, either 0 or trace) * Adequate coagulation function, INR ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 5 seconds above ULN * Adequate contraception * Signed informed consent
Exclusion criteria
* Untreated CNS metastases * Prior bevacizumab therapy * Radiologically documented evidence of major blood vessel invasion or encasement by cancer * Prior systemic chemotherapy for Stage IIIB/IV NSCLC * Prior systemic chemotherapy or radiation therapy for Stage I-IIIA NSCLC \< 1 year prior * Any concurrent malignancy other than basal cell skin cancer, or carcinoma in situ of the cervix * Concurrent treatment with other anticancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, radiotherapy, chemoembolization, or targeted therapy * Ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Uncontrolled thrombotic or hemorrhagic disorders * Poorly-controlled hypertension * Chronic daily treatment with aspirin (\> 325 mg/day) or other known inhibitors of platelet function * History of gross hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon) * Serious non-healing wound, ulcer, or bone fracture * Undergone major surgery or subcutaneous venous access device placement. Post-operative bleeding complications or wound complications from a surgical procedures performed in the last 2 months * Elective or a planned major surgery to be performed during the course of the trial * Peripheral neuropathy ≥ Grade 2 (National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 3.0 \[NCI-CTCAE v 3.0\]) * If female, is pregnant or lactating * Radiographic evidence of intratumor cavitation * Grade 3-4 gastrointestinal bleeding within 3 months prior to study entry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Are Progression-free (PFS) at 6 Months | 6 months | Data presented are the percentage of participants without disease progression or death at 6 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). Progressive disease was defined as having at least a 20% increase in sum of longest diameter of target lesions or the appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate ([ORR]) | First dose to measured progressive disease or death due to any cause up to 32.5 months | Objective response is Complete Response (CR) + Partial Response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST 1.0) guidelines. CR is a disappearance of all target and non-target lesions; PR is at least a 30% decrease in the sum of the longest diameter of target lesions without new lesions and progression of non-target lesions. Objective response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with measurable disease, multiplied by 100. |
| Duration of Response | First dose up to 32.5 months | The duration of a complete response (CR) or partial response (PR) was defined as the time from first objective status assessment of CR or PR to the first time of progression, initiation of additional antitumor therapy is first reported, or death as a result of any cause. CR was defined as the disappearance of all target lesions. PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions. |
| Overall Survival (OS) at 1 Year | First dose to 1 year | Data presented are the percentage of participants surviving at least 12 months after first dose of study medication. |
| Summary of Participants Reporting Adverse Events | Baseline up to 32.5 months | Data presented are the number of participants who experienced ramucirumab related treatment-emergent adverse events (TEAE), treatment related serious adverse events (SAE), or any Grade 3 or higher TEAE; any TEAE leading to discontinuation of ramucirumab treatment, and any TEAE leading to dose modification ramucirumab. A summary of SAEs and other nonserious AEs, regardless of causality, is located in the Reported Adverse Event section. |
| Overall Survival (OS) | First dose to death due to any cause, up to 32.5 months | Overall survival is defined as the time from the first dose of study medication to the date of death from any cause. Participants who were alive at the end of the follow-up period or lost to follow-up were censored on the last date the patient was known to be alive. |
| Serum Anti-Ramucirumab Antibody Assessment | Week 15 (Cycle 5) | The number of participants who developed treatment emergent antibody responses to ramucirumab after baseline. |
| Maximum Concentration of Ramucirumab (Cmax) | Week 18 (Cycle 6), at 1-Hour Post End of Infusion | — |
| Progression-free Survival (PFS) | First dose to measured progressive disease or death due to any cause, up to 32.5 months | Defined as the time from date of first dose of study medication to the first documented disease progression as defined by Response Evaluation Criteria In Solid Tumors (RECIST 1.0), initiation of additional antitumor therapy was first reported or death due to any cause. Participants who did not progress, who discontinued treatment for toxicity or a reason other than documented progression, or who were lost to follow-up before documented progression or death were censored at date of last tumor assessment. Participants who started new therapeutic anticancer treatment prior to documented progression or death were censored at date of last tumor assessment prior to new therapeutic anticancer therapy. |
Countries
United Kingdom, United States
Participant flow
Pre-assignment details
52 participants signed informed consent
Participants by arm
| Arm | Count |
|---|---|
| Ramucirumab + Paclitaxel + Carboplatin ramucirumab: 10 mg/kg administered intravenously on day 1 of each 21-day cycle.
paclitaxel: 200 mg/m\^2 administered intravenously on day 1 of each 21-day cycle for up to six cycles.
carboplatin: administered intravenously on day 1 of each 21-day cycle, dose calculated based on the participant's body weight.
Participants will receive ramucirumab in combination with paclitaxel and carboplatin until disease progression, the development of an unacceptable toxicity, or other withdrawal criteria, for up to six cycles (3 weeks per cycle). In the absence of any withdrawal criteria, participants will continue to receive ramucirumab monotherapy every 3 weeks, provided there is ongoing evidence of benefit upon review every 6 weeks. | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Enrolled but never Treated | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Ramucirumab + Paclitaxel + Carboplatin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 13 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants |
| Race/Ethnicity, Customized White | 34 Participants |
| Region of Enrollment United Kingdom | 4 participants |
| Region of Enrollment United States | 36 participants |
| Sex: Female, Male Female | 25 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 40 / 40 |
| serious Total, serious adverse events | 19 / 40 |
Outcome results
Primary
Percentage of Participants Who Are Progression-free (PFS) at 6 Months
Data presented are the percentage of participants without disease progression or death at 6 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). Progressive disease was defined as having at least a 20% increase in sum of longest diameter of target lesions or the appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions.
Time frame: 6 months
Population: Modified intent to treat population (mITT): All participants who received any quantity of study drug.~Nine participants were censored.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab + Paclitaxel + Carboplatin | Percentage of Participants Who Are Progression-free (PFS) at 6 Months | 59.0 percentage of participants |
Secondary
Duration of Response
The duration of a complete response (CR) or partial response (PR) was defined as the time from first objective status assessment of CR or PR to the first time of progression, initiation of additional antitumor therapy is first reported, or death as a result of any cause. CR was defined as the disappearance of all target lesions. PR was defined as having at least a 30% decrease in sum of longest diameter of target lesions.
Time frame: First dose up to 32.5 months
Population: Participants who had tumor response. Two participants who had tumor response did not progress by the data cut-off date, therefore were censored for duration of response analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab + Paclitaxel + Carboplatin | Duration of Response | 5.54 months |
Secondary
Maximum Concentration of Ramucirumab (Cmax)
Time frame: Week 18 (Cycle 6), at 1-Hour Post End of Infusion
Population: Participants who received any quantity of study medication and had evaluable concentration data at the specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ramucirumab + Paclitaxel + Carboplatin | Maximum Concentration of Ramucirumab (Cmax) | 372 micrograms/milliliter (mcg/mL) | Standard Deviation 82.9 |
Secondary
Overall Survival (OS)
Overall survival is defined as the time from the first dose of study medication to the date of death from any cause. Participants who were alive at the end of the follow-up period or lost to follow-up were censored on the last date the patient was known to be alive.
Time frame: First dose to death due to any cause, up to 32.5 months
Population: Modified intent to treat population (mITT): All participants who received any quantity of study drug.~Fourteen participants were censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab + Paclitaxel + Carboplatin | Overall Survival (OS) | 16.85 months |
Secondary
Overall Survival (OS) at 1 Year
Data presented are the percentage of participants surviving at least 12 months after first dose of study medication.
Time frame: First dose to 1 year
Population: Modified intent to treat population (mITT): All participants who received any quantity of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab + Paclitaxel + Carboplatin | Overall Survival (OS) at 1 Year | 74.6 percentage of participants |
Secondary
Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate ([ORR])
Objective response is Complete Response (CR) + Partial Response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST 1.0) guidelines. CR is a disappearance of all target and non-target lesions; PR is at least a 30% decrease in the sum of the longest diameter of target lesions without new lesions and progression of non-target lesions. Objective response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with measurable disease, multiplied by 100.
Time frame: First dose to measured progressive disease or death due to any cause up to 32.5 months
Population: Modified intent to treat population (mITT): All participants who received any quantity of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab + Paclitaxel + Carboplatin | Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate ([ORR]) | 55.0 percentage of participants |
Secondary
Progression-free Survival (PFS)
Defined as the time from date of first dose of study medication to the first documented disease progression as defined by Response Evaluation Criteria In Solid Tumors (RECIST 1.0), initiation of additional antitumor therapy was first reported or death due to any cause. Participants who did not progress, who discontinued treatment for toxicity or a reason other than documented progression, or who were lost to follow-up before documented progression or death were censored at date of last tumor assessment. Participants who started new therapeutic anticancer treatment prior to documented progression or death were censored at date of last tumor assessment prior to new therapeutic anticancer therapy.
Time frame: First dose to measured progressive disease or death due to any cause, up to 32.5 months
Population: Modified intent to treat population (mITT): All participants who received any quantity of study drug.~Nine participants were censored.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ramucirumab + Paclitaxel + Carboplatin | Progression-free Survival (PFS) | 7.85 months |
Secondary
Serum Anti-Ramucirumab Antibody Assessment
The number of participants who developed treatment emergent antibody responses to ramucirumab after baseline.
Time frame: Week 15 (Cycle 5)
Population: Participants who had Anti-Ramucirumab Antibody assessment at week 15 (cycle 5).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ramucirumab + Paclitaxel + Carboplatin | Serum Anti-Ramucirumab Antibody Assessment | 1 participants |
Secondary
Summary of Participants Reporting Adverse Events
Data presented are the number of participants who experienced ramucirumab related treatment-emergent adverse events (TEAE), treatment related serious adverse events (SAE), or any Grade 3 or higher TEAE; any TEAE leading to discontinuation of ramucirumab treatment, and any TEAE leading to dose modification ramucirumab. A summary of SAEs and other nonserious AEs, regardless of causality, is located in the Reported Adverse Event section.
Time frame: Baseline up to 32.5 months
Population: Safety Population: All participants who received any quantity of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ramucirumab + Paclitaxel + Carboplatin | Summary of Participants Reporting Adverse Events | Any ramucirumab related TEAE | 34 participants |
| Ramucirumab + Paclitaxel + Carboplatin | Summary of Participants Reporting Adverse Events | Any ramucirumab related Serious TEAE | 8 participants |
| Ramucirumab + Paclitaxel + Carboplatin | Summary of Participants Reporting Adverse Events | Any ramucirumab related Grade >= 3 TEAE | 15 participants |
| Ramucirumab + Paclitaxel + Carboplatin | Summary of Participants Reporting Adverse Events | Any TEAE Leading to Discontinuation of ramucirumab | 13 participants |
| Ramucirumab + Paclitaxel + Carboplatin | Summary of Participants Reporting Adverse Events | TEAE Leading to Dose Modification of ramucirumab | 24 participants |
| Ramucirumab + Paclitaxel + Carboplatin | Summary of Participants Reporting Adverse Events | Any ramucirumab related TEAE with Outcome of Death | 0 participants |