Lung Cancer, Non-small Cell Lung Cancer
Conditions
Keywords
Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Bronchogenic, Bronchial Neoplasms, Respiratory Tract Neoplasms, Thoracic Neoplasms, Neoplasms by Site, Neoplasms, Lung Diseases, Respiratory Tract Diseases, Erlotinib, Therapeutic Uses, Pharmacologic Actions, Molecular Mechanisms of Pharmacological Action
Brief summary
1. Part A: Subjects will receive Patritumab or placebo with erlotinib. Progression-free survival will be the primary outcome. Subjects will need to have Epidermal Growth Factor Receptor (EGFR) wild-type, locally advance or metastatic NSCLC and have their cancer progressed after at least one prior systemic anti-cancer therapy, available recent or archival tumor specimen and may not have had previous EGFR-targeted regimen, anti-HER2 (Human Epidermal Growth Factor Receptor 2), anti-HER3, or anti-HER4 therapy. Subjects may have high heregulin or low heregulin. 2. Part B: Subjects will receive Patritumab or placebo with erlotinib. Overall survival will be the primary outcome. Subjects will need to have EGFR wild-type, locally advance or metastatic NSCLC and have their cancer progressed after at least one prior systemic anti-cancer therapy, available recent or archival tumor specimen and may not have had previous EGFR-targeted regimen, anti-HER2, anti-HER3, or anti-HER4 therapy. Only subjects with high heregulin will be enrolled.
Interventions
DRUGPatritumab
Infusion of Patritumab (loading dose of 18 mg/kg, followed by 9 mg/kg every 3 weeks)
DRUGErlotinib
Oral erlotinib 150 mg/day
DRUGPlacebo
Placebo infusion every 3 weeks
Sponsors
Parexel
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Must be greater or equal to 20 years of age 2. Must have cytologically or histologically confirmed NSCLC with either: * Metastatic disease (Stage IV) OR * Stage IIIB disease not amenable to surgery or curative intent. Note: It is permissible to use either AJCC Version 6.0 or the AJCC Version 7.0 staging system. For sites that use AJCC Version 7.0, T4M0 patients with other ipsilateral nodules and N0-N2 are still eligible. 3. If tumor histology is adenocarcinoma, must have wild-type EGFR genotype as assessed by a validated assay that includes exon 19 deletion and exon 21 (L858R) substitution. 4. Must have received one or two prior lines of systemic chemotherapy for advanced or metastatic disease, one of which must be a platinum-doublet therapy. 5. Must have disease progression or recurrence documented by radiographic assessment following treatment after last chemotherapy or chemoradiation regimen (completed within the previous 12 months). 6. Must have available recent (before treatment start) or archival tumor specimen. 7. Must have measurable disease for Part A, measurable disease or non-measurable disease for Part B 8. Must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 9. Must have adequate hematological function 10. Must have adequate renal function 11. Must have adequate hepatic function 12. Agreement to use effective contraception while on treatment and for at least 6 months after end of treatment 13. Must have provided informed consent for study participation.
Exclusion criteria
1. Lung adenocarcinoma with an Anaplastic Lymphoma Kinase (ALK) gene rearrangement 2. Left ventricular ejection fraction (LVEF) less than 45% 3. Prior EGFR-targeted regimen, anti-HER2, anti-HER3, or anti-HER4 therapy 4. History of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated with no evidence of disease for greater or equal to 5 years 5. History of corneal disease 6. History of interstitial lung disease (ILD) 7. Clinically active brain metastases 8. Uncontrolled hypertension 9. Clinically significant ECG changes 10. Clinically significant (in the opinion of the Investigator) ascites or pleural effusion requiring chronic medical intervention 11. Myocardial infarction within 1 year before enrollment, symptomatic congestive heart failure, unstable angina, or unstable cardiac arrhythmia requiring medication 12. Treatment with anticancer therapy, antibody-based therapy, retinoid therapy, or hormonal therapy within 4 weeks before study drug treatment 13. Therapeutic radiation therapy or major surgery within 4 weeks before study drug treatment; or palliative radiation within 2 weeks before study drug treatment 14. Participation in clinical drug trials within 4 weeks 15. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. 16. History of hypersensitivity to any of the study drugs or to any excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Progression Free Survival (PFS) in Heregulin-high Participants | by trial termination (at 20 months) | PFS is defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression (as per RECIST Version 1.1 per investigator assessment) or death resulting from any cause. Kaplan-Meier Estimate. Confidence interval (CI) for median was computed using the Brookmeyer-Crowley method. 80% confidence interval is included in the data table. |
| Part A: Progression Free Survival (PFS) in Heregulin-low Participants | by trial termination (at 20 months) | PFS is defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression (as per RECIST Version 1.1 per investigator assessment) or death resulting from any cause. Kaplan-Meier Estimate. Confidence interval (CI) for median was computed using the Brookmeyer-Crowley method. 80% confidence interval is included in the data table. |
| Part B: Overall Survival | 4 years | Percentage of participants still alive at the end of Part B |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Objective Response Rate (ORR) in HRG High Participants | by trial termination (at 20 months) | Key secondary efficacy endpoint: Objective response is defined as percentage of participants achieving complete response (CR) or partial response (PR) Denominator for percentages is the number of subjects with measurable disease in the full analysis set. The best overall response is the best response \[in the order of CR, PR, stable disease (SD), and progressive disease (PD)\] among all overall responses recorded from the start of treatment until the subject withdraws from the study. If there is no post-baseline tumor assessment or all post-baseline tumor assessments with overall response being Inevaluable captured in the CRF, the best overall response is classified as Inevaluable. |
| Part A: Overall Survival in HRG High Participants | by trial termination (at 20 months) | Key secondary efficacy endpoint: Percentage of participants who survived for the length of the trial |
| Part A: Objective Response Rate (ORR) in HRG Low Participants | by trial termination (at 20 months) | Key secondary efficacy endpoint: Objective response is defined as percentage of participants achieving complete response or partial response Denominator for percentages is the number of subjects with measurable disease in the full analysis set. The best overall response is the best response (in the order of CR, PR, SD, and PD) among all overall responses recorded from the start of treatment until the subject withdraws from the study. If there is no post-baseline tumor assessment or all post-baseline tumor assessments with overall response being Inevaluable captured in the CRF, the best overall response is classified as Inevaluable. |
| Part A: Key Secondary Efficacy Endpoint: Overall Survival in HRG Low Participants | by trial termination (at 20 months) | Key secondary efficacy endpoint: Percentage of participants who survived for the length of the trial |
| Part B: Key Secondary Efficacy Endpoint: PFS, TTD | 4 years | PFS is defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression (TTD, as per RECIST Version 1.1 per investigator assessment) or death resulting from any cause. |
Countries
Belgium, Canada, Czechia, Germany, Hungary, Italy, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
The first participant was randomized on 11 Jun 2014, and the last patient's last visit occurred on 11 Nov 2016. All randomized participants received study treatment and were included in both the Full Analysis Set and the Safety Analysis Set.
Pre-assignment details
Of 537 patients screened, a total of 145 patients were randomized into this trial in 9 countries: United States (26 at 12 sites), Spain (19 at 5 sites), Hungary (18 at 4 sites), Italy (20 at 6 sites), Great Britain (11 at 5 sites), Poland (30 at 3 sites), Germany (16 at 6 sites), Canada (2 at 1 site) and Belgium (3 at 1 site).
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Erlotinib Placebo infusion every 3 weeks and oral erlotinib 150 mg/day | 71 |
| Patritumab + Erlotinib Infusion of Patritumab (loading dose of 18 mg/kg, followed by 9 mg/kg every 3 weeks) and oral erlotinib 150 mg/day | 74 |
| Total | 145 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 10 |
| Overall Study | Clinical progression | 14 | 7 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Progressive disease (per RECIST 1.1) | 40 | 43 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Reason not provided | 1 | 2 |
| Overall Study | Study terminated by sponsor | 2 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 7 |
Baseline characteristics
| Characteristic | Placebo + Erlotinib | Patritumab + Erlotinib | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 33 Participants | 34 Participants | 67 Participants |
| Age, Categorical Between 18 and 65 years | 38 Participants | 40 Participants | 78 Participants |
| Age, Continuous | 63.3 years STANDARD_DEVIATION 9.15 | 63.9 years STANDARD_DEVIATION 8.25 | 63.6 years STANDARD_DEVIATION 8.68 |
| Eastern Cooperative Oncology Group (ECOG) Score 0 - Fully Active | 24 Participants | 25 Participants | 49 Participants |
| Eastern Cooperative Oncology Group (ECOG) Score 1 - Restricted in Physically Strenuous Activity | 47 Participants | 49 Participants | 96 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 59 Participants | 66 Participants | 125 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 7 Participants | 14 Participants |
| Heregulin (HRG) expression from Interactive Web/Voice Response System (IXRS) HRG High | 48 Participants | 47 Participants | 95 Participants |
| Heregulin (HRG) expression from Interactive Web/Voice Response System (IXRS) HRG Low | 23 Participants | 27 Participants | 50 Participants |
| Histology subtype Adenocarcinoma | 39 Participants | 40 Participants | 79 Participants |
| Histology subtype Large Cell | 1 Participants | 1 Participants | 2 Participants |
| Histology subtype Other | 3 Participants | 5 Participants | 8 Participants |
| Histology subtype Squamous | 28 Participants | 28 Participants | 56 Participants |
| Histology subtype (for randomization) Adenocarcinoma | 38 Participants | 40 Participants | 78 Participants |
| Histology subtype (for randomization) Squamous-cell carcinoma/Not otherwise specified | 33 Participants | 34 Participants | 67 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 71 Participants | 70 Participants | 141 Participants |
| Sex: Female, Male Female | 22 Participants | 30 Participants | 52 Participants |
| Sex: Female, Male Male | 49 Participants | 44 Participants | 93 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 71 | 5 / 74 |
| other Total, other adverse events | 66 / 71 | 68 / 74 |
| serious Total, serious adverse events | 29 / 71 | 27 / 74 |
Outcome results
Primary
Part A: Progression Free Survival (PFS) in Heregulin-high Participants
PFS is defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression (as per RECIST Version 1.1 per investigator assessment) or death resulting from any cause. Kaplan-Meier Estimate. Confidence interval (CI) for median was computed using the Brookmeyer-Crowley method. 80% confidence interval is included in the data table.
Time frame: by trial termination (at 20 months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Erlotinib | Part A: Progression Free Survival (PFS) in Heregulin-high Participants | 2.7 months |
| Patritumab + Erlotinib | Part A: Progression Free Survival (PFS) in Heregulin-high Participants | 1.9 months |
Primary
Part A: Progression Free Survival (PFS) in Heregulin-low Participants
PFS is defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression (as per RECIST Version 1.1 per investigator assessment) or death resulting from any cause. Kaplan-Meier Estimate. Confidence interval (CI) for median was computed using the Brookmeyer-Crowley method. 80% confidence interval is included in the data table.
Time frame: by trial termination (at 20 months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Erlotinib | Part A: Progression Free Survival (PFS) in Heregulin-low Participants | 2.8 months |
| Patritumab + Erlotinib | Part A: Progression Free Survival (PFS) in Heregulin-low Participants | 1.5 months |
Primary
Part B: Overall Survival
Percentage of participants still alive at the end of Part B
Time frame: 4 years
Population: No participants were analyzed for Part B endpoints because the trial was terminated at the end of Part A.
Secondary
Part A: Key Secondary Efficacy Endpoint: Overall Survival in HRG Low Participants
Key secondary efficacy endpoint: Percentage of participants who survived for the length of the trial
Time frame: by trial termination (at 20 months)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo + Erlotinib | Part A: Key Secondary Efficacy Endpoint: Overall Survival in HRG Low Participants | 7 Participants |
| Patritumab + Erlotinib | Part A: Key Secondary Efficacy Endpoint: Overall Survival in HRG Low Participants | 8 Participants |
Secondary
Part A: Objective Response Rate (ORR) in HRG High Participants
Key secondary efficacy endpoint: Objective response is defined as percentage of participants achieving complete response (CR) or partial response (PR) Denominator for percentages is the number of subjects with measurable disease in the full analysis set. The best overall response is the best response \[in the order of CR, PR, stable disease (SD), and progressive disease (PD)\] among all overall responses recorded from the start of treatment until the subject withdraws from the study. If there is no post-baseline tumor assessment or all post-baseline tumor assessments with overall response being Inevaluable captured in the CRF, the best overall response is classified as Inevaluable.
Time frame: by trial termination (at 20 months)
Population: Evaluable participants in the full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo + Erlotinib | Part A: Objective Response Rate (ORR) in HRG High Participants | 3 Participants |
| Patritumab + Erlotinib | Part A: Objective Response Rate (ORR) in HRG High Participants | 1 Participants |
Secondary
Part A: Objective Response Rate (ORR) in HRG Low Participants
Key secondary efficacy endpoint: Objective response is defined as percentage of participants achieving complete response or partial response Denominator for percentages is the number of subjects with measurable disease in the full analysis set. The best overall response is the best response (in the order of CR, PR, SD, and PD) among all overall responses recorded from the start of treatment until the subject withdraws from the study. If there is no post-baseline tumor assessment or all post-baseline tumor assessments with overall response being Inevaluable captured in the CRF, the best overall response is classified as Inevaluable.
Time frame: by trial termination (at 20 months)
Population: Evaluable participants in the full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo + Erlotinib | Part A: Objective Response Rate (ORR) in HRG Low Participants | 3 Participants |
| Patritumab + Erlotinib | Part A: Objective Response Rate (ORR) in HRG Low Participants | 1 Participants |
Secondary
Part A: Overall Survival in HRG High Participants
Key secondary efficacy endpoint: Percentage of participants who survived for the length of the trial
Time frame: by trial termination (at 20 months)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo + Erlotinib | Part A: Overall Survival in HRG High Participants | 15 Participants |
| Patritumab + Erlotinib | Part A: Overall Survival in HRG High Participants | 17 Participants |
Secondary
Part B: Key Secondary Efficacy Endpoint: PFS, TTD
PFS is defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression (TTD, as per RECIST Version 1.1 per investigator assessment) or death resulting from any cause.
Time frame: 4 years
Population: No participants were analyzed for Part B endpoints because the trial was terminated at the end of Part A.