A Safety and Efficacy Study of Farletuzumab in Participants With Adenocarcinoma of the Lung

Study Overview
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Brief Summary
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The primary objective of this study is to compare the effect of farletuzumab versus placebo in combination with either a platinum agent (carboplatin) with paclitaxel or a platinum agent (carboplatin or cisplatin) with pemetrexed followed by farletuzumab or placebo on investigator-assessed progression free survival (PFS) as determined by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 or definitive clinical disease progression (eg, new occurrence of positive fluid cytology) in chemotherapy naive participants with folate receptoralpha (FRA)-expressing Stage IV adenocarcinoma of the lung.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Study of the Safety and Efficacy of Farletuzumab in Combination With a Platinum-Containing Doublet in Chemotherapy-Naive Subjects With Stage IV Adenocarcinoma of the Lung (FLAIR)

Conditions
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Adenocarcinoma of the Lung

Intervention / Treatment
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* Biological: Farletuzumab
* Other: Placebo
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Pemetrexed
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the lung classified as stage IV Confirmed folate receptor-alpha (FRA) expression by immunohistochemistry (IHC) Measurable disease with at least one unidimensionally measurable lesion according to RECIST criteria version 1.1 by computed tomography (CT) or magnetic resonance imaging (MRI) scans (CT or MRI scans must have been performed within 30 days prior to the first dose of farletuzumab or placebo) Must have received no prior chemotherapy, radiation therapy or surgery with curative intent for adenocarcinoma of the lung Exclusion Criteria: Participants who have had previous chemotherapy for adenocarcinoma of the lung Prior surgery with curative intent for adenocarcinoma of the lung Prior radiotherapy for adenocarcinoma of the lung. (Prior treatment with local radiotherapy for symptom control [i.e., palliative radiation with non-curative intent] is permitted)

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Farletuzumab plus Chemotherapy<br>During Combination Therapy, farletuzumab will be given with a protocol-approved platinum doublet (either carboplatin/paclitaxel, carboplatin/pemetrexed, or cisplatin/pemetrexed) for at least 4, but not more than 6, cycles. Participants who experience clinical benefit from the Combination Therapy will enter the Monotherapy Phase and receive farletuzumab as monotherapy until disease progression. | Biological: Farletuzumab<br>* Combination Therapy: Farletuzumab 7.5 mg/kg will be administered intravenously on Cycle 1, Week 1 and Cycle 1, Week 2 (loading dose). Beginning on Cycle 2, Week 1, farletuzumab (7.5 mg/kg) will be administered intravenously on Week 1 of all additional cycles. Monotherapy: Farletuzumab 7.5 mg/kg will be administered intravenously on Week 1 of every 3-week cycle until disease progression.<br>* Other names: MORAb-003;Drug: Carboplatin<br>* Carboplatin will be administered intravenously to achieve area under the serum concentration-time curve of 5 to 6 mg/mL^min [AUC5-6].<br>Drug: Paclitaxel<br>* Paclitaxel 200 mg/m^2 will be administered intravenously.<br>Drug: Pemetrexed<br>* Pemetrexed 500 mg/m^2 will be administered intravenously.<br>Drug: Cisplatin<br>* Cisplatin 75 mg/m^2 will be administered intravenously.<br>|
| Placebo Comparator: Placebo plus Chemotherapy<br>During Combination Therapy, placebo will be given with a protocol-approved platinum doublet (either carboplatin/paclitaxel, carboplatin/pemetrexed, or cisplatin/pemetrexed) for at least 4, but not more than 6 cycles. Participants who experience clinical benefit from the Combination Therapy will enter the Monotherapy Phase and receive placebo as monotherapy until disease progression. | Other: Placebo<br>* Combination Therapy: Placebo will be administered intravenously on Cycle 1, Week 1 and Cycle 1, Week 2 (loading dose). Beginning on Cycle 2, Week 1, placebo will be administered IV on Week 1 of all additional cycles. Monotherapy: Placebo will be administered intravenously on Week 1 of every 3-week cycle until disease progression.<br>Drug: Carboplatin<br>* Carboplatin will be administered intravenously to achieve area under the serum concentration-time curve of 5 to 6 mg/mL^min [AUC5-6].<br>Drug: Paclitaxel<br>* Paclitaxel 200 mg/m^2 will be administered intravenously.<br>Drug: Pemetrexed<br>* Pemetrexed 500 mg/m^2 will be administered intravenously.<br>Drug: Cisplatin<br>* Cisplatin 75 mg/m^2 will be administered intravenously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS was defined as the time from the date of randomization to the date of the first observation of investigator-assessed (radiology review) progression based on Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1 or other protocol-approved measures of disease progression (e.g., new occurrence of positive fluid cytology, newly diagnosed evidence of disease progression from histologic samples, PET-positive metastases, or new bone or brain metastases), or date of death, whatever the cause. Disease progression as assessed by the investigator per RECIST v1.0 was defined as at least a 20% increase in sum of longest diameters (RECIST definition) compared to baseline (or lowest sum while on study if less than baseline), or any new lesions (measurable or nonmeasurable). | From date of first administration of study drug up to 6 month follow-up from randomization of the last participant, i.e., cut-off date 15 Dec 2012 for primary analysis and cut-off date of 1 Nov 2013 or up to approximately 28 months for final analysis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR, defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by investigator's radiologic assessments using RECIST 1.1 for target lesions and assessed by Magnetic resonance imaging (MRI) and computerized tomography (CT) scan (for double blind treatment period i.e. Randomization Phase). CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR = CR + PR. | From Day 1 until documented radiographic progression, other protocol-approved measures of disease progression, withdrawal by participant, death due to any cause, or cut-off date of 1 Nov 2013, i.e., up to approximately 28 months for final analysis | 
| Duration of Response (DR) | DR was derived for those participants with objective evidence of CR or PR. DR was defined as the time (in months) from first documentation of objective response (CR or PR) to the first documentation of disease progression (ie, objective tumor progression as assessed by investigator's radiology review or other protocol-approved measures of disease progression) or death due to any cause. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From the first documentation of objective response (CR or PR) to the first documentation of disease progression, death due to any cause, or cut-off date of 1 Nov 2013, i.e., up to approximately 28 months for final analysis | 
| Overall Survival (OS) | OS was defined as the time (in months) from the date of randomization to the date of death, regardless of cause. | From the date of randomization to the date of death due to any cause or up to cut-off date of 1 Nov 2013 (up to approximately 28 months) for final analysis | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (SAEs) | An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered with an investigational product. A serious adverse event (SAE) was defined as any untoward medical occurrence that at any dose; resulted in death, was life-threatening (i.e., the participant was at a risk of death at the time of the event; this did not include an event that hypothetically might have caused death if it had been more severe), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, or was a congenital abnormality/birth defect. In this study, TEAEs (defined as an AE that started/increased in severity on/after the first dose of study medication up to 30 days after the final dose of study medication) were assessed. | For each participant, from the first dose till 30 days after the last dose or cut-off date of 1 Nov 2013, i.e., up to approximately 28 months for final analysis |