A Randomized, Open-label, Multicenter, Phase 3 Study to Compare the Efficacy and Safety of Eribulin With Treatment of Physician's Choice in Subjects With Advanced Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This is a randomized, open-label, multicenter, Phase 3 study, comparing efficacy and safety of eribulin with TPC in subjects with advanced and disease progression following at least two prior regimens for advanced disease, which should have included a platinum-based regimen.

Conditions
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Non-Small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Drug: Eribulin
* Drug: TPC -Vinorelbine,Gemcitabine,Docetaxel, and Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion: Subjects must meet all of the following criteria to be included in this study: Histologically or cytologically confirmed diagnosis of NSCLC. Documented evidence of advanced NSCLC not amenable to surgery or radiotherapy. Confirmation of the presence or absence of EGFR mutations prior to study enrolment in all subjects. Subjects must have received at least two prior regimens for advanced NSCLC, which should have included a platinum-based regimen and, in all subjects with tumors harbouring EGFR mutations, an EGFR TKI. Radiographic evidence of disease progression on, or after, the last anti-cancer regimen prior to study entry. Presence of measurable disease. ECOG performance status of 0, 1, or 2. Adequate bone marrow Adequate renal function. Adequate liver function. Female subjects of child-bearing potential must agree to use two forms of highly effective contraception. Male subjects and their female partners who are of child-bearing potential must agree to use two forms of highly effective contraception. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol. Males or females aged at least 18 years (or any age greater than 18 years as determined by country legislation) at the time of informed consent. Exclusion: Subjects who meet any of the following criteria will be excluded from this study: Subjects who have received any anti-cancer therapy within 14 days, or five half-lives of the drug (whichever is longer), prior to randomization. Subjects who have not recovered from toxicities as a result of prior anti-cancer therapy to less than Grade 2. Subjects who have previously been treated, or participated in a study with eribulin, whether treated with eribulin or not. The TPC option must not include the same agent which the subject received in a prior regimen. Peripheral neuropathy more than CTCAE Grade 2. Significant cardiovascular impairment. Subjects with a high probability of Long QT Syndrome, or QTc interval >500 ms. Subjects with brain or subdural metastases are not eligible, unless the metastases are asymptomatic and do not require treatment or have been adequately treated by local therapy. Any serious concomitant illness. Known HIV positive, or have an infection requiring treatment. Any malignancy that required treatment, or has shown evidence of recurrence (except for NSCLC, non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in-situ) during the 5 years prior to study entry. Female subjects must not be pregnant, and must not be breastfeeding. Hypersensitivity to either HalB or HalB chemical derivatives or both, or to any of the excipients of the eribulin formulation.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br> | Drug: Eribulin<br>* Administration of eribulin mesylate at a dose of 1.4 mg/m2 i.v. over 2 to 5 minutes on Days 1 and Day 8 of every cycle, where the duration of each cycle is 21 days.<br>|
| Active Comparator: Arm B<br> | Drug: TPC -Vinorelbine,Gemcitabine,Docetaxel, and Pemetrexed<br>* Vinorelbine 30 mg/m2 i.v. on Day 1, every 7 days Gemcitabine 1250 mg/m2 i.v. on Days 1 and 8, every 21 days Docetaxel 75 mg/m2 i.v. on Day 1 every 21 days Pemetrexed 500 mg/m2 i.v. on Day 1 every 21 days (nonsquamous histology only).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | The OS was defined as the time in months from the date of randomization to the date of death, regardless of cause. In the absence of confirmation of death, the participants were censored either at the date that participant was last known to be alive or the date of study cut-off, whichever was earlier. The two treatment arms were compared using the log-rank test, stratified by histology, TPC option, and geographic region; and the treatment difference between eribulin mesylate and TPC was tested at a significance level of 0.05 (2-sided). Kaplan-Meier (K-M) survival probabilities for each arm were plotted over time. The treatment effect was estimated by fitting a Cox Proportional Hazards model to the OS times including treatment arm as a factor and histology, TPC option and geographic region as strata. | Randomization (Day 1) until date of death from any cause, or 37 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) | PFS was defined as the time from the date of randomization to the date of first documentation of disease progression, or date of death, whichever occurred first. The difference in PFS (based on the tumor response evaluation as determined by the investigator) between eribulin mesylate and TPC was evaluated using the log rank test, stratified by histology, TPC option, and geographic region, tested at an alpha level of 0.05 (2-sided). PFS censoring rules will be defined in the SAP and follow Federal Department of Agriculture (FDA) guidance. | Randomization (Day 1) until date of disease progression or death (whichever occurred first), or 37 months | 
| Objective Response Rate (ORR) | The ORR was defined as the proportion of participants with best overall response of complete response (CR) or partial response (PR) per RECIST criteria. The ORR was estimated by study arm based on the tumor response evaluation as determined by the investigator, according to RECIST 1.1. Participants with unknown response were treated as non-responders. The statistical difference in ORR between treatment arms was evaluated using the Cochran-Mantel-Haenszel (CMH) chi-square test with histology, TPC option, and geographic region as strata, tested at an alpha level of 0.05 (2-sided). The 95 percent confidence interval (CI) was calculated using Clopper Pearson method. | Randomization (Day 1) to CR or PR |