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Eribulin mesylate (eribulin; E7389) administered as a 2-5 minute intravenous (IV) bolus in one of two dosing schedules for both the Phase Ib and Phase 2 portions: either Days 1 and 8 of a 21 day cycle in ascending doses of 0.7, 1.1, or 1.4 mg/m2 or on Day 1 of the 21-day cycle at doses at ascending doses of 0.9, 1.4, or 2.0 mg/m2.

eribulin mesylate

Pemetrexed given at a dose of 500 mg/m2 as an IV infusion on Day 1 of a 21-day cycle. Patients will also receive dexamethasone and vitamin supplements as recommended in the prescribing information for pemetrexed.

pemetrexed

Eribulin mesylate (eribulin; E7389)

Harish Dave

The purpose of this study is to determine whether Eribulin Mesylate Administered in Combination with Pemetrexed is safe and tolerable and to gain a preliminary indication of clinical benefit when administered to Patients with Stage IIIB or IV Nonsquamous Non Small Cell Lung Cancer.

This open-label, multicenter, randomized study will consist of a Phase Ib portion: a safety run-in period with 3 ascending doses of eribulin; and a Phase II portion: a randomized 3-arm design. .

Phase Ib-Patients will be recruited into cohorts, into one of two parallel arms evaluating different eribulin dosing schedules (Arm 1: eribulin on Day 1; Arm 2: eribulin on Days 1 and 8), with a minimum of 3 and a maximum of 6 patients per cohort. All patients will receive pemetrexed (500 mg/m2) in combination with eribulin. All patients in a cohort will receive the same dose level of eribulin and there will not be any intra-patient dose escalation.

The dose level of eribulin will be escalated for additional cohorts in each of the two arms unless greater than or equal to 2 dose limiting toxicities (DLTs) are reported at the lower dose level(s) prior to enrollment of the next dose level.

Phase II- Patients will be randomized in a 1:1:1 ratio to receive either eribulin in combination with pemetrexed, in each of two dosing schedules (Arms 1 and 2), or pemetrexed alone (Arm 3). For both the Phase Ib and II portions, 1 cycle of therapy will last 21 days, with an estimated number of 6 cycles. Radiologic examinations including a computed tomography (CT) scan of the chest, abdomen, and pelvis as appropriate (and CT or magnetic resonance imaging \[MRI\] as appropriate), will be performed during Screening and thereafter every 2 cycles until disease progression.

Eribulin Mesylate Administered in Combination With Pemetrexed Versus Pemetrexed Alone as Second Line Therapy in Patients With Stage IIIB or IV Nonsquamous Non Small Cell Lung Cancer

An Open-Label, Multicenter, Randomized Phase Ib/II Study of Eribulin Mesylate Administered in Combination With Pemetrexed Versus Pemetrexed Alone as Second Line Therapy in Patients With Stage IIIB or IV Nonsquamous Non Small Cell Lung Cancer

DLT were defined as clinically significant adverse events (AE) occurring less than or equal to (\<=) 21 days after treatment. Events as: Non-hematological: 1) Grade greater than or equal to (\>=) 3 peripheral neuropathy; 2) Grade \>=3 nausea, vomiting despite optimal antiemetic treatment; 3) Any nonhematologic toxicity of Grade \>=3, with exceptions as alopecia, single laboratory values out of normal range, hypersensitivity reaction. Hematological:1) Grade 4 neutropenia lasting \>7 days; 2) Febrile neutropenia as fever \>=38.5 degree Celsius with absolute neutrophil count less than (\<)1.0\*10\^9 per liter(/L); 3) Grade 3 thrombocytopenia with nontraumatic bleeding requiring platelet transfusion; 4) Grade 4 thrombocytopenia with/without nontraumatic bleeding. Other 1) Study drug related death; 2) Toxicity that dose escalation committee believed to be DLT that was not covered by above DLT criteria.

Safety assessment included monitoring and recording all AE including all Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grades (for both increasing and decreasing severity), and serious adverse events (SAE); regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs and electrocardiograms (ECGs); and performance of physical examinations. A TEAE was defined as an AE that had on onset date, or a worsening in severity from Baseline (pretreatment), on or after the first dose of study drug up to the end of the study. As per CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE.

Safety assessment included monitoring and recording all AE including all CTCAE version 4.0 grades (for both increasing and decreasing severity), and SAE; regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs and ECGs; and performance of physical examinations. A TEAE was defined as an AE that had on onset date, or a worsening in severity from Baseline (pretreatment), on or after the first dose of study drug up to the end of the study.

PFS was defined as the time from the date of randomization until the earlier of the following two events: the date of progressive disease (PD) or the date of death. Progressive disease was defined as at least a 20 percent (%) increase in the sum of the longest diameter of target lesions (taking as reference the smallest sum on study), recorded since the treatment started or the appearance of 1 or more new lesions based on investigator assessments according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). If a participant did not progress, they were censored at the date of last tumor assessment, last known alive date, or until the start of a next line of therapy, whichever occurred first. PFS was estimated using Kaplan-Meier method and presented with 2-sided 95% confidence interval.

Quintiles, Inc.

Eisai Inc.

Participants received IV bolus of eribulin 0.9 mg/m\^2 in combination with IV infused pemetrexed 500 mg/m\^2 on Day 1 of each 21-day treatment cycle. Participants within the same cohort received the same dose of eribulin. Participants also received dexamethasone and vitamin supplements as recommended in the prescribing information for pemetrexed. The dose of eribulin was escalated to 1.4 mg/m\^2 in Cohort 2 of Arm 1.

Phase 1b, Arm 1 - Cohort 1: 0.9 mg/m^2 Eribulin Plus Pemetrexed

Participants received IV bolus of eribulin 1.4 mg/m\^2 in combination with IV infused pemetrexed (500 mg/m\^2) on Day 1 of each 21-day treatment cycle. Participants within the same cohort received the same dose of eribulin. Participants also received dexamethasone and vitamin supplements as recommended in the prescribing information for pemetrexed. The dose of eribulin was not further escalated.

Phase 1b, Arm 1 - Cohort 2: 1.4 mg/m^2 Eribulin Plus Pemetrexed

Participants received IV bolus of eribulin 0.7 mg/m\^2 on Days 1 and 8 of each 21-day treatment cycle. On Day 1 only of each 21-day treatment cycle, participants also received IV infused pemetrexed (500 mg/m\^2). Participants within the same cohort received the same dose of eribulin. Participants also received dexamethasone and vitamin supplements as recommended in the prescribing information for pemetrexed. The dose of eribulin was not further escalated.

Phase 1b, Arm 2 - Cohort 1: 0.7 mg/m^2 Eribulin Plus Pemetrexed

Participants received IV bolus of eribulin 0.9 mg/m\^2 in combination with IV infused pemetrexed (500 mg/m\^2) on Day 1 of each 21-day treatment cycle. Dexamethasone and vitamin supplements were administered as recommended in the prescribing information for pemetrexed.

Phase 2, Arm 1: 0.9 mg/m^2 Eribulin Plus 500 mg/m^2 Pemetrexed

Participant received IV infused pemetrexed (500 mg/m\^2) alone on Day 1 of each 21-day treatment cycle. Dexamethasone and vitamin supplements were administered as recommended in the prescribing information for pemetrexed.

Phase 2, Arm 2: 500 mg/m^2 Pemetrexed

Total

Age, Categorical

Sex: Female, Male

Race/Ethnicity, Customized

Eisai Medical Information

Alanine transaminase (ALT) increased (grade 3)

Aspartate transaminase (AST) increased (grade 3)

Febrile neutropenia (grade 4)

Neutropenia (grade 4)

Pneumonia (grade 4)

Thrombocytopenia (grade 4)

Phase 1b Safety Analysis Set was defined as all participants enrolled into the Phase 1b portion of this study.

Phase 1b: Number of Participants With Dose-Limiting Toxicity (DLTs)

Phase 1b: Percentage of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs)

Phase 2 safety population included all participants enrolled and randomized to treatment in the Phase 2 portion of the study, except for those who (I) dropped out prior to receiving any study drug, (ii) were without any safety assessment following the first dose of study drug.

Phase 2: Percentage of Participants Who Experienced TEAEs

MITT population included all randomized participants who received at least one dose of study drug without major protocol eligibility violations.

Phase 2: Progression-free Survival (PFS)

Participants received intravenous (IV) bolus of eribulin 0.9 milligram per square meter (mg/m\^2) in combination with IV infused pemetrexed 500 mg/m\^2 on Day 1 of each 21-day treatment cycle. Participants within the same cohort received the same dose of eribulin. Participants also received dexamethasone and vitamin supplements as recommended in the prescribing information for pemetrexed. The dose of eribulin was escalated to 1.4 mg/m\^2 in Cohort 2 of Arm 1.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Eribulin Mesylate Administered in Combination With Pemetrexed Versus Pemetrexed Alone as Second Line Therapy in Patients With Stage IIIB or IV Nonsquamous Non Small Cell Lung Cancer	NCT01126736	Non Small Cell ...	eribulin mesyla... pemetrexed Eribulin mesyla...	18 Years -	Eisai Inc.
Eribulin Mesylate Administered in Combination With Pemetrexed Versus Pemetrexed Alone as Second Line Therapy in Patients With Stage IIIB or IV Nonsquamous Non Small Cell Lung Cancer	NCT01126736	Non Small Cell ...	eribulin mesyla... pemetrexed Eribulin mesyla...	18 Years -	Eisai Inc.

Spots Global Cancer Trial Database for eribulin mesylate (eribulin; e7389)