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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Non Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: eribulin mesylate
* Drug: pemetrexed
* Drug: Eribulin mesylate (eribulin; E7389)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients may be entered in the study only if they meet all of the following criteria: Male or female patient greater than or equal to 18 years of age; Histologically or cytologically confirmed nonsquamous NSCLC stage IIIB with malignant pleural effusion or stage IV disease not amenable to curative therapy. Patients with history of stage III disease that have relapsed after chemo- and radiotherapy are also eligible; Have at least 1 site of measurable disease by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST) criteria; Have failed 1 prior platinum-doublet containing chemotherapy regimen for stage IIIB with malignant pleural effusion or stage IV nonsquamous NSCLC. One additional cytotoxic regimen is allowed for neoadjuvant, adjuvant, or neoadjuvant plus adjuvant therapy for Phase II patients. For patients enrolled in the Phase Ib portion, a maximum of three total prior regimens is allowed. Definition of a Chemotherapy Regimen: Any platinum-doublet containing chemotherapy, that may also include biological or targeted agents, and/or humanized antibodies, given concomitantly, sequentially, or both, is considered 1 regimen. If, due to toxicity, the dosing of 1 or more of the components must be reduced, or 1 or more of the components of the regimen must be omitted, or 1 of the components must be replaced with another similar drug, the changed version of the original regimen is not considered a new regimen. However, if a new component, dissimilar to any of the original components, is added to the regimen, the new combination is considered a new regimen. If the treatment is interrupted for surgery or radiotherapy, and then continues with an unchanged schedule and components, that treatment is considered as one regimen despite the interruption. Life expectancy of greater than 3 months; Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) less than 1; Patients must have adequate renal function as evidenced by calculated creatinine clearance greater than 45 mL/min per the Cockcroft and Gault formula; Patients receiving daily treatment with non-steroidal anti-inflammatory agents (NSAIDS) are eligible. Patients with creatinine clearance 45-79 ml/min must be able to interrupt NSAIDS 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of pemetrexed; Patients must have adequate bone marrow function as evidenced by absolute neutrophil count (ANC) greater than 1.5 x 10^9/L, hemoglobin greater than 9.0 g/dL (a hemoglobin less than 9.0 g/dL at Screening is acceptable if it is corrected to greater than 9 g/dL by growth factor or transfusion prior to first dose), and platelet count greater than 100 x 10^9/L; Patients must have adequate liver function as evidenced by bilirubin less than 1.5 times the upper limit of the normal range (ULN), and alkaline phosphatase, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than 3 x ULN (in the case of liver metastases, less than 5 x ULN). If there are bone metastases, liver-specific alkaline phosphatase may be separated from the total and used to assess liver function instead of total alkaline phosphatase; Male or female patients of child-producing potential must agree to use double barrier contraception, oral contraceptives, or avoidance of pregnancy measures during the study and for 90 days after the last day of treatment; Females of childbearing potential must have a negative serum pregnancy test; Females may not be breastfeeding; and Ability to understand and willingness to sign a written informed consent. Exclusion Criteria: Patients may be entered in the study only if they meet all of the following criteria: Prior treatment with pemetrexed, epothilone, ixabepilone, patupilone, halichondrin B or halichondrin B-like compounds; Received chemotherapy, targeted therapy, radiotherapy, surgery, or immunotherapy within the 30 days prior to commencing study treatment or have not recovered from all treatment-related toxicities to Grade less than 1, except for alopecia; History of other malignancies except: (1) adequately treated basal or squamous cell carcinoma of the skin; (2) curatively treated, a) in situ carcinoma of the uterine cervix, b) prostate cancer, or c) superficial bladder cancer; or (3) other curatively treated solid tumor with no evidence of disease for greater than 5 years; Presence of brain metastases, unless the patient has received adequate treatment at least 4 weeks prior to randomization, and is stable, asymptomatic, and off steroids for at least 4 weeks prior to randomization; Received treatment in another clinical study within the 30 days prior to commencing study treatment or patients who have not recovered from side effects of an investigational drug to Grade less than 1, except for alopecia; Are currently receiving any other treatment, including palliative radiotherapy for the tumor aside from control of symptoms; Common Toxicity Criteria (CTC) greater than Grade 3 peripheral neuropathy; Require therapeutic doses of vitamin K antagonists; Uncontrolled pleural effusions, ascites, or other third space fluid collections; Uncontrolled diabetes mellitus Type 1 or 2; Significant cardiovascular impairment (history of congestive heart failure greater than New York Heart Association (NYHA) Grade II, unstable angina or myocardial infarction within the past 6 months, or serious cardiac arrhythmia); Patients with organ allografts requiring immunosuppression; Known positive human immunodeficiency virus (HIV), known hepatitis B surface antigen, or hepatitis C positive; Hypersensitivity to halichondrin B and/or halichondrin B chemical derivative; or Have any medical condition that would interfere with the conduct of the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose E7389 in Combination with Pemetrexed<br> | Drug: eribulin mesylate<br>* 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.<br>* Other names: halichrondrin B analog; Alimta;|
| Active Comparator: Pemetrexed<br> | Drug: pemetrexed<br>* 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.<br>* Other names: halichrondrin B analog; Alimta;|
| Experimental: High Dose E7389 in Cominbation with Pemetrexed<br>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. | Drug: Eribulin mesylate (eribulin; E7389)<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of Participants With Dose-Limiting Toxicity (DLTs) | 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. | Cycle 1 (cycle length=21 days) | 
| Phase 1b: Percentage of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs) | 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. | From date of first dose up to 30 days after the last dose of study drug in Phase 1b, up to approximately 1 year 2 months | 
| Phase 2: Percentage of Participants Who Experienced TEAEs | 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. | From date of first dose up to 30 days after the last dose of study drug in Phase 2, up to approximately 3 years 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Progression-free Survival (PFS) | 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. | From the date of randomization until the earlier of the following two events: the date of PD or the date of death (Up to approximately 3 years 5 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
neoplams, lung neoplasms, Stage IIIB, IV Nonsquamous Non Small Cell Lung Cancer