A Confirmation Study of Eribulin in Combination With Capecitabine

Study Overview
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Brief Summary
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This is a Phase 1b/2, multi-center, open-label, dose escalation (in 2 different dosing schedules [1 and 2]) and dose-confirmation study of eribulin administered in combination with capecitabine.

Official Title
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A Phase 1b/2, Multicenter, Open-Label, Dose-Escalation and Confirmation Study of Eribulin in Combination With Capecitabine

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Eribulin mesylate
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Subjects who meet all of the following criteria will be included in the study: Dose-escalation cohorts (Phase 1b): Histologically or cytologically confirmed cancer that is advanced and/or metastatic Resistant/refractory to approved therapies (defined as progressive disease during or within 6 months after the last anti-cancer therapy) or for whom single agent capecitabine at this dose level and schedule would be a reasonable treatment option in the opinion of the investigator For subjects that previously received capecitabine, all capecitabine related toxicities must have completely resolved Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) greater than or equal to 1.5 x 10^9/L, hemoglobin greater than or equal to 10.0 g/dL (this may have been corrected by growth factor or transfusion), and platelet count greater than or equal to 100 x 10^9/L Adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the upper limit of normal (ULN) and alkaline phosphatase (AP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 x ULN (in the case of liver metastases less than or equal to 5 x ULN). In case AP is greater than 3 x ULN (in absence of liver metastases) or greater than 5 x ULN (in presence of liver metastases) AND subject also is known to have bone metastases, the liver specific AP must be separated from the total and used to assess the liver function instead of the total AP. Adequate renal function as evidenced by calculated creatinine clearance greater than or equal to 50 mL/min as per the Cockcroft-Gault formula (Appendix 1) or radioisotope measurement. Females of childbearing potential must have a negative urine or serum beta human chorionic gonadotropin (hCG) at Visit 1 (Screening) and prior to starting study drugs on Day 1. Female subjects of childbearing potential must agree to be abstinent or to use highly effective methods of contraception (e.g., condom + spermicide, condom + diaphragm with spermicide, intrauterine device (IUD), or have a vasectomized partner) having starting for at least one menstrual cycle prior to starting study drug(s) and throughout the entire study period and for 30 days (longer if appropriate) after the last dose of study drug. Those women using hormonal contraceptives must also be using an additional approved method of contraception (as described previously). Perimenopausal women must be amenorrheic for at least 12 months to be considered of nonchildbearing potential. Male subjects who are not abstinent or have not undergone a successful vasectomy, who are partners of women of childbearing potential must use, or their partners must use, a highly affective method of contraception (e.g. condom + spermicide, condom + diaphragm with spermicide, IUD) starting for at least one menstrual cycle prior to starting study drug(s) and throughout the entire study period and for 30 days (longer if appropriate) after the last dose of study drug. Those with partners using hormonal contraceptives must also be using an additional approved method of contraception (as described previously) Life expectancy of greater than 3 months Willing and able to comply with all aspects of the protocol Provide written informed consent Eastern Cooperative Oncology Group (ECOG) performance status (PS) less than or equal to 2 Males and females, age greater than or equal to18 years Dose-confirmation cohorts (Phase 2): Histologically or cytologically confirmed carcinoma of the breast that is advanced and/or metastatic Received up to three prior chemotherapy regimens in any setting (sequential neoadjuvant/ adjuvant treatment counting as one regimen) Chemotherapy regimens must have included an anthracycline (unless anthracycline containing chemotherapy is inappropriate) and a taxane, either in combination or in separate regimens No prior treatment with capecitabine in any setting At least one lesion of greater than or equal to 1.5cm in longest diameter for non-lymph nodes and greater than or equal to 1.5cm in shortest diameter for lymph nodes which is serially measurable according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 7 Adequate bone marrow function as evidenced by ANC greater than or equal to 1.5 x 10^9/L, hemoglobin greater than or equal to 10.0 g/dL (this may have been corrected by growth factor or transfusion), and platelet count greater than or equal to 100 x 10^9/L Adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the upper limits of normal (ULN) and alkaline phosphatase (AP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal 3 x ULN (in the case of liver metastases less than or equal to 5 x ULN). In case AP is greater than 3 x ULN (in absence of liver metastases) or greater than 5 x ULN (in presence of liver metastases) AND subject also is known to have bone metastases, the liver specific AP must be separated from the total and used to assess the liver function instead of the total AP. Adequate renal function as evidenced by calculated creatinine clearance greater than or equal to 50 mL/min as per the Cockcroft-Gault formula (Appendix 1) or radioisotope measurement. Females of childbearing potential must have a negative urine or serum beta hCG at Visit 1 (Screening) and prior to starting study drugs on Day 1. Female subjects of childbearing potential must agree to be abstinent or to use highly effective methods of contraception (e.g., condom + spermicide, condom + diaphragm with spermicide, IUD, or have a vasectomized partner) having starting for at least one menstrual cycle prior to starting study drug(s) and throughout the entire study period and for 30 days (longer if appropriate) after the last dose of study drug. Those women using hormonal contraceptives must also be using an additional approved method of contraception (as described previously). Perimenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential Life expectancy of greater than 3 months Willing and able to comply with all aspects of the protocol ECOG-PS 0 or 1 Females, age greater than or equal to 18 years Exclusion Criteria Subjects who meet any of the following criteria will be excluded from participation in the study: Radiotherapy, chemotherapy, biological therapy or investigational agents within 4 weeks prior to the start of study treatment; subjects must have recovered from any previous therapy related toxicity to less than Grade 1 at study entry (except for stable sensory neuropathy less than or equal to Grade 2 and alopecia) Treatment with mitomycin C or nitrosourea within 6 weeks prior to commencing on study treatment Hormonal treatment within 2 weeks prior to start of study treatment (continued use of antiandrogens and/or gonadorelin analogues for treatment of prostate cancer permitted) Prior participation in an eribulin clinical study, even if not assigned to eribulin treatment Subject with hypersensitivity to halochondrin B and /or halochondrin B chemical derivates or capecitabine or any of the excipients Suspected dihydropyrimidine dehydrogenase (DPD) deficiency Previous radiotherapy encompassing greater than 30% of marrow Previous organ allograft requiring immunosuppression Subjects with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication at least 4 weeks before starting study treatment. Any symptoms attributed to brain metastases must be stable for at least 4 weeks before starting study treatment; radiographic stability should be determined by comparing contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) brain scan performed during screening to a prior scan performed at least 4 weeks earlier Meningeal carcinomatosis 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) Electrocardiogram (ECG) with QT interval corrected for heart rate (QTc) interval greater than 470 msec (as measured either by Bazett's or Fredericia's formula) Pre-existing neuropathy greater than Grade 2 Anti-coagulant therapy with warfarin or related compounds, other than for line patency, that cannot be changed to heparin-based therapy for the duration of the study Subjects with known positive serology for Human Immunodeficiency Virus (HIV), or Hepatitis B or C Subjects with other significant disease or disorder that, in the Investigator's opinion, would exclude the subject from the study Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study Unable to swallow tablets

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose-escalation Phase (Phase 1b)<br>Participants with advanced and/or metastatic tumors will receive eribulin mesylate as a 2 to 5 min Intravenous (IV) bolus or infusion in two different schedules (Schedule 1 [1.2, 1.6, 2.0 mg/m2], given on Day 1 only, and Schedule 2 [0.7, 1.1, 1.7 mg/m^2], given on Days 1 and 8) and oral capecitabine 1000 mg/m2 bid on Days 1-14 (21-day cycles) in both schedules. If maximum tolerated dose (MTD) is not observed at dose level 3 the dose of capecitabine might be escalated to 1250 mg/m^2 bid on Days 1-14 (21-day cycles) depending on the Dose limiting toxicities (DLTs) observed and/or pharmacokinetic (PK) data when available. Based on the data and safety monitoring board review of dose escalation phase data (DLTs that will be observed in first cycle), Dose-Confirmation Phase (Phase 2) will may get initiated. | Drug: Eribulin mesylate<br>* Intravenous (IV) bolus or infusion.<br>Drug: Capecitabine<br>* Oral film-coated tablets.<br>|
| Experimental: Dose-confirmation Phase (Phase 2)<br>Participants with advanced and/or metastatic tumors will receive Eribulin mesylate at the MTD for the selected schedule of dose escalation phase based on safety/PK data. | Drug: Eribulin mesylate<br>* Intravenous (IV) bolus or infusion.<br>Drug: Capecitabine<br>* Oral film-coated tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs) as Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 (NCI CTCAE v3.0) | DLTs as per NCI CTCAE v3.0 were defined as:1) Neutropenia Grade 4 that lasted at least 7 days, 2) Neutropenia Grade 3 or 4 complicated by fever and/or infection (absolute neutrophil count [ANC] less than 1.0*10^9/liter [L], fever of at least 38.5 degree celsius [°C]), 3)Thrombocytopenia Grade 4, 4) Thrombocytopenia Grade 3 complicated by bleeding and/or requiring platelet or blood transfusion, 5) Non-hematological toxicity Grade 3 or higher (excluding Grade 3 nausea, and Grade 3 or 4 vomiting or diarrhea in participants who had not received optimal treatment with antiemetic and/or antidiarrheal medication; excluding laboratory abnormalities without clinical symptoms), 6) Delayed recovery from treatment-related toxicity resulting in dose delay greater than 14 days, 7) Failure to administer at least 75 percent (%) of planned study drugs during Cycle 1 as result of Grade 2 or higher treatment-related toxicity that constituted increase of at least 2 grades from baseline. | Cycle 1 (21 days) | 
| Phase 2: Objective Response Rate (ORR) | ORR was defined as the percentage of participants who had either a confirmed complete response (CR) or partial response (PR). ORR was assessed based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1). CR was defined as disappearance of all target lesions. All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10 millimeter (mm). PR was defined as at least a 30 percent (%) decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter. ORR was summarized using the Clopper-Pearson method. | From the first dose of study drug until PD or up to 30 days after the last dose of study treatment (up to approximately 3.75 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Time to Response | Time to response (CR or PR) was defined as the time from the first dose until first documented evidence of CR or PR (whichever status was recorded first). Time to response was assessed based on RECIST v 1.1. CR was defined as disappearance of all target lesions. All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter. Time to response was summarized using the Kaplan-Meier method. | From the first dose of study drug treatment start date until date of first documented evidence of CR or PR or up to 30 days after the last dose of study treatment (up to approximately 3.75 years) | 
| Phase 2: Duration of Response (DOR) | DOR: time from first documented evidence of CR or PR until first documented sign of PD or death. DOR was assessed based on RECIST v 1.1. CR: disappearance of all target lesions. All pathological lymph nodes (whether target/non-target) must have a reduction in their short axis to >10 mm. PR: at least a 30% decrease in sum of longest diameter of target lesions, taking as reference the baseline sum of longest diameter. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). DOR was summarized using the Kaplan-Meier method. | From date of the first CR or PR until the date of first documentation of PD or death or up to 30 days after the last dose of study treatment (up to approximately 3.75 years) | 
| Phase 2: Stable Disease (SD) Rate | SD rate was defined as the percentage of participants with a SD that lasted for a minimum of 5 weeks. SD rate was assessed based on RECIST version 1.1. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PR: at least a 30% decrease in sum of longest diameter of target lesions, taking as reference the baseline sum of longest diameter. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). | From the first dose of study drug until PD or up to 30 days after the last dose of study treatment (up to approximately 3.75 years) | 
| Phase 1b and Phase 2: Percentage of Participants With Non-CR/Non-PD | Non-CR/Non-PD was for participants who had non-target disease only (minimum duration from randomization to Non-CR/Non-PD >=7 weeks) and assessed by investigator based on RECIST v1.1. Non-CR/Non-PD: persistence of one or more non-target lesions, maintenance of tumor marker level above the normal limits. | From the first dose of study drug until PD or up to 30 days after the last dose of study treatment (up to approximately 3.75 years) | 
| Phase 2: Duration of Stable Disease (SD) | Duration of SD was measured from date of the first dose until progression. Duration of SD was assessed based on RECIST v1.1. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PR: at least a 30% decrease in sum of longest diameter of target lesions, taking as reference the baseline sum of longest diameter. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). Duration of SD was summarized using the Kaplan-Meier method. | From the first dose of study drug until PD or 30 days after the last dose of study treatment (up to approximately 3.75 years) | 
| Phase 2: Disease Control Rate (DCR) | DCR was defined as the percentage of participants with a confirmed CR, PR, or SD divided by the number of participants in the analysis set. DCR was assessed by an investigator based on RECIST v1.1. CR: disappearance of all target lesions. All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to <10 mm. PR: at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). DCR was summarized using the Clopper-Pearson method. | From the first dose of study drug until PD or 30 days after the last dose of study treatment (up to approximately 3.75 years) | 
| Phase 2: Clinical Benefit Rate (CBR) | CBR was defined as the percentage of participants with a confirmed CR, PR, or SD of at least 6 months duration (durable SD) divided by the number of participants in the analysis set. CBR was determined by an investigator based on RECIST v1.1. CR: disappearance of all target lesions. All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to <10 mm. PR: at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). CBR was summarized using the Clopper-Pearson method. | From the first dose of study drug until PD or 30 days after the last dose of study treatment (up to approximately 3.75 years) | 
| Phase 2: Progression-free Survival (PFS) | PFS was defined as the time from the first dose date until PD or death due to any cause. PFS was determined by an investigator based on RECIST v1.1. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study (this includes baseline sum if that is the smallest on study). PFS was summarized using the Kaplan-Meier method. | From the first dose of study drug until PD or death due to any cause or 30 days after the last dose of study treatment (up to approximately 3.75 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic breast cancer