A Confirmation Study of Eribulin in Combination With Cape... | NCT01323530

NCT01323530

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
2009-011217-24	EudraCT Number

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Dose-escalation Phase (Phase 1b)	Experimental	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 Drug: Capecitabine
Dose-confirmation Phase (Phase 2)	Experimental	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 Drug: Capecitabine

Name	Type	Description	Arm Group Labels	Other Names
Eribulin mesylate	Drug	Intravenous (IV) bolus or infusion.	Dose-confirmation Phase (Phase 2) Dose-escalation Phase (Phase 1b)

Outcomes Module

Primary Outcomes

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 Outcomes

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.

Eligibility Module

Eligibility Criteria

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

Contacts/Locations Module

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
30783204	Derived	Twelves C, Anthoney A, Savulsky CI, Guo M, Reyderman L, Cresti N, Semiglazov V, Timcheva C, Zubairi I, Morrison R, Plummer R, Evans TRJ. A phase 1b/2, open-label, dose-escalation, and dose-confirmation study of eribulin mesilate in combination with capecitabine. Br J Cancer. 2019 Mar;120(6):579-586. doi: 10.1038/s41416-018-0366-5. Epub 2019 Feb 20.

IPD Sharing Statement Module

No data available

No data is available for this block.

Phase 1b (Dose Escalation Phase): total 43 participants with solid tumors were screened, of which 9 were screen failures and 34 received study treatment; Phase 2 (Dose Confirmation Phase): total 54 female participants with breast cancer were screened, of which 12 were screen failures and 42 received study treatment.

Arm/Group Information

ID	Title	Description
FG000	Phase 1b (Schedule 1): Eribulin Mesilate (1.2 mg/m^2)	Participants received eribulin mesilate 1.2 milligrams per square meter (mg/m^2), injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of progressive disease (PD), undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).
FG001	Phase 1b (Schedule 1): Eribulin Mesilate (1.6 mg/m^2)	Participants received eribulin mesilate 1.6 mg/m^2, injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).
FG002	Phase 1b (Schedule 1): Eribulin Mesilate (2.0 mg/m^2)	Participants received eribulin mesilate 2.0 mg/m^2, injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).
FG003	Phase 1b (Schedule 2): Eribulin Mesilate (0.7 mg/m^2)	Participants received eribulin mesilate 0.7 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).
FG004	Phase 1b (Schedule 2): Eribulin Mesilate (1.1 mg/m^2)	Participants received eribulin mesilate 1.1 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).
FG005	Phase 1b (Schedule 2): Eribulin Mesilate (1.4 mg/m^2)	Participants received eribulin mesilate 1.4 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 2).
FG006	Phase 2: Eribulin Mesilate 1.4 mg/m^2	Participants received eribulin mesilate 1.4 mg/m^2, injection, intravenously, once, on Days 1 and 8, and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 2.

Periods

Title

Milestones

Reasons Not Completed

Phase 1b (Dose Escalation Phase)

Type	Comment	Milestone Data
STARTED		FG0008 subjects FG0016 subjects FG0025 subjects FG0033 subjects FG004
COMPLETED		FG0005 subjects FG0014 subjects FG0024 subjects FG0033 subjects FG004
NOT COMPLETED		FG0003 subjects FG0012 subjects FG0021 subjects FG0030 subjects FG004

Type	Comment	Reasons
Adverse Event		FG0002 subjects FG0010 subjects FG0020 subjects FG003

Phase 2 (Dose-confirmation Phase)

Type	Comment	Milestone Data
STARTED		FG0000 subjects FG0010 subjects FG0020 subjects FG003

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Phase 1b (Schedule 1): Eribulin Mesilate (1.2 mg/m^2)	Participants received eribulin mesilate 1.2 mg/m^2, injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
Primary	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.	The safety set included the group of participants who received study drug and had at least 1 post dose safety assessment.	Posted		Count of Participants		Participants		Cycle 1 (21 days)

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Phase 1b (Schedule 1): Eribulin Mesilate (1.2 mg/m^2)	Participants received eribulin mesilate 1.2 mg/m^2, injection, intravenously, once, on Day 1 and capecitabine 1000 mg/m^2, tablets, orally, twice daily from Day 1 to 14 in each 21-day treatment cycle for as long as the treatment was clinically appropriate according to the judgment of the investigator or until the occurrence of PD, undue toxicity, the presence of other medical conditions that prohibit continuation of therapy, pregnancy, a delay of more than 14 days in starting the next cycle during Phase 1b (Schedule 1).

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA 18.0	Systematic Assessment

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Neutropenia	Blood and lymphatic system disorders	MedDRA 18.0	Systematic Assessment

More Info Module

Certain Agreements

Title	Organization	Phone	Extension	Email
Eisai Medical Information	Eisai Inc.	+1-888-274-2378		esi_oncmedinfo@eisai.com

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

ID	Term
D001943	Breast Neoplasms

ID	Term
D009371	Neoplasms by Site
D009369	Neoplasms
D001941	Breast Diseases
D012871	Skin Diseases

Intervention Browse Module

ID	Term
C490954	eribulin
D000069287	Capecitabine

ID	Term
D003841	Deoxycytidine
D003562	Cytidine
D011741	Pyrimidine Nucleosides
D011743	Pyrimidines

Masking Info

EG0001 events1 affected8 at risk

EG0010 events0 affected6 at risk

EG0020 events0 affected5 at risk

EG0030 events0 affected3 at risk

EG0040 events0 affected6 at risk

EG0050 events0 affected6 at risk

EG0061 events1 affected42 at risk

EG0002 events1 affected8 at risk

EG0014 events1 affected6 at risk

EG0020 events0 affected5 at risk

EG0030 events0 affected3 at risk

EG0043 events2 affected6 at risk

EG00519 events5 affected6 at risk

EG006238 events34 affected42 at risk

Facility	Status	City	State	ZIP	Country	Contacts
		Pleven			Bulgaria