A Confirmation Study of Eribulin in Combination With Capecitabine

NCT01323530 | Completed Phase 1 Results DMC

• 2 other identifiers: E7389-E044-2032009-011217-24
• Study Type: interventional
• Target: 76
• Locations: 3 countries
• Sites: 10

Brief Summary

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.

Conditions

Metastatic Breast Cancer

Keywords

metastatic breast cancer

Outcome Measures

Primary Outcomes (2)

• 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 (8)

• Phase 2: Time to Response

  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)

  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

  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

  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)

  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)

Study Arms (2)

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

Interventions

Eribulin mesylate DRUG

Intravenous (IV) bolus or infusion.

Dose-confirmation Phase (Phase 2); Dose-escalation Phase (Phase 1b)

Capecitabine DRUG

Oral film-coated tablets.

Dose-confirmation Phase (Phase 2); Dose-escalation Phase (Phase 1b)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Eisai Limited: lead

Study Sites (10)

Unknown Facility

Pleven, Bulgaria

Location

Unknown Facility

Plovdiv, Bulgaria

Location

Unknown Facility

Sofia, Bulgaria

Location

Unknown Facility

Chelyabinsk, Russia

Location

Unknown Facility

Krasnodarsky Region, Russia

Location

Unknown Facility

Saint Petersburg, Russia

Location

Unknown Facility

Stavropol Krai, Russia

Location

Unknown Facility

Glasgow, United Kingdom

Location

Unknown Facility

Leeds, United Kingdom

Location

Unknown Facility

Newcastle upon Tyne, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 30783204 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

eribulin; Capecitabine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Eisai Medical Information
• Organization: Eisai Inc.

esi_oncmedinfo@eisai.com

+1-888-274-2378

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 24, 2011
• First Posted: March 25, 2011
• Study Start: January 26, 2010
• Primary Completion: July 28, 2014
• Study Completion: October 13, 2015
• Last Updated: January 11, 2021
• Results First Posted: January 11, 2021

Record last verified: 2020-08

Locations

RU (4); GB (3); BU (3)