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

Inclusion Criteria

Subjects who meet all of the following criteria will be included in the study:

Dose-escalation cohorts (Phase 1b):

1. Histologically or cytologically confirmed cancer that is advanced and/or metastatic
2. 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
3. For subjects that previously received capecitabine, all capecitabine related toxicities must have completely resolved
4. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) ≥ 1.5 x 109/L, hemoglobin ≥ 10.0 g/dL (this may have been corrected by growth factor or transfusion), and platelet count ≥ 100 x 109/L
5. Adequate liver function as evidenced by bilirubin ≤ 1.5 times the upper limit of normal (ULN) and alkaline phosphatase (AP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 3 x ULN (in the case of liver metastases ≤ 5 x ULN). In case AP is > 3 x ULN (in absence of liver metastases) or > 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.
6. Adequate renal function as evidenced by calculated creatinine clearance ≥50 mL/min as per the Cockcroft-Gault formula (Appendix 1) or radioisotope measurement.
7. Females of childbearing potential must have a negative urine or serum ßhCG 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.
8. 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)
9. Life expectancy of > 3 months
10. Willing and able to comply with all aspects of the protocol
11. Provide written informed consent
12. Eastern Cooperative Oncology Group (ECOG)- performance status (PS) ≤ 2
13. Males and females, age ≥18 years

Dose-confirmation cohorts (Phase 2):

1. Histologically or cytologically confirmed carcinoma of the breast that is advanced and/or metastatic
2. Received up to three prior chemotherapy regimens in any setting (sequential neoadjuvant/ adjuvant treatment counting as one regimen)
3. Chemotherapy regimens must have included an anthracycline (unless anthracycline containing chemotherapy is inappropriate) and a taxane, either in combination or in separate regimens
4. No prior treatment with capecitabine in any setting
5. At least one lesion of ≥ 1.5cm in longest diameter for non-lymph nodes and ≥ 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
6. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) ≥ 1.5 x 109/L, hemoglobin ≥ 10.0 g/dL (this may have been corrected by growth factor or transfusion), and platelet count ≥ 100 x 109/L
7. Adequate liver function as evidenced by bilirubin ≤ 1.5 times the upper limits of normal (ULN) and alkaline phosphatase (AP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 3 x ULN (in the case of liver metastases ≤ 5 x ULN). In case AP is > 3 x ULN (in absence of liver metastases) or > 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.
8. Adequate renal function as evidenced by calculated creatinine clearance ≥50 mL/min as per the Cockcroft-Gault formula (Appendix 1) or radioisotope measurement.
9. Females of childbearing potential must have a negative urine or serum ßhCG 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
10. Life expectancy of > 3 months
11. Willing and able to comply with all aspects of the protocol
12. ECOG-PS 0 or 1
13. Females, age ≥18 years

Exclusion Criteria

Subjects who meet any of the following criteria will be excluded from participation in the study:

1. 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 <Grade 1 at study entry (except for stable sensory neuropathy ≤Grade 2 and alopecia)
2. Treatment with mitomycin C or nitrosourea within 6 weeks prior to commencing on study treatment
3. 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)
4. Prior participation in an eribulin clinical study, even if not assigned to eribulin treatment
5. Subject with hypersensitivity to halochondrin B and /or halochondrin B chemical derivates or capecitabine or any of the excipients
6. Suspected dihydropyrimidine dehydrogenase (DPD) deficiency
7. Previous radiotherapy encompassing > 30% of marrow
8. Previous organ allograft requiring immunosuppression
9. 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
10. Meningeal carcinomatosis
11. Significant cardiovascular impairment (history of congestive heart failure >NYHA grade II, unstable angina or myocardial infarction within the past 6 months, or serious cardiac arrhythmia)
12. Electrocardiogram (ECG) with QTc interval > 470 msec (as measured either by Bazett's or Fredericia's formula)
13. Pre-existing neuropathy > Grade 2
14. 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
15. Continued treatment with potent cytochrome P450 (CYP)3A4 inhibitor or inducer
16. Subjects with known positive serology for Human Immunodeficiency Virus (HIV), or Hepatitis B or C
17. Subjects with other significant disease or disorder that, in the Investigator's opinion, would exclude the subject from the study
18. Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study
19. Unable to swallow tablets