This is a nonrandomized, open-label, dosed escalation, safety activity, and PK study to
determine the MTD and optimal dosing regimen of Eribulin ORA.
This is a multicenter, open-label safety, tolerability, pharmacokinetic, and activity study.
Eligible subjects will be adults with advanced solid tumors.
Groups of 3 to 6 subjects will receive a single dose of Eribulin ORA on Day 1 and Day 8 of a
21 day cycle and will be followed for toxicity. If non linearity in PK is observed,
additional subjects will be added with study drug administered on Day 1 and 8 once every
three weeks cycle. Subjects who tolerate the study drug and have stable disease or better
response will be eligible to receive ongoing treatment.
Inclusion Criteria:
1. Able to understand and sign an informed consent form (ICF)
2. Male and female adults, ≥18 years of age
3. Histologically or cytologically confirmed solid tumor that is metastatic or
unresectable and for which standard curative or palliative measures do not exist or
are no longer effective; subjects enrolling in the dose expansion cohort must have
breast cancer or liposarcoma.
4. Must have at least one measurable site of disease as defined as per RECIST v1.1
criteria (dose expansion) or evaluable disease (dose escalation only)
5. Eastern Cooperative Oncology Group (ECOG)2 Performance Status ≤1
6. Adequate hematologic status as demonstrated by not requiring transfusion support or
granulocyte-colony stimulating factor (G-CSF) to maintain:
- Absolute neutrophil count (ANC) ≥1.5 x 109/L
- Platelet count ≥100 x 109/L
- Hemoglobin ≥9.0 g/dL
7. Adequate liver function as demonstrated by:
- Total and direct bilirubin within normal range
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 upper
limit of normal (ULN)
- Gamma-glutamyl transferase (GGT) ≤5 x ULN
- Alkaline phosphatase ≤3 x ULN or ≤5 x ULN if bone or liver metastasis is present
8. Serum creatinine ≤1.5 x ULN, or estimated creatinine clearance ≥50 mL/min according to
the Cockcroft-Gault equation
9. Prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time
(PTT) ≤1.5 x ULN OR if a subject is receiving anticoagulant therapy and PT or PTT is
within therapeutic range of intended use of coagulants for 7 days prior to receiving
study treatment
10. Subjects receiving warfarin who are otherwise eligible and who may be appropriately
managed with low molecular weight heparin, in the opinion of the Investigator, may be
enrolled in the study provided they are switched to low molecular weight heparin at
least 7 days prior to receiving study treatment.
11. Willing and able to comply with scheduled visits, treatment plan and laboratory tests
12. No concurrent malignancy except curatively treated basal or squamous cell carcinoma of
the skin or carcinoma in situ of the cervix, breast, or bladder
13. Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis)
OR agree to use a condom with spermicide and to not donate sperm during the study and
for at least 90 days following last dose of Eribulin ORA
14. Female subjects must be postmenopausal (>12 months without menses) or surgically
sterile (ie, by hysterectomy and/or bilateral oophorectomy) or must be using highly
effective contraception (ie, oral contraceptives, intrauterine device, double barrier
method of condom and spermicide) and agree to continue use of contraception for 90
days after their last dose of assigned study treatment.
15. Subjects who are of childbearing potential must have a negative serum pregnancy test
at Screening and within 72 hours before the first dose.
Exclusion Criteria:
1. Subjects who have received recent anti-cancer therapy defined by:
- Chemotherapy, immunotherapy, hormonal therapy and monoclonal antibodies (but
excluding nitrosurea, mitomycin-C, targeted therapy) ≤28 days prior to starting
study drug, or who have not recovered from side effects of such therapy to Grade
1. Subjects receiving luteinizing hormone-releasing hormone (LHRH) agonists may
be considered for enrollment after discussion with the Sponsor.
- Last administration of nitrosurea or mitomycin-C ≤42 days prior to starting study
drug, or who have not recovered from the side effects of such therapy to Grade 1
- Targeted therapy (eg, sunitinib, sorafenib, pazopanib) ≤14 days prior to starting
study drug, or who have not recovered from the side effects of such therapy to
Grade 1; or
- Radiotherapy ≤28 days prior to starting study drug, or ≤14 days prior to starting
study drug in the case of localized radiotherapy (eg, for analgesic purpose or
for lytic lesions at risk of fracture), or who have not recovered from
radiotherapy toxicities to Grade 1.
2. Subject who have impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of study drugs (including gastric bypass surgery
and total gastrectomy).
3. Subjects who have undergone major surgery (eg, intra-thoracic, intra-abdominal or
intrapelvic), open biopsy or significant traumatic injury ≤28 days prior to starting
study treatment, or subjects who have had minor procedures, percutaneous biopsies or
placement of vascular access device ≤7 days prior to starting study drug, or who have
not recovered from side effects of such procedure or injury
4. Subjects with congenital long QT syndrome
5. Uncontrolled concurrent illness, including but not limited to ongoing or active
serious infection requiring systemic antimicrobials (within 14 days prior to first
dose), uncontrolled arterial hypertension (>160/100 mm/Hg on antihypertensive
medications), chronic pulmonary disease requiring oxygen, known bleeding disorders,
uncontrolled endocrine diseases, altered mental status or psychiatric illness/social
situations that would limit compliance with protocol requirements.
6. Known or suspected diagnosis of human immunodeficiency virus (HIV) or chronic active
Hepatitis B or C, or cirrhosis.
7. Symptomatic or uncontrolled brain metastases requiring current treatment (less than 28
days from last cranial radiation or 28 days from last steroids use).
8. Impaired cardiac function or clinically significant cardiac disease including the
following:
- Clinically significant arrhythmias (except chronic well controlled atrial
fibrillation)
- New York Heart Association (NYHA) Class III or IV congestive heart failure
- Unstable angina pectoris within the last 6 months
- Myocardial infarction within the last 6 months
9. Subjects with a healing or open wound
10. Lack of recovery of prior AEs to Grade ≤1 severity (National Cancer Institute [NCI]
Common Terminology Criteria for Adverse Events [CTCAE] v4.03)3 (except alopecia or
lymphopenia) due to medications administered prior to the first dose of the trial
drugs.
11. Any other condition or finding (including social situation) that in the opinion of the
Investigator may render the patient at excessive risk for treatment complications or
may not be able to provide evaluable outcome information.
12. Pregnant or breast-feeding women
13. Known allergy to any of the formulation components of Eribulin ORA
14. Currently taking following prohibited concomitant medication:
- Strong cytochrome P450 (CYP) 3A4 inducer (eg, rifampin or St. John's Wort) or a
strong CYP3A4 inhibitor (eg, ketoconazole) within 14 days prior to treatment
administration
- Medication known to be strong P-gp inhibitors or inducers. Subjects who are
taking such medications but who are otherwise eligible may be enrolled if they
discontinue the medication 7 days before dosing and remain off that medication
during treatment with Eribulin ORA.
- An oral medication with a narrow therapeutic index known to be a P-gp substrate
(eg, digoxin, dabigatran, colchicine) within 1 day prior to start of Eribulin ORA
dosing in the study
- Drugs known to prolong the QT interval, including Class Ia and III
antiarrhythmics
