Eribulin in Combination With Cyclophosphamide in Patients With Solid Tumor Malignancies

This is a phase Ib/II trial designed to determine the MTD and DLTs of the combination of
eribulin and cyclophosphamide in solid tumors and make preliminary estimates regarding
efficacy of this treatment in patients with advanced breast cancer.

The study includes a standard dose-confirmation schema (phase Ib portion) enrolling 3 to 6
patients/subjects, with any solid tumors, per cohort (3+3 design) with a total of 18
patients. The dose-expansion (phase II portion) will enroll 40 patients with advanced breast
cancer to detect an effect size of 15% with a power of 80% with endpoints of safety,
efficacy, and clinical benefit rate. A maximum of 58 patients will be enrolled on the phase
Ib and II portions of this trial combined and will be treated until disease progression or
toxicity mandate treatment change.

Eribulin is a non-taxane microtubule inhibitor that is FDA approved as monotherapy for the
treatment of taxane and anthracycline resistant metastatic breast cancer. The combination of
docetaxel and cyclophosphamide is a well-accepted adjuvant chemotherapy regimen that has
become an increasingly common therapeutic choice for intermediate risk early stage breast
cancer. Eribulin has a favorable toxicity profile compared to docetaxel with the most common
adverse reactions (incidence ≤25%) including neutropenia, anemia, asthenia/fatigue, alopecia,
peripheral neuropathy, nausea, and constipation. Eribulin appears to have activity in taxane
resistant disease, making it an attractive partner with cyclophosphamide.

Neuropathy can be a devastating complication from adjuvant chemotherapy and in the metastatic
setting, may limit effective therapy and reduce quality of life. Understanding the host
factors that predict risk for neuropathy is critical, as these patients may in particular
benefit from the lower risk of neuropathy associated with eribulin therapy. In conjunction
with this trial, we have included correlative studies to study the proposed pharmacogenomic
factors associated with risk of neuropathy. In this way we will potentially be able to
identify patients who could preferentially be treated with less neurotoxic microtubule
inhibitors.

INCLUSION

1. Phase Ib: Patient must have histologically or cytologically documented solid tumor
malignancies.

Phase II: Patients must have histologically or cytologically confirmed locally
advanced, unresectable or metastatic carcinoma of the breast.

2. Patient is male or female and ≥18 years of age on the day of signing informed consent.

3. Patient must have performance status of 0-2 on the ECOG Performance Scale and life
expectancy > 3 months.

4. Patient must have evaluable disease. Measureable disease is not required

5. Patient must have adequate organ function

6. Female patient of childbearing potential must have a negative serum or urine pregnancy
test β-hCG within 72 hours prior to receiving the first dose of study medication and
agree to the use of effective methods of contraception while on study.

7. Any number of prior lines of chemotherapy in the metastatic setting is allowed.

8. Concomitant use of bisphosphonates is allowed.

9. Patients with stable and clinically insignificant CNS disease are allowed. Patients
must be off steroids with no new CNS symptoms or findings on radiographic imaging for
1 month.

10. Patients willing and able to complete the questionnaires.

11. Patients willing and able to comply with the study protocol for the duration of the
study.

12. Written informed consent prior to any study-specific screening procedures with the
understanding that the patient may withdraw consent at any time without prejudice.

EXCLUSION

1. Patients who have had chemotherapy or radiotherapy within two weeks, 4 weeks for
nitrosoureas, mitomycin C, pegylated-doxorubicin and one half-life for bevacizumab,
hormone therapy within one week, trastuzumab within 2 weeks or lapatinib within one
week of study Day 1.

2. If the patient has residual toxicity from prior treatment, toxicity must be ≤ Grade 1.

3. Patients with non-healing surgical wounds. Patients must be at least two weeks from a
major surgical procedure, and surgical wounds must be completely healed.

4. Patients with known active CNS metastases and/or carcinomatous meningitis. However,
patients with CNS metastases who have completed a course of therapy would be eligible
for the study provided they are clinically stable for at least 1 month prior to entry
as defined as:

1. no evidence of new or enlarging CNS metastasis

2. off steroids that are used to minimize surrounding brain edema. Patients with
clinically insignificant brain metastases that do not require treatment are
eligible.

5. Patients with known hypersensitivity to the components of study drug or its analogs.

6. Significant cardiovascular impairment:

1. Congestive heart failure, Clinically significant cardiac arrhythmia, history or
current evidence of a myocardial infarction during the last 6 months, and/or a
current ECG tracing that is abnormal in the opinion of the treating Investigator,
or unstable angina

2. QTc prolongation >480 msec (Bazett's Formula) or congenitally long QT syndrome

7. Severe/uncontrolled concurrent illness/infection

8. Patients with other active, current primary malignancies, other than carcinoma in situ
of the cervix or non-melanoma skin cancer

9. Patients with > Grade 1 neuropathy at screening

10. Patients with a hypersensitivity to halichondrin B and/or halichondrin B chemical
derivative

11. Patient is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the study.

12. Patients with other significant disease or disorders that, in the Investigator's
opinion, would exclude the patient from the study