Eribulin in Combination With Cyclophosphamide in Patients With Solid Tumor Malignancies

The purpose of this study is to test the safety of eribulin (Halaven™) and cyclophosphamide (Cytoxan®) given together at different doses. This study will look at what effects, good and/or bad, that these drugs have on solid tumors. Eribulin is a drug that has been approved by the FDA for breast cancer that has spread to other parts of the body. Cyclophosphamide has been approved for different types of cancers (including breast cancer). However, the combination of eribulin and cyclophosphamide is considered experimental; that means this combination has not been approved by the FDA.

The funding for this study is provided by Eisai Inc., the maker of eribulin.

This is a phase Ib/II trial designed to determine the maximum tolerated dose (MTD) and does limiting toxicities (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.

Eligibility Criteria:
INCLUSION CRITERIA:

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 Eastern Cooperative Oncology Group (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 quantitative human chorionic gonadotropin (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 CRITERIA:

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 central nervous system (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 (LQTS)
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