Phase 3 Study to Compare the Efficacy and Safety of Eribulin With Dacarbazine in Subjects With Soft Tissue Sarcoma

A Randomized, Open-label, Multicenter, Phase 3 Study to Compare the Efficacy and Safety of Eribulin With Dacarbazine in Subjects With Soft Tissue Sarcoma

This is a randomized, open-label, multicenter, Phase 3 study comparing the efficacy and safety of eribulin with dacarbazine in subjects with advanced soft tissue sarcoma who have disease progression within 6 months prior to study enrolment following standard therapies which must have included an anthracycline, unless contraindicated and then at least one additional regimen after failure of the anthracycline.

Inclusion Criteria:

1. Histologically confirmed diagnosis of soft tissue sarcoma of high or intermediate grade with one of the following histological subtypes:

   • Adipocytic sarcoma, including:
   • Dedifferentiated
   • Myxoid
   • Round Cell
   • Pleomorphic - Leiomyosarcoma

2. Documented evidence of advanced (locally recurrent, locally advanced and/or metastatic) adipocytic (restricted to subtypes listed in Inclusion 1) or leiomyosarcoma, incurable by surgery and/or radiotherapy.

3. Subjects should have received at least two standard systematic regimens for advanced soft tissue sarcoma one of which must have included an anthracycline (unless contraindicated).

4. Radiographic evidence of disease progression by RECIST criteria on or after the last anti-cancer therapy within the 6 months prior to randomization.

5. Presence of measurable disease meeting the following criteria:

   • At least one lesion of greater than or equal to 1.0 cm in long-axis diameter for non lymph nodes or greater than or equal to 1.5 cm in short-axis diameter for lymph nodes which is serially measurable according to RECIST 1.1 using either computerized tomography or magnetic resonance imaging or panoramic and close-up color photography.
   • Lesions that have had radiotherapy must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion.

6. Eastern Cooperative Oncology Group, performance status of 0, 1 or 2.

7. Adequate renal function defined as calculated creatinine clearance greater than 50 mL/min per the Cockroft and Gault formula.

8. Adequate bone marrow function, defined as:

   • Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3 or greater than or equal to 1.5 x 10^9/L.
   • Platelet count greater than or equal to 100,000/mm3 or greater than or equal to 100 x 10^9/L.
   • Hemoglobin (Hb) greater than or equal to 10g/dL at baseline (blood transfusions,hematopoietic growth factors and hematinics are allowed during the Prerandomization Phase to correct Hb values less than 10g/dL).

9. Adequate liver function, defined as:

   • Bilirubin less than or equal to 1.5 times the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome.
   • Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 times ULN. For total ALP greater than 3 times ULN, the ALP liver isoenzyme must be less than or equal to 3 times ULN.

10. All female subjects will be considered to be of child-bearing potential unless they are postmenopausal (at least 12 months consecutive amenorrhea, in the appropriate age group and without other known or suspected cause), or have been sterilized surgically (i.e., bilateral tubal ligation greater than or equal to 1 menstrual cycle prior to randomization, or have undergone a hysterectomy and/or bilateral oophorectomy).

    Female subjects of child-bearing potential must agree to use two forms of highly effective contraception from the last menstrual period prior to randomization (or use a double barrier method as described below until they are on two forms of highly effective contraception for at least one menstrual cycle), during the study treatment, and for 3 months after the final dose of study treatment. Female subjects exempt from this requirement are subjects who practice total abstinence. If currently abstinent, the subject must agree to use a double barrier method of contraception, i.e., condom and occlusive cap (diaphragm or cervical/vault caps) with spermicide or until they are on two forms of highly effective contraception for at least one menstrual cycle if they become sexually active during the study treatment and for 3 months after the final dose of study treatment. Highly effective contraception includes:

    • Placement of intrauterine device or system,
    • Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault cap) with spermicide,
    • Established hormonal contraceptive methods: oral, injectable or implant. Female subjects who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product from the last menstrual period prior to randomization, and must continue to use the same hormonal contraceptive product during study treatment, and for 3 months after the first dose of study treatment.
    • Vasectomized partner with confirmed azoospermia.

11. Male subjects and their female partner who are of child-bearing potential (as defined in Inclusion 10), and are not practicing total abstinence, must agree to use two forms of highly effective contraception from the last menstrual period of their female partner prior to randomization (or use a double barrier method as described above until they are on two forms of highly effective contraception for at least one menstrual cycle), during study treatment, and for 3 months (or 6 months if they received dacarbazine) after the final dose of study treatment. If currently abstinent, must agree to use a double barrier method of contraception if they become sexually active, or until they are on two forms of highly effective contraception as described above.

12. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.

13. Males or females aged greater than or equal to 18 years at the time of informed consent.

Exclusion Criteria:

1. Subjects who have received any anti-cancer therapy, including radiotherapy, cytotoxic, hormonal, biological (including humanized antibodies) and targeted agents within 21 days, or five half-lives of the drug (whichever is longer) prior to randomization.

2. Subjects who have not recovered from acute toxicities as a result of prior anti-cancer therapy to less than or equal to Grade 1, according to Common Terminology Criteria for Adverse Events (CTCAE), except for peripheral neuropathy (see Exclusion 6) and alopecia.

3. Subjects that have previously been treated with dacarbazine or its analogue temozolomide or eribulin.

4. Major surgery within 21 days prior to randomization.

5. Pre-existing peripheral neuropathy greater than CTCAE Grade 2.

6. Significant cardiovascular impairment, defined as:

   • Cardiac failure, New York Heart Association (NYHA) Class II according to the NYHA Functional Classification,
   • Unstable angina or myocardial infarction within 6 months of enrolment,
   • Serious and potentially life-threatening arrhythmia.

7. Subjects with a high probability of Long QT Syndrome or QTc interval prolongation of more than or equal to 501 msec on at least two separate ECGs, following correction of any electrolyte imbalance.

8. Subjects with known central nervous system metastases.

9. Any serious concomitant illness or infectious disease requiring treatment, or infectious disease not requiring treatment, but with significant risks for myelosuppressive complications associated with chemotherapy.

10. Any malignancy that required treatment, or has shown evidence of recurrence (except for soft tissue sarcoma, non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in situ) during the 5 years prior to randomization.

11. Female subjects must not be pregnant as documented by a negative beta-human chorionic gonadotropin (beta-hCG) test with a minimum sensitivity 25 IU/L or equivalent unit of beta-hCG at Screening and Baseline, or breastfeeding.

12. Hypersensitivity to the active substance, or any of the excipients of the eribulin drug product, or dacarbazine, (please refer to the dacarbazine prescribing information).

13. Any medical or other condition which, in the opinion of the PI or designee, will preclude participation in a clinical trial.