An Open-label, Multicenter, Multiple Dose, Phase 1 Study to Establish the Maximum Tolerated Dose of E7389 Liposomal Formulation in Patients With Solid Tumors

Study E7389-E044-112 is a Phase 1 study designed to assess the safety, tolerability and preliminary efficacy of eribulin-liposomal formulation (E7389-LF) in patients with solid tumors. This dose-escalation study will determine the maximum tolerated dose, dosing schedules tested, the dose schedule regimen with a more favorable tolerability profile, and a preliminary indication of efficacy.

This is a Phase 1 first-in-human, non-randomized (individuals will not be assigned by chance to study treatments), open-label (individuals will know the identity of study treatments), multicenter, 2-part, dose-escalation study to evaluate the safety, pharmacokinetics (study of what the body does to a drug) of eribulin-LF administered intravenously to patients with solid tumors. Each treatment cycle will be 21 days (Schedule 1) or 28 days (Schedule 1a or 2). Part 1 is the dose-escalation phase, which will be guided by pharmacokinetics and safety. Three to 6 new patients will be enrolled in sequential cohorts (first cohort will receive the starting dose and subsequent cohorts will receive increased doses of eribulin-LF). Enrollment in each cohort will be staggered; the second and third participant in every cohort will not be dosed until the first patient in that cohort completes 2 weeks of Cycle 1. If no dose-limiting toxicities (DLTs) have been observed during the first 2 week of Cycle 1 in the first patient, the second and third patients in the cohort will initiate treatment. Enrollment will be first initiated into cohort 1 of Schedule 1 (dosing on Day 1 of 21 day cycle). Interim analysis will be conducted upon completion of this cohort. The following decisions will be made based upon the results of the interim analysis 1) proceed with escalating to next dose level (cohort 2) of Schedule 1 (dosing on Day 1 of 21 day cycle) and initiate cohort 1 of Schedule 2 (dosing on Day 1 and Day 15 of 28 day cycle), or 2) discontinue plans to evaluate Schedule 2 and initiate Schedule 1a (dosing on Day 1 of 28 day cycle).

After the last patient in each cohort completes Cycle 1, the safety for DLT determination will be evaluated and a decision will be made on whether to escalate the dose in a new cohort of 3 to 6 new patients. Dose escalation will halt when the maximum tolerated dose (MTD) is reached. The total number of patients to be enrolled in Part 1 will depend on the dose level at which the DLT will be achieved. After MTD for each schedule is determined, patients will be enrolled into Expansion Part of the study to confirm safety and tolerability of each dosing schedule. Nine to 12 patients will be treated with MTD for each schedule for 6 cycles. The total study duration for each participant will be approximately 18 months.

Eligibility Criteria:
Inclusion Criteria:

1. Age 18 years or older.
2. Histological or cytological evidence of an unresectable or refractory solid tumor.
3. Participants who have at least one measurable lesion (long axis in non-lymph node: greater than or equal to 10 millimeters (mm); short axis in lymph node: greater than or equal to 15 mm) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the Expansion Part.
4. Adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the upper limits of normal (ULN) and alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 x ULN (in the case of liver metastases less than or equal to 5 x ULN). In case ALP is greater than 3 x ULN (in absence of liver metastases) or greater than 5 x ULN (in presence of liver metastases) AND participant also is known to have bone metastases, the liver specific ALP must be separated from the total and used to assess the liver function instead of the total ALP.
5. Adequate renal function as evidenced by serum creatinine less than or equal to 2.0 milligrams/deciliter (mg/dL) (177 micromole/liter (umol/L)) or calculated creatinine clearance greater than or equal to 40 milliliter/minute (mL/min) per the Cockcroft and Gault formula.
6. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) greater than or equal to 1.5 x 10\^9/liter (L), hemoglobin greater than or equal to 9 grams/deciliter (g/dL) (5.5 millimol/liter (mmol/L)) and platelet count greater than or equal to 100 x 10\^9/L.
7. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin \[B-hCG\]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
8. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least one month before dosing).
9. Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use two highly effective methods of contraception (e.g., total abstinence, an intrauterine device, a double-barrier method \[condom and occlusive cap - diaphragm or cervical/vault caps - with spermicidal foam/gel/film/cream/suppository\], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the participant must agree to use a double barrier method with spermicide as described above if she becomes sexually active during the study period or for 30 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation.
10. Male participants must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (i.e., not of childbearing potential or practicing highly effective contraception throughout the study period and for 30 days after study drug discontinuation). No sperm donation is allowed during the study period and for 30 days after study drug discontinuation.
11. Provide written informed consent.
12. Willing and able to comply with all aspects of the protocol.

Exclusion Criteria:

1. Females who are pregnant (positive B-hCG \[or hCG\] test) or breastfeeding.
2. Participants who have received any anticancer therapy within 21 days prior to study entry for cytotoxic agents (42 days for mitomycin C and nitrosoureas), radiotherapy, hormonal, biological (including humanized antibodies) and targeted agents, or within 30 days for an investigational agent.
3. Participants who have not recovered from acute toxicities as a result of prior anti-cancer therapy to less than Grade 2, according to Common Terminology Criteria for Adverse Events (CTCAE), except alopecia.
4. Participants who have previously been treated with eribulin-LF.
5. Radiation therapy encompassing greater than 30% of the bone marrow.
6. Major surgery within 21 days prior to enrollment.
7. Pre-existing peripheral neuropathy greater than CTCAE Grade 1.
8. Significant cardiovascular impairment, defined as:

   1. Congestive heart failure greater than Class II according to the New York Heart Association.
   2. Unstable angina or myocardial infarction within 6 months of enrollment, or cardiac arrhythmia requiring treatment.
   3. A clinically significant electrocardiogram (ECG) abnormality, including a marked baseline prolonged QT/QTc interval (e.g., a repeated demonstration of a QTc interval greater than 500 milliseconds (ms)).
   4. A history of risk factors for torsade de pointes (e.g., heart failure, hypokalemia, family history of long QT Syndrome) or the use of concomitant medications that prolonged the QT/QTc interval.
9. Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments.
10. Diagnosed with meningeal carcinomatosis.
11. Participants with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks prior to enrollment. Any symptom(s) attributed to brain metastases must be stable for at least 4 weeks prior to enrollment, and radiographic stability should be confirmed by comparing a brain scan (CT with contrast or MRI with and without contrast) performed during the Screening Period to a brain scan performed at least 4 weeks earlier using the same modality.
12. Any serious concomitant illness or infection requiring treatment: known active human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C infection (asymptomatic positive serology is not exclusionary).
13. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen.
14. History of drug or alcohol dependency or abuse within approximately the last 2 years or current use of illegal recreational drugs.
15. Known intolerance to Halaven (eribulin-LF; E7389-LF) or any of the excipients.
16. Any medical or other condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study.
17. Scheduled for surgery during the study.
18. Participants with body mass index (BMI) less than 35.
19. Participants with proven abdominal malignancy with concurrent refractory ascites defined by one of the following criteria:

    1. Symptomatic ascites (more than 2 L) that did not respond clinically to at least 2 weeks of diuretics OR
    2. Removal of at least 10 L in the preceding 2 months for symptoms relief OR
    3. Symptomatic ascites that recurred on at least three occasions within a 2 month period despite diuretic treatment.
20. Participants with concurrent refractory pleural effusion defined by the following criteria:

    1. Symptomatic pleural effusion that did not respond clinically to the treatment and needed pleural drainage in the preceding 2 months for symptoms relief OR
    2. Recurrent symptomatic pleural effusion on at least three occasions within a 2 month period despite treatment.
21. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days or 5X the half-life, whichever is longer preceding informed consent.