An Open-label, Multicenter, Multiple Dose, Phase 1 Study to Establish the Maximum Tolerated Dose of E7389 Liposomal Formulation in Patients With Solid Tumors
Condition: Solid Tumors
MeSH terms: Neoplasms
Intervention: Eribulin-LF
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 62.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Tumors

Summary:

      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.
    

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.