| Eligibility |
Inclusion Criteria:
All subjects:
1. Subjects with measurable or non-measurable disease following the Response Evaluation
Criteria in Solid Tumors (RECIST 1.1, Appendix 1) for Phase 1 part of the study. (Only
subjects with measurable disease are allowed to enter at the MTD during the expanded
cohort of Phase 1)
2. Histologically and/or cytologically confirmed advanced or metastatic solid tumor or
Bcell malignancies which have progressed after treatment with approved therapies or
for which there are no standard therapies available (Phase 1).
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Appendix 2).
4. Life expectancy greater than or equal to 3 months after starting E7449.
5. Subjects with known brain metastases will be eligible under the following conditions
(see Exclusion Criterion #2):
- has undergone complete surgical excision and are more than 1 month post surgery
with no radiographic evidence of brain disease recurrence Or
- has undergone stereotactic radio surgery (gamma knife procedure) and are more
than 1 month post procedure and with no radiographic evidence of brain disease
progression And
- is asymptomatic And
- discontinued corticosteroid treatment at least 30 days prior to C1D1.
6. Adequate renal function defined as Serum Creatinine less than 1.5 x ULN, or use SI
units or calculated creatinine clearance greater than or equal to 50 mL/min per the
Cockroft-Gault formula (Appendix 3).
7. Adequate bone marrow function:
- Absolute neutrophil count (ANC) greater than or equal to1500/mm3 (greater than or
equal to 1.5 x 10^3/mL);
- Platelets greater than or equal to 100,000/mm3 (greater than or equal to 100 x
10^9/L);
- Hemoglobin greater than or equal to 10.0 g/dL.
8. Adequate liver function:
- Bilirubin less than or equal to 1.5 x the upper limit of normal (ULN) except for
unconjugated hyperbilirubinemia of Gilbert's syndrome;
- Alkaline phosphatase (in the absence of bone disease), alanine aminotransferase
(ALT), and aspartate aminotransferase (AST) less than or equal to 3 x ULN (less
than or equal to 5 x ULN if subject has liver metastasis).
9. Left ventricular ejection fraction (LVEF) greater than 50% on echocardiography or
multiple-gated acquisition (MUGA) scanning
10. Males or females age greater than or equal to 18 years at the time of informed
consent.
11. Females must not be lactating or pregnant at Screening or Baseline (as documented by a
negative beta-human chorionic gonadotropin [beta-hCG] test with a minimum sensitivity
of 25 IU/L or equivalent units of beta-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. All females will be considered to be of childbearing
potential unless they are postmenopausal (at least 12 months consecutive amenorrheic,
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 1 month before dosing). Females of
childbearing potential must not have had unprotected sexual intercourse within 30 days
prior to study entry and must agree to use a highly effective method of contraception
(e.g., total abstinence, an intrauterine device, a double-barrier method [such as
condom plus diaphragm with spermicide], 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 subject must agree to use a double-barrier method 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 prior to
dosing and must continue to use the same contraceptive during the study and for 30
days after study drug discontinuation.
12. Male subjects must have had a successful vasectomy (confirmed azoospermia) or they and
their female partner 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).
13. Voluntary agreement to provide written informed consent and the willingness and
ability to comply with all aspects of the protocol.
For the Phase 2 Cohort 1 (Platinum-sensitive recurrent high-grade serous ovarian
cancer) only:
14. Histologically confirmed platinum-sensitive recurrent high grade serous ovarian cancer
locally advanced or metastatic with disease progression after standard treatments.
(Exclude platinum refractory/resistant defined as progression on platinum or relapse
within six months of prior platinum.
15. At least one lesion of greater than or equal to 1.0 cm in the longest diameter for a
non-lymph node or greater than or equal to 1.5 cm in the short-axis diameter for a
lymph node which is serially measurable according to RECIST 1.1 using computerized
tomography/magnetic resonance imaging (CT/MRI) or photography. If there is only one
target lesion, it should have a longest diameter of greater than or equal to 1.5 cm
(for a non-lymph node) or greater than or equal to 1.5 cm in the short-axis diameter
(for a lymph node).
For the Phase 2 Cohort 2 (B-cell malignancies) Only:
16. Subjects with one of the following relapsed and/or refractory B-cell malignancies with
disease progression following up to three prior systemic treatment regimens:
- Mantle cell, Marginal zone, Follicular, Diffuse large B-cell, B-cell chronic
lymphocytic leukemia (B-CLL).
- ATM-deficient.
For the Phase 2 Cohort 3 (Melanoma) only:
17. Histopathologically confirmed advanced melanoma (except melanoma of intraocular
origin) with disease progression following up to two systemic treatment regimens
18. At least one lesion of greater than or equal to 1.0 cm in the longest diameter for a
non-lymph node or greater than or equal to 1.5 cm in the short-axis diameter for a
lymph node which is serially measurable according to RECIST 1.1 using computerized
tomography/magnetic resonance imaging (CT/MRI) or photography. If there is only one
target lesion, it should have a longest diameter of greater than or equal to 1.5 cm
(for a non-lymph node) or greater than or equal to 1.5 cm in the short-axis diameter
(for a lymph node).
19. No previous treatment with dacarbazine (DTIC) or TMZ containing regimens
For the Phase 2 Cohort 4 (mTNBC) only:
20. Histologically confirmed metastatic triple-negative breast cancer. Estrogen receptor
(ER)-negative, Progesterone Receptor (PR)-negative, Human Epidermal Growth Factor 2
(HER2)-negative (mTNBC) with disease progression after one standard treatment.
21. At least one lesion of greater than or equal to 1.0 cm in the longest diameter for a
non-lymph node or greater than or equal to 1.5 cm in the short-axis diameter for a
lymph node which is serially measurable according to RECIST 1.1 using computerized
tomography/magnetic resonance imaging (CT/MRI) or photography. If there is only one
target lesion, it should have a longest diameter of greater than or equal to 1.5 cm
(for a non-lymph node) or greater than or equal to 1.5 cm in the short-axis diameter
(for a lymph node).
22. No previous treatment with carboplatin and/or paclitaxel.
Exclusion Criteria:
All subjects
1. Prior exposure to E7449.
2. Leptomeningeal metastases or brain metastases (except as for Inclusion Criterion #5).
3. Prior treatment with a PARP inhibitor (Phase 2 only).
4. Subjects taking medications which are either strong CYP inhibitors or inducers.
5. Subjects with active malignancies other than advanced ovarian cancer (Cohort 1 only),
ATM-deficient B-cell malignancies (Cohort 2 only), advanced melanoma (Cohort 3 only),
and mTNBC (Cohort 4 only), will be excluded from Phase 2.
6. Subjects who have received any anticancer treatment within 4 weeks or any
investigational agent within 30 days prior to the first dose of study drug or who have
not recovered from any acute toxicity greater than Grade 0 or 1 related to previous
anticancer treatment.
7. Major surgery within 4 weeks prior to the first dose of study drug.
8. Inability to take oral medication, or malabsorption syndrome or any other uncontrolled
gastrointestinal condition (e.g., nausea, diarrhea, or vomiting) that might impair the
bioavailability of E7449.
9. Significant cardiovascular impairment: history of congestive heart failure greater
than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension,
unstable angina, myocardial infarction or stroke within 6 months of the first dose of
study drug; or cardiac arrhythmia requiring medical treatment.
10. Prolongation of QTc interval to greater than 480 msec when electrolytes balance is
normal.
11. Active infection requiring systemic therapy.
12. Known hypersensitivity to any component of E7449
13. Achlorhydria or use of antacids, proton-pump inhibitors, or other drugs known to raise
gastric pH within 2 weeks prior to study drug administration.
14. Other relevant disease or adverse clinical conditions such as:
History of significant neurological (no neuropathy greater than Grade 2) or
psychiatric disorders.
- Significant non-neoplastic liver disease (e.g., cirrhosis, active chronic
hepatitis).
- Significant non-neoplastic renal disease.
- Immunocompromised patients, including patients known to be infected with human
immunodeficiency virus (HIV).
- Uncontrolled endocrine diseases (e.g., diabetes mellitus, hypothyroidism or
hyperthyroidism, adrenal disorder) i.e., requiring relevant changes in medication
within the last month or hospital admission within the last three months.
- Tumor bleeding
15. Any other major illness that, in the investigator's judgment, will substantially
increase the risk associated with the subject's participation in this study
16. Females who are pregnant or breastfeeding.
For Phase 1 Arm 2 and Phase 2 Arm 2 (E7449 in combination with TMZ) only:
17. Known intolerance or known hypersensitivity to any of the study drugs or any of the
Excipients (E7449 and/or TMZ) For Phase 1 Arm 3 and Phase 2 Arm 3 (E7449 in
combination with carboplatin and paclitaxel) only:
18. Known intolerance or known hypersensitivity reactions to E7449, carboplatin or other
platinum containing compounds, paclitaxel, macrogolglycerol ricinoleate (poloxyl
castor oil) or any of the excipients
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