E7050 in Combination With E7080 in Subjects With Advanced Solid Tumors (Dose Escalation) and in Subjects With Recurrent Glioblastoma or Unresectable Stage III or Stage IV Melanoma After Prior Systemic Therapy (Expansion Cohort and Phase 2)
Phase: Phase 1/Phase 2
Diagnosis: Solid Tumor/Phase I
NCT ID: NCT01433991
(View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 11-175
This is a multicenter, open-label, Phase 1b/2 study which will be conducted in two parts: a Phase 1b part comprising a dose escalation and an expansion cohort; and a Phase 2 part which will comprise two cohorts. The purpose of the Phase 1b part is to identify the maximum tolerated dose (MTD) of E7080 and E7050 in combination in subjects with unresectable advanced or metastatic solid tumors. In the subsequent Phase 1b expansion cohort and Phase 2 cohorts, additional subjects with recurrent glioblastoma or unresectable Stage III or Stage IV melanoma and disease progression after prior systemic treatment will be enrolled to confirm the MTD (expansion cohort) and to further explore the clinical activity of E7050 and E7080.
Dana-Farber Cancer Institute, Massachusetts General Hospital
Eunice Kwak, MD,
Massachusetts General Hospital
Geoffrey Shapiro, MD, PhD,
Dana-Farber Cancer Institute
Massachusetts General Hospital:
Cancer Trials Call Center, 877-789-6100
Dana-Farber Cancer Institute:
Andrew Wolanski, 617-632-6623,
1. Phase 1b: unresectable advanced or metastatic solid tumors.
2. Phase 1b expansion cohort and Phase 2: Histological confirmed diagnosis of
glioblastoma (expansion cohort and Cohort 1) or melanoma (expansion cohort and Cohort
Phase 1b expansion cohort glioblastoma subjects, Phase 2 Cohort 1:
3. No evidence of active central nervous system (CNS) hemorrhage on baseline scans other
than in those subjects with recurrent glioblastoma who are stable grade 1.
4. Subjects having first or second recurrence documented by magnetic resonance imaging
(MRI), following primary management with surgical resection or biopsy, radiotherapy
and up to two prior systemic treatments.
5. If subject is on corticosteroids, they must be on a stable dose for 1 week prior to
the first dose of study drug.
6. Measurable disease meeting protocol defined criteria.
Phase 1b expansion cohort melanoma subjects, Phase 2 cohort 2:
7. Radiographic/ photographic evidence of disease progression according to Response
Evaluation Criteria in Solid Tumors (RECIST 1.1) after no more than two prior
systemic regimens for unresectable Stage III or Stage IV disease.
8. American Joint Committee on Cancer (AJCC) unresectable Stage III or Stage IV
9. Measurable disease meeting protocol defined criteria.
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
11. Adequately controlled blood pressure (BP) with or without antihypertensive
medications, defined as BP ? 150/90 mmHg at Screening and no change in
antihypertensive medications within 1 week before the Screening Visit.
12. Adequate renal function
13. Adequate bone marrow function:
14. Adequate blood coagulation function, as evidenced by an International Normalized
Ratio (INR) ?1.5.
15. Adequate liver function:
16. Males or females age ?18 years at the time of informed consent.
17. All females must have a negative pregnancy test and those of child-bearing potential
must agree to use the protocol defined contraception methods.
18. Male subjects must agree to use protocol defined contraception methods.
19. Voluntary agreement to provide written informed consent and the willingness and
ability to comply with all aspects of the protocol.
1. Phase 1b Dose Escalation: Subjects who discontinued prior tyrosine kinase inhibitor
(including vascular endothelial growth factor receptor [VEGFR] and c-Met receptor
targeted therapy) due to toxicity will be ineligible.
2. Phase 1b Dose Escalation (3+3 portion) subjects with primary CNS tumors
3. Phase 1b Dose Escalation subjects, melanoma subjects in expansion cohort and Phase 2
Cohort 2: Subjects with untreated or unstable metastases to the central nervous
system (CNS) are excluded. Subjects who have completed local therapy and have
discontinued the use of steroids for this indication at least 4 weeks prior to
commencing treatment and have remained asymptomatic for at least 4 weeks prior to
commencing treatment are eligible.
4. Phase 2: Prior exposure to VEGF-targeted treatment or c-Met or human growth factor
(HGF) targeted treatment.
5. Phase 2: Active malignancy (except for study indications; or melanoma in situ, basal
or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix) within
the past 24 months.
Phase 1b expansion cohort glioblastoma subjects and Phase 2 Cohort 1:
6. More than two recurrences of glioblastoma.
7. Prior bevacizumab treatment.
8. Surgical resection of brain tumor within 4 weeks, or prior stereotactic biopsy within
2 weeks of Screening visit.
9. Prior radiotherapy within 12 weeks unless there is progression meeting protocol
10. Subjects who have received enzyme-inducing anti-epileptic agents within 14 days
before the first dose of study drug (e.g., carbamazepine, phenytoin, phenobarbital,
primidone, or oxcarbazepine).
Phase 1b expansion cohort subjects with melanoma and Phase 2 Cohort 2:
11. More than two prior systemic regimens for unresectable Stage III or Stage IV disease.
12. Prior exposure to E7050 or E7080.
13. Melanoma of intraocular origin.
14. Subjects who have received any anticancer treatment within 21 days (6 weeks for
nitrosureas Cohort 1) or any investigational agent within 30 days prior to the first
dose of study drug or who have not recovered from any acute toxicity related to
previous anticancer treatment.
15. Major surgery within 3 weeks prior to the first dose of study drug.
16. If &gt;1+ proteinuria on urinalysis will undergo 24-hour urine collection for
quantitative assessment of proteinuria. Subjects with urine protein ?1 g/24-hour
will be ineligible.
17. Inability to take oral medication or any other condition that might affect the
absorption of E7050 or E7080.
18. Significant cardiovascular impairment: history of congestive heart failure greater
than New York Heart Association (NYHA) Class II, unstable angina, myocardial
infarction or stroke within 6 months of the first dose of study drug; or cardiac
arrhythmia requiring medical treatment.
19. Prolongation of QTc interval to &gt;480 msec.
20. Bleeding disorder or thrombotic disorder requiring anticoagulant therapy, such as
warfarin, or similar agents requiring therapeutic INR monitoring (treatment with low
molecular weight heparin is allowed).
21. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to
the first dose of study drug.
22. Active infection (any infection requiring antibiotics).
23. Known intolerance or known hypersensitivity to any of the study drugs (or any of the
24. Any medical or other condition which, in the opinion of the investigator, would
preclude participation in a clinical trial.
25. Females who are pregnant or breastfeeding.