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)

Status: Recruiting
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.


Conducting Institutions:
Dana-Farber Cancer Institute, Massachusetts General Hospital

Overall PI:
Eunice Kwak, MD, Massachusetts General Hospital

Site-responsible Investigators:
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, andrew_wolanski@dfci.harvard.edu

Eligibility Criteria

Inclusion 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 2). 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 melanoma. 9. Measurable disease meeting protocol defined criteria. All subjects: 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. Exclusion 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 criteria. 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. All subjects: 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 >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 >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 excipients). 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.
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