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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)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.
ClinicalTrials.gov Identifier:
NCT01433991
First received: September 7, 2011
Last updated: June 18, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Advanced Solid Tumors
Drug: E7050 plus E7080
Drug: E7080 plus E7050
Drug: E7050 plus E7080 or E7080 alone plus E7050 add-on therapy
Drug: E7050
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Multicenter Phase 1b/2 Study of 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)

Resource links provided by NLM:


Further study details as provided by Eisai Inc.:

Primary Outcome Measures:
  • Phase 1b: dose limiting toxicities and maximum tolerated dose, as characterized by adverse event assessment and changes in safety assessments including laboratory parameters, vital signs, and ECG parameters. [ Time Frame: Subjects continue on study drug until progression of disease, unacceptable toxicity, withdrawal of consent or another discontinuation criterion is met ] [ Designated as safety issue: Yes ]
  • Phase 2: anti-tumor activity measured by 6-month progression free survival (Cohort 1) and by objective response rate (Cohort 2) [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Safety and tolerability (adverse event assessment and changes in safety assessments including laboratory parameters, vital signs, and ECG parameters). [ Time Frame: Subjects continue on study drug until progression of disease, unacceptable toxicity, withdrawal of consent or another discontinuation criterion is met ] [ Designated as safety issue: No ]
  • To determine the pharmacokinetic (PK) profile of E7050 and E7080 when administered as single agents and in combination. [ Time Frame: Subjects continue on study drug until progression of disease, unacceptable toxicity, withdrawal of consent or another discontinuation criterion is met ] [ Designated as safety issue: No ]
  • To assess the PK and pharmacodynamic (PD) relationship of E7050 and E7080 when administered as single agents and in combination. [ Time Frame: Subjects continue on study drug until progression of disease, unacceptable toxicity, withdrawal of consent or another discontinuation criterion is met ] [ Designated as safety issue: No ]
  • Anti-tumor activity measured by progression free survival, objective response rate (Cohort 1 only), disease control rate, durable stable disease, clinical benefit rate and overall survival. [ Time Frame: ARQ 197 treatment will be continued until progression of disease, unacceptable toxicity, or another discontinuation criterion is met ] [ Designated as safety issue: No ]

Estimated Enrollment: 226
Study Start Date: October 2011
Estimated Study Completion Date: April 2017
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: E7050 plus E7080

Dose Escalation: Up to 36 patients with unresectable advanced or metastatic solid tumors will be dosed with E7050 in combination with E7080 to identify a Maximum Tolerated Dose. Subjects will continue on treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent.

Expansion: A minimum of 6 subjects with either recurrent glioblastoma or unresectable Stage III or Stage IV melanoma will receive E7050 in combination with E7080 at the recommended dose from the Dose Escalation phase. Subjects will continue on treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent.

Cohort 1: Up to 100 patients with Recurrent Glioblastoma will be treated. Cohort 2: Up to 84 patients with unresectable Stage III or Stage IV Melanoma

Drug: E7050 plus E7080
Dose escalation will begin at low doses of both E7050 and E7080, then gradually increase in future cohorts until a recommended combination dose is identified. This recommended dose will be used to treat patients with Glioblastoma and Melanoma in later groups in this study.
Drug: E7080 plus E7050
The recommended dose for the combination of E7050 plus E7080 determined from the Dose escalation phase will be given to subjects to confirm it as the MTD. This recommended dose will be used to treat patients with Glioblastoma and Melanoma in later groups in this study.
Drug: E7050 plus E7080 or E7080 alone plus E7050 add-on therapy
Phase 2 Cohort 1 Arm A: E7050 will be taken once daily for 28 day cycles starting C1D1 in combination with E7080 at Recommended phase 2 (RP2) dose Arm B: E7050 at RP2 dose will be added on to single agent E7080 at time of disease progression.
Drug: E7050 plus E7080

Phase 2 Cohort 2:

Arm C: E7050 will be taken once daily for 28 day cycles starting C1D1 in combination with E7080 at Recommended phase 2 (RP2) dose

Experimental: E7050
Cohort 2: Up to 84 patients with unresectable Stage III or Stage IV Melanoma
Drug: E7050
Phase 2 Cohort 2: Arm D: E7050 will be taken alone at 400 mg daily for 28 day cycles.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

Subjects must meet all of the following criteria to be included in this study:

  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 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 first dose of study drug.
  6. Measurable disease defined as bidimensionally contrast enhancing lesions with clearly defined margins by computerized tomography (CT) or MRI scan, with a minimal diameter of 1 cm, and visible on two axial slices which are preferably at most 5 mm apart with 0 mm skip.

    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) (Appendix 3) 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 the following criteria:

    1. At least one lesion of ≥1.0 cm in the longest diameter for a non-lymph node or ≥1.5 cm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1 using CT/MRI or photography. If there is only one target lesion and it is a non-lymph node, it should have a longest diameter of ≥1.5 cm.
    2. Lesions that have had external beam radiotherapy or loco-regional therapies such as radiofrequency ablation must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion.

    All subjects:

  10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  11. Adequately controlled 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 as evidenced by serum creatinine ≤2.0 mg/dL or calculated creatinine clearance ≥40 mL/min per the Cockcroft and Gault formula (see Appendix 5).
  13. Adequate bone marrow function:

    • Absolute neutrophil count ≥1500/mm3 (≥1.5 x 103/μL);
    • Platelets ≥100,000/mm3 (≥100 x 109/L);
    • Hemoglobin ≥9.0 g/dL.
  14. Adequate blood coagulation function, as evidenced by an International Normalized Ratio (INR) ≤1.5.
  15. Adequate liver function:

    • Bilirubin ≤1.5 x the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome;
    • ALP, ALT, and AST ≤3 x ULN (≤5 x ULN if subject has liver metastases).
  16. Males or females age ≥18 years at the time of informed consent.
  17. All females must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human chorionic gonadotropin [β-hCG] at the Screening and Baseline Visit (a separate Baseline assessment is not required if a negative Screening pregnancy test was obtained within 72 hours before the first dose of study drug). Females of child-bearing potential, if not practising total abstinence or having a vasectomized partner with confirmed azoospermia, must agree to use two highly effective methods of contraception: e.g., 1) an intrauterine device (IUD) or intrauterine system (IUS); 2) a barrier method such as a condom or occlusive cup (diaphragm or cervical/vault caps) + spermicide (foam, gel, cream, etc.); 3) oral, injected, or implanted hormonal contraceptives throughout the entire study period and for 30 days after study drug discontinuation. Use of a double-barrier method (i.e., use at the same time of a condom + occlusive cup [diaphragm or cervical/vault caps] + spermicide [foam, gel, cream, etc.]) is accepted as two highly effective methods of contraception. The only subjects who will be exempt from this requirement are postmenopausal women (defined as women who have been amenorrheic for at least 12 consecutive months, in the appropriate age group, without other known or suspected primary cause) or subjects who have been sterilized surgically or who are otherwise proven sterile (i.e., bilateral tubal ligation with surgery at least 1 month prior to dosing, total hysterectomy, or bilateral oophorectomy with surgery at least 1 month prior to dosing). All women who are of reproductive potential and 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.
  18. Male subjects who are partners of women of childbearing potential must use a condom + spermicide and their female partners, if of childbearing potential, must use a highly effective method of contraception (see methods described in Inclusion Criterion #18) beginning at least 1 menstrual cycle prior to starting study drug, throughout the entire study period, and for 30 days after the last dose of study drug, unless the male subjects are totally abstinent sexually or have undergone a successful vasectomy with confirmed azoospermia or unless the female partners have been sterilized surgically or are otherwise proven sterile (see Inclusion Criterion #18).
  19. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.

Exclusion Criteria

Subjects who meet any of the following criteria will be excluded from this study:

  1. Phase 1b Dose Escalation: Subjects who discontinued prior TK inhibitor (including 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 hepatocyte growth factor (HGF) targeted treatment.
  5. Phase 2: Active malignancy (except for glioblastoma (Cohort 1) or unresectable Stage III or Stage IV melanoma (Cohort 2); 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 a new area of enhancement consistent with recurrent tumor outside of the radiation field (beyond the high dose region or 80% isodose line), or there is biopsy-proven unequivocal viable tumor on histopathology sampling (e.g., "solid" tumor areas (i.e. >70% tumor cell nuclei in areas), high or progressive increase in MIB-1 proliferation index compared to prior biopsy, or evidence for histological progression or increased anaplasia in the tumor).
  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. Subjects having >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, gastrointestinal malabsorption, gastrointestinal anastomosis, 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 [LMWH] 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01433991

Locations
United States, Massachusetts
Massachusetts General Hospital / Dana Farber Cancer Institute
Boston, Massachusetts, United States
Sponsors and Collaborators
Eisai Inc.
  More Information

No publications provided

Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT01433991     History of Changes
Other Study ID Numbers: E7050-G000-901
Study First Received: September 7, 2011
Last Updated: June 18, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Glioblastoma
Neoplasms
Astrocytoma
Glioma
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors

ClinicalTrials.gov processed this record on November 20, 2014