A Study of E7050 in Combination With E7080 in Participants With Advanced Solid Tumors (Dose Escalation) and in Participants With Recurrent Glioblastoma or Unresectable Stage III or Stage IV Melanoma After Prior Systemic Therapy (Expansion Cohort and Phase 2)

NCT01433991 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: E7050-G000-901
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 2

Brief Summary

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 E7050 and E7080 (lenvatinib) in combination in participants with unresectable advanced or metastatic solid tumors. In the subsequent Phase 1b expansion cohort and Phase 2 cohorts, additional participants 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 lenvatinib.

Conditions

Advanced Solid Tumors

Outcome Measures

Primary Outcomes (3)

• Phase 1b: Number of Participants Who Experienced Any Dose Limiting Toxicity (DLT)- Combination Treatment

  DLT was defined as toxicity related to the combination therapy and was graded according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Hematological DLTs were Grade 4 neutropenia for greater than or equal to (\>=) 7 days or Grade 3 neutropenia with fever (greater than \[\>\] 38.5 degree Celsius (°C) in axilla), Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding or lasting \>7 days and decrease of hemoglobin of Grade 4. Non-hematological DLTS were Grade 3 fatigue, or a 2 point decline in Eastern Cooperative Oncology Group (ECOG) performance status must persist for \>7days, Nausea, vomiting or diarrhea must persist at Grade 3 or 4 despite maximal medical therapy, Grade 4 hypertension or Grade 3 hypertension not able to be controlled by medication and any Grade 3 or higher non-hematological laboratory abnormalities that require hospitalization.

  Cycle 1 (Cycle length= 28 days)

• Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Golvatinib in Combination With Lenvatinib

  The MTD was defined as the highest dose level at which no more than 1/6 participants experienced a DLTs, with the next higher dose having at least 0 of 3 or 1 of 6 participants experiencing DLTs. MTD was determined by summarizing the number and percentage of participants with DLTs for the first cycle, by study dosing schedule, initial dosing level and overall for the dose escalation part. The RP2D of golvatinib in Combination with lenvatinib was MTD determined by Dose Escalation Committee (DEC) based on safety, PK and clinical data. DLT was defined as toxicity related to the combination therapy and was graded according to CTCAE v4.0.

  Cycle 1 (Cycle length= 28 days)

• Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Lenvatinib in Combination With Golvatinib

  The MTD was defined as the highest dose level at which no more than 1/6 participants experienced a DLTs, with the next higher dose having at least 0 of 3 or 1 of 6 participants experiencing DLTs. MTD was determined by summarizing the number and percentage of participants with DLTs for the first cycle, by study dosing schedule, initial dosing level and overall for the dose escalation part. The RP2D of lenvatinib in Combination with golvatinib was MTD determined by DEC based on safety, PK and clinical data. DLT was defined as toxicity related to the combination therapy and was graded according to CTCAE v4.0.

  Cycle 1 (Cycle length= 28 days)

Secondary Outcomes (32)

• Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Laboratory Values- Combination Treatment

  From baseline up to approximately 5 years 5 months

• Phase 1b: Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values- Combination Treatment

  From baseline up to approximately 5 years 5 months

• Phase 1b: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Values- Combination Treatment

  From baseline up to approximately 5 years 5 months

• Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)- Combination Treatment

  From baseline up to approximately up to 5 years 5 months

• Phase 1b: Cmax; Maximum Observed Plasma Concentration for Golvatinib When Administered as a Single Agent at Day -7

  Day -7: 0-24 hours post-dose

Study Arms (5)

Phase 1B

EXPERIMENTAL

Participants with unresectable advanced or metastatic solid tumors will receive E7050 in combination with lenvatinib to identify a Maximum Tolerated Dose. Dose escalation will begin at low doses of both E7050 and lenvatinib, and then gradually increase in future cohorts until a recommended combination dose is identified. A dose of E7050 and lenvatinib to be used in combination in Phase 2 will be recommended (RP2 dose). Participants will continue on treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent.

Drug: Golvatinib; Drug: Lenvatinib

Phase 2 Cohort 1 Arm A:

EXPERIMENTAL

Participants with recurrent glioblastoma (bevacizumab-naïve) will receive E7050 and lenvatinib at the RP2 dose.

Drug: Golvatinib; Drug: Lenvatinib

Phase 2 Cohort 1 Arm B:

EXPERIMENTAL

Participants with recurrent glioblastoma (bevacizumab-naïve) will receive single agent lenvatinib 24 mg/day (1\*4 mg capsule + 2\*10 mg capsule) and at time of progression, E7050 add-on therapy at the RP2 dose (in combination with lenvatinib at dose of either the RP2 dose or the most recent dose of single agent lenvatinib, whichever is the lowest).

Drug: Golvatinib; Drug: Lenvatinib

Phase 2 Cohort 2 Arm C:

EXPERIMENTAL

Participants with unresectable Stage III or Stage IV melanoma and disease progression after prior systemic treatment will receive E7050 and lenvatinib at the RP2 dose.

Drug: Golvatinib; Drug: Lenvatinib

Phase 2 Cohort 2 Arm D:

EXPERIMENTAL

Participants with unresectable Stage III or Stage IV melanoma and disease progression after prior systemic treatment will receive single agent E7050 400 mg/day.

Drug: Golvatinib

Interventions

Golvatinib DRUG

Participants will receive E7050 50 mg and/or 100 mg tablets. E7050 will be administered orally once daily, in 28-day cycles.

Also known as: E7050

Phase 1B; Phase 2 Cohort 1 Arm A:; Phase 2 Cohort 1 Arm B:; Phase 2 Cohort 2 Arm C:; Phase 2 Cohort 2 Arm D:

Lenvatinib DRUG

Participants will receive lenvatinib 1 mg and/or 4 mg and/or 10 mg capsules. Lenvatinib will be administered orally once daily, in 28-day cycles.

Also known as: E7080

Phase 1B; Phase 2 Cohort 1 Arm A:; Phase 2 Cohort 2 Arm C:

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must meet all of the following criteria to be included in this study:
• Phase 1b: Unresectable advanced or metastatic solid tumors.
• 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 participants, Phase 2 Cohort 1:
• No evidence of active central nervous systems (CNS) hemorrhage on baseline scans other than in those participants with recurrent glioblastoma who are stable Grade 1.
• Participants 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.
• If participants is on corticosteroids, they must be on a stable dose for 1 week prior to first dose of study drug.
• 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 millimeter (mm) apart with 0 mm skip.
• Phase 1b expansion cohort melanoma participants, Phase 2 Cohort 2:
• 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.
• American Joint Committee on Cancer (AJCC) unresectable Stage III or Stage IV melanoma.
• Measurable disease meeting the following criteria:
• 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 centimeter (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 greater than or equal to 1.5 cm.
• Lesions that have had external beam radiotherapy or loco-regional therapies such as radio frequency ablation must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion.
• All participants:

You may not qualify if:

• Participants who meet any of the following criteria will be excluded from this study:
• Phase 1b Dose Escalation: Participants who discontinued prior TK inhibitor (including VEGFR and c-Met receptor targeted therapy) due to toxicity will be ineligible.
• Phase 1b Dose Escalation (3+3 portion) participants with primary CNS tumors
• Phase 1b Dose Escalation participants, melanoma participants in expansion cohort and Phase 2 Cohort 2: Participants with untreated or unstable metastases to the central nervous system (CNS) are excluded. participants 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.
• Phase 2: Prior exposure to VEGF-targeted treatment or c-Met or hepatocyte growth factor (HGF) targeted treatment.
• 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 participants and Phase 2 Cohort 1:
• More than two recurrences of glioblastoma.
• Prior bevacizumab treatment.
• Surgical resection of brain tumor within 4 weeks, or prior stereotactic biopsy within 2 weeks of Screening visit.
• 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. greater than 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).
• Participants 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 participants with melanoma and Phase 2 Cohort 2:
• More than two prior systemic regimens for unresectable Stage III or Stage IV disease.
• All participants

Sponsors & Collaborators

• Eisai Inc.: lead

Study Sites (2)

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Location

Massachusetts General Hospital / Dana Farber Cancer Institute

Boston, Massachusetts, United States

Location

MeSH Terms

Interventions

N-(2-fluoro-4-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)carbonylaminopyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide; lenvatinib

Limitations and Caveats

The study was terminated by the sponsor at the end of Phase 1b due to a change in corporate strategy, hence Phase 2 was not carried out.

Results Point of Contact

• Title: Eisai Medical Information
• Organization: Eisai Inc.

esi_oncmedinfo@eisai.com

1-888-274-2378

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 7, 2011
• First Posted: September 14, 2011
• Study Start: October 13, 2011
• Primary Completion: March 18, 2015
• Study Completion: March 1, 2017
• Last Updated: June 8, 2021
• Results First Posted: June 8, 2021

Record last verified: 2021-05

Locations

US (2)