An Open Label Phase I Dose Escalation Study of E7080 Administered to Patients With Solid Tumors

The purpose of this study is to determine the maximum tolerable dose (MTD) and the related effects of E7080 administered to patients with solid tumors that are resistant to approved existing anti-tumor therapies, or for which no appropriate treatment is available.

Study Overview

• Status: Completed
• Conditions: Cancer: Solid Tumors
• Intervention / Treatment: Drug: E7080

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Tokyo, Japan, 104-0045

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Patients who have histologically and/or cytologically confirmed solid tumors requiring treatment.
2. Patients with solid tumors which are resistant to approved conventional anti-tumor therapies, or for which no appropriate treatment is available.
3. Patients who had completed all previous treatments (including surgery and radiotherapy) and supportive care (such as transfusion of blood, blood components and granulocyte colony-stimulating factor [G-CSF] treatment) at least 4 weeks before registration, and no sign or symptom of acute toxicity occurred in previous treatments.
4. Patients 20 years or older and less than 75 years of age at the time of registration.
5. Patients with 0 or 1 Performance Status (PS) established by Eastern Cooperative Oncology Group (ECOG.)
6. Patients who can stay in hospital for more than 1 cycle of treatment.
7. Patients who are expected to survive for more than 3 months from the start of study drug administration.
8. Patients who have provided written informed consent for the participation in the study.

Exclusion criteria:

1. Patients with clinical symptoms due to brain metastases requiring treatment.

2. Patients who have any of the following laboratory test findings:

   1. Hemoglobin less than 9.0 g/dL
   2. Neutrophil count less than 1.5 x 10 9/L
   3. Platelet count less than 100 x 10 9/L
   4. Serum bilirubin greater than 1.5 mg/dL
   5. AST, ALT greater than 100 IU/L
   6. Serum creatinine greater than 1.5 mg/dL or creatinine clearance less than 50 mL/minute
3. Patients with positive reaction for human immunodeficiency virus (HIV) or hepatitis virus C (HCV) antibody or hepatitis B virus surface (HBs) antigen, or patients with untreated serious infections.
4. Patients with clinically significant cardiac disorders or unstable ischemic heart diseases including myocardial infarction within six months before the registration for the study.
5. Patients with marked Baseline prolongation of QT/QTc interval (QTc interval greater than 450 msec for males or greater than 470 msec for females) using the Fridericia method for QTc analysis.
6. Patients with hemorrhagic or thrombotic diseases or who are using therapeutic doses of anticoagulants such as aspirin, warfarin, or ticlopidine.
7. Patients who are diagnosed with hypertension (defined as repeatedly measured blood pressure = 160/90 mmHg) at Screening, irrespective of use of antihypertensive drugs.
8. Patients who have proteinuria greater than 1 on bedside testing.
9. Patients who have history of insufficient gastrointestinal absorption, or patients who received gastric or intestinal anastomoses within 4 weeks before registration.
10. Patients who have history of alcoholism, drug addiction or mental or physical disorders, which, in the investigators opinion, may impair study compliance.
11. Patients who received any investigational drug within 30 days before the registration of the study.
12. Patients who received CYP3A4 inhibitors including itraconazole, erythromycin, clarithromycin, diltiazem or verapamil during screening and who have to use these drugs during the study.
13. Pregnant or nursing patients (all female patients with pregnancy potential must have negative pregnancy test performed before registration, and post-menopausal women must be amenorrheic for at least 12 months.) Female patients must use appropriate contraception.
14. Fertile male patients who refuse to use contraception, or whose female partners are not using appropriate contraception.
15. Patients who are judged by the investigator to be inappropriate for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: E7080; E7080 is administered orally twice a day for 2 weeks to patients with solid tumors that are resistant to approved conventional therapies or for which no appropriate treatment is available.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerable Dose (MTD) of E7080 Repeatedly Administered Twice a Day	The MTD was defined as the highest dose at which no dose limiting toxicity (DLT) was experienced by the first 3 patients in that cohort, or the dose at which a DLT was experienced by no more than 1 of 6 patients evaluable for toxicity.	up to 4 weeks
DLT of E7080 Repeatedly Administered Twice a Day	DLTs were defined as grade 3 or more platelet count decrease, grade 4 neutropenia, any grade 3 or more nonhematologic toxicity (with exceptions of grade 4 hypertension not controlled by any antihypertensive drugs and grade greater than or equal to 3 vomiting and diarrhea not controlled by antiemetic or antidiarrheal drugs), and failure to administer more than 75% of the planned doses of E7080 during the same cycle due to toxicity.	up to 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Elucidate the Pharmacokinetic Profile of E7080		Every 3 weeks
Number of Participants With Adverse Events / Serious Adverse Events	Treatment emergent adverse events (AEs) and serious adverse events (SAEs) were evaluated.	Until tumor progression, unacceptable toxicity, or withdrawal due to other reasons.
Determine the Clinical Dose for Phase II Study Based on Safety and Pharmacokinetic Profile		Every 3 weeks
Evaluate the Anti-tumor Activity of E7080		Every 3 weeks
To Make Exploratory Analyses of Pharmacodynamic Markers		Every 3 weeks

Collaborators and Investigators

• Sponsor: Eisai Inc.
• Investigators: Study Director: Akihiko Tsuruoka, Eisai Co., Ltd.

Publications and helpful links

General Publications

• Koyama N, Saito K, Nishioka Y, Yusa W, Yamamoto N, Yamada Y, Nokihara H, Koizumi F, Nishio K, Tamura T. Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib. BMC Cancer. 2014 Jul 21;14:530. doi: 10.1186/1471-2407-14-530.
• Yamada K, Yamamoto N, Yamada Y, Nokihara H, Fujiwara Y, Hirata T, Koizumi F, Nishio K, Koyama N, Tamura T. Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors. Clin Cancer Res. 2011 Apr 15;17(8):2528-37. doi: 10.1158/1078-0432.CCR-10-2638. Epub 2011 Mar 3.

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): September 1, 2008
• Study Completion (Actual): November 1, 2008

Study Registration Dates

• First Submitted: January 20, 2006
• First Submitted That Met QC Criteria: January 20, 2006
• First Posted (Estimate): January 23, 2006

Study Record Updates

• Last Update Posted (Estimate): October 7, 2016
• Last Update Submitted That Met QC Criteria: August 29, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Cancer, solid tumors
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Lenvatinib
• Other Study ID Numbers: E7080-J081-103