A Study Comparing the Combination of the Best Supportive Care Plus E7080 Versus Best Supportive Care Alone, in Patients With Advanced Lung Cancer or Lung Cancer That Has Spread, Who Have Been Previously Treated, Unsuccessfully, With at Least 2 Different Treatments

Non-Small Cell Lung Cancer Clinical Trial

Official title:

A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Oral E7080 in Addition to Best Supportive Care (BSC) Versus BSC Alone in Patients With Locally Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer Who Have Failed at Least Two Systemic Anticancer Regimens

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01529112
• Other study ID #: E7080-703
• Status: Completed
• Phase: Phase 2
• First received: January 6, 2012
• Last updated: August 28, 2017
• Start date: November 2011
• Est. completion date: June 27, 2015

Study information

• Verified date: August 2017
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to compare the overall survival of patients receiving E7080 + Best Supportive Care (BSC) with those receiving placebo + Best Supportive Care.

Description:

This double-blind, placebo-controlled, multicenter, randomized Phase II study will consist of a 2-arm design, comparing E7080 + BSC (Arm 1) with placebo + BSC (Arm 2). Participants will be randomized in the ratio of 2:1 to receive either E7080 or placebo in a blinded manner.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 135
• Est. completion date: June 27, 2015
• Est. primary completion date: January 21, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria

1. Age greater than or equal to 18 years;

2. Participants with histologically or cytologically confirmed non-squamous NSCLC with locally advanced or metastatic disease based on Tumor, Node, Metastasis (TNM) staging according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, Seventh Edition, who had failed at least two lines of systemic anticancer therapy for advanced or metastatic NSCLC (did not include adjuvant chemotherapy). In countries where erlotinib was approved and marketed for the treatment of NSCLC, participants must have received erlotinib treatment (or gefitinib for participants outside of the US) for their NSCLC if they had known EGFR-activating mutations. Participants of unknown EGFR status who had not received prior erlotinib (or gefitinib) should have been tested for EGFR-activating mutations prior to study entry. In countries where crizotinib was approved and marketed, participants must have received crizotinib treatment for NSCLC that was ALK-positive. Participants with ALK positive NCSLC or participants with KRAS mutations were not required to have prior treatment with erlotinib or gefitinib

3. Participants must have at least 1 site of measurable disease by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1);

4. ECOG PS of 0 to 2;

5. Participants must have adequate renal function as evidenced by serum creatinine less than or equal to 1.5 x upper limit of normal (ULN) or calculated creatinine clearance greater than or equal to 30 mL/min per the Cockcroft and Gault formula;

6. Blood pressure must be well-controlled (less than or equal to140/90 mm Hg at Screening) with or without antihypertensive medication. Participants must have no history of hypertensive crisis or hypertensive encephalopathy;

7. Participants must have adequate bone marrow function as evidenced by absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L, hemoglobin greater than or equal to 9.0 g/dL, and platelet count greater than or equal to 100 x 109/L;

8. Participants must have adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the ULN, and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 x ULN (in the case of liver metastases, less than or equal to 5 x ULN).

9. Participants must have adequate coagulation system function as defined by prothrombin time/International normalized ratio (INR) less than or equal to 1.5 x ULN.

10. Male or female participants of child-producing potential must agree to use double barrier contraception, oral contraceptives, or avoidance of pregnancy measures during the study and for 90 days after the last day of treatment;

11. Females of childbearing potential must have a negative serum pregnancy test;

12. Females may not be breastfeeding;

13. Ability to understand and willingness to sign a written informed consent.

Exclusion Criteria

1. Prior therapy with E7080 or other small molecule vascular endothelial growth factor inhibitors;

2. Presence of brain metastases, unless the participant has received adequate treatment at least 4 weeks prior to randomization, and is stable, asymptomatic, and off steroids for at least 4 weeks prior to randomization;

3. Meningeal carcinomatosis;

4. Received chemotherapy, targeted therapy, radiotherapy, surgery, or immunotherapy within the 21 days prior to commencing study treatment or have not recovered from all treatment-related toxicities to Grade less than or equal to 2, except for alopecia;

5. Received treatment with another investigational agent within the 30 days prior to commencing study treatment or participants who have not recovered from side effects of an investigational drug to Grade less than or equal to 2, except for alopecia;

6. Participants with proteinuria greater than 1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with 24-hour urine protein greater than or equal to 1 g/24 hours will be ineligible;

7. Serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury within the 28 days prior to commencing study treatment.

8. Major surgery scheduled during the projected course of the study;

9. History of bleeding diathesis or coagulopathy;

10. Active hemoptysis (defined as bright red blood of a half teaspoon or more) within the 30 days prior to study entry;

11. Refractory nausea and vomiting, malabsorption, significant bowel resection, or any other medical condition that would preclude adequate absorption or result in the inability to take oral medication;

12. Other malignancy within 3 years of randomization, with the exception of adequately treated carcinoma in situ of the cervix or non-melanoma skin cancer, with no subsequent evidence of recurrence and/or malignancies diagnosed at a stage where definitive therapy results in near certain cures.

13. Significant cardiovascular impairment (history of congestive heart failure New York Heart Association [NYHA] Class greater than II, unstable angina or myocardial infarction within the past 6 months, or serious cardiac arrhythmia);

14. Any history of cerebral vascular accident (CVA), transient ischemic attack (TIA), or Grade greater than or equal to 2 peripheral vascular disease unless they have had no evidence of active disease for at least 6 months prior to randomization;

15. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the 6 months prior to enrollment;

16. Participants with organ allografts requiring immunosuppression;

17. Known positive human immunodeficiency virus (HIV), known hepatitis B surface antigen, or hepatitis C positive;

18. Hypersensitivity to E7080 or any of the excipients;

19. Any history of or concomitant medical condition that, in the opinion of the Investigator, would compromise the participant's ability to safely complete the study.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-Small Cell Lung Cancer

Intervention

Drug:
• Lenvatinib

• Lenvatinib matched placebo

• BSC

Locations

Country	Name	City	State
Belgium	OLV Ziekenhuis	Aalst
Belgium	Grand Hopital de Charleroi	Charleroi
Belgium	AZ Sint-Maarten	Duffel
Belgium	UZ Antwerpen	Edegem
Belgium	UZ Leuven	Leuven
Belgium	C. H. R. de la Citadelle	Liege
Belgium	Domaine Universitaire du Sart-Tilman	Liege
Czechia	Institut onkologie a rehabilitace Na Plesi	Nova Ves pod Plesi
Czechia	Avicennus, s.r.o.	Nymburk
Czechia	Fakultni nemocnice Na Bulovce	Praha 8
Czechia	Oblastni nemocnice Pribram, a.s.	Pribram
Hungary	Orszagos Koranyi TBC es Pulmonologiai Intezet	Budapest
Hungary	Semmelweis Egyetem AOK	Budapest
Hungary	Matrai Gyogyintezet	Matrahaza
Hungary	Fejer Megyei Szent Gyorgy Korhaz	Szekesfehervar
Hungary	Komarom-Esztergom Megyei Onkorm. Szent Borbala Korhaza	Tatabanya
Hungary	Tudogyogyintezet Torokbalint	Torokbalint
Hungary	Zala Megyei Korhaz	Zalaegerszeg
Italy	Azienda Ospedaliera G. Rummo	Benevento
Italy	Azienda Ospedaliero Universitaria San Martino	Genova
Italy	Azienda Ospedaliera San Gerardo	Milano
Italy	Istituto Clinico Humanitas	Milano
Italy	Azienda Ospedaliera Universitaria di Parma	Parma
Italy	Fondazione Salvatore Maugeri IRCCS	Pavia
Italy	Azienda Ospedaliera di Perugia Ospedale S. Maria della Misericordia	Perugia
Italy	Azienda Ospedaliera San Camillo Forlanini	Roma
Italy	Ospedale Mater Salutis	Verona
Korea, Republic of	Chungbuk National University Hospital	Chungcheongbuk-do
Korea, Republic of	Chonnam National University Hwasun Hospital	Hwasun-gun
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si
Korea, Republic of	Korea University Guro Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Korea, Republic of	The Catholic University of Korea Yeouido St. Mary's Hospital	Seoul
Korea, Republic of	Ulsan University Hospital	Ulsan
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow	Strathclyde
United Kingdom	The Christie NHS Foundation Trust	Manchester	Greater Manchester
United Kingdom	Southampton General Hospital	Southampton	Hampshire
United Kingdom	North Staffs Royal Infirmary	Stoke-on-Trent	Staffordshire
United Kingdom	New Cross Hospital	Wolverhampton	West Midlands
United States	Cancer Treatment and Research Centre Bismarck North Dakota 58501	Bismarck	North Dakota
United States	Donald W. Hill, M.D., F.A.C.P.	Casa Grande	Arizona
United States	New York Oncology Heamatology - Latham	Clifton Park	New York
United States	Ronald Yanagihara, MD 9360 North Name Uno Suite 130 Gilroy California 95020	Gilroy	California
United States	Montefiore Medical Park 1695 Easchester Road Floor 1 Bronx, NY 10461	New York	New York
United States	Ocala Oncology Center, P.L.	Ocala	Florida
United States	Texas Oncology, P.A. - Paris	Paris	Texas
United States	Texas Oncology, P.A. - Plano	Plano	Texas
United States	Washington University 660 South Euclid Avenue Campus Box 8124 St Louis Missouri 63110	Saint Louis	Missouri
United States	Arizona Oncology Associates , PC - HOPE	Tucson	Arizona
United States	Texas Oncology, P.A. - Waco	Waco	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Eisai Inc.	Quintiles, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  Czechia,  Hungary,  Italy,  Korea, Republic of,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	OS was defined as the time from the date of randomization until the date of death from any cause.	From date of randomization (Day 1) until occurrence of 90 deaths in the study (cut off date 26 November 2013), approximately 22 months
Secondary	Number of Participants With Treatment Emergent Non-serious Adverse Events (AEs) and Treatment Emergent Serious Adverse Events (SAEs)	An AE was defined as any untoward medical occurrence in a clinical investigation participant administered with an investigational product. A SAE was defined as any untoward medical occurrence that at any dose; resulted in death, was life-threatening (i.e., the subject was at a risk of death at the time of the event; this did not include an event that hypothetically might have caused death if it had been more severe), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, or was a congenital abnormality/birth defect. In this study, treatment emergent adverse events (TEAEs) (defined as an AE (serious/non-serious) that started/increased in severity on/after the first dose of study medication up to 30 days after the final dose of study medication) were assessed.	For each participant, from the first dose till 30 days after the last dose or up to approximately 2 years (data cut-off date of 21 January 2014)
Secondary	6-Month Survival Rate	Event-free survival rate was calculated using Kaplan Meier estimations. The percentage of participants with event free survival up to 6 months and the corresponding 95% confidence interval were estimated for each treatment group. The data presented is based on the data cut-off date of 26 November 2013 while the study is still ongoing.	From date of randomization (Day 1) up to 6 months
Secondary	1-year Survival Rate	Event-free survival rate was calculated using Kaplan Meier estimations. The percentage of participants with event free survival up to 1 year and the corresponding 95% confidence interval were estimated for each treatment group. The data presented is based on the data cut-off date of 26 November 2013 while the study is still ongoing.	From date of randomization (Day 1) up to 1 year
Secondary	Progression-Free Survival (PFS)	PFS was defined as the time from the date of the randomization until the date of first documented disease progression according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 or date of death from any cause (whichever occurred first), assessed based on investigator's assessment. Disease progression per RECIST v1.1 was defined as at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), recorded since the treatment started or the appearance of 1 or more new lesions. The data presented is based on the data cut-off date of 21 January 2014 while the study is still ongoing.	From date of randomization (Day 1) until date of first documentation of disease progression or death from any cause (whichever occurred first) or up to approximately 2 years (data cut-off date of 21 January 2014)
Secondary	Overall Response Rate (ORR)	ORR, defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by investigator using RECIST 1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR = CR + PR. The data presented is based on the data cut-off date of 21 January 2014 while the study is still ongoing.	From date of randomization (Day 1) until disease progression or death, development of unacceptable toxicity, withdrawal of consent, withdrawal by Investigator, or up to approximately 2 years (data cut-off date of 21 January 2014)
Secondary	Response Duration (RD)	Response duration, defined as the time from the date of the first assessment demonstrating a CR or PR to the date of the first assessment demonstrating progressive disease or death, whichever occurred first. This is an investigator assessed outcome, measured using RECIST 1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Response duration was summarized by including only subjects with events. The data presented is based on the data cut-off date of 21 January 2014 while the study is still ongoing.	From date of randomization (Day 1) until disease progression or death, development of unacceptable toxicity, withdrawal of consent, withdrawal by Investigator, or up to approximately 2 years (data cut-off date of 21 January 2014)
Secondary	Disease Control Rate (DCR)	The percentage of participants with CR, PR, or stable disease (SD) for greater than or equal to 12 weeks. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable disease was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on the study. The data presented is based on the data cut-off date of 21 January 2014 while the study is still ongoing.	From date of randomization (Day 1) until disease progression or death, development of unacceptable toxicity, withdrawal of consent, withdrawal by Investigator, or up to approximately 2 years (data cut-off date of 21 January 2014)
Secondary	The Percentage of Participants With The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Symptom Scores Achieving Clinically Significant Deterioration on Quality of Life (QOL)	The EORTC QLQ-C30 symptom score, a cancer specific self-reporting questionnaire was composed of 9-symptom scales assessing fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties. All of the multi-item scales and single-item measures ranged in score from 0 to 100. For each domain and item, a linear transformation was applied to standardize the raw score to a range from 0 to 100, with a higher scale score representing a higher response level/ high level of symptomatology / problems. The data is presented as percentage of participants with EORTC QLQ-C30 symptom score achieving clinically significant deterioration on QOL. Participants were considered as deteriorated for a given symptom if the change in score from Baseline was 10 points or higher at any time point after Baseline. The data presented is based on the data cut-off date of 21 January 2014 while the study is still ongoing.	Baseline (Day 1 of Cycle 1 (prior to treatment in Cycle 1)), every 4 weeks during treatment, and 4 weeks after completing treatment or up to approximately 2 years (data cut-off date of 21 January 2014)
Secondary	The Percentage of Participants With The European Organization for Research and Treatment of Cancer (EORTC) Module QLQ-LC13 (Lung Cancer 13) Symptom Scores Achieving Clinically Significant Deterioration on QOL	The EORTC module QLQ-LC13 symptom score was a self-reporting cancer-specific questionnaire composed of 13 questions incorporated into 1 multi-item scale designed to evaluate dyspnea and a series of single items assessing different types of pain, as well as, cough, hemoptysis, dysphagia, sore mouth, alopecia, and peripheral neuropathy. For each domain and item, a linear transformation was applied to standardize the raw score to a range from 0 to 100, with 100 representing the best possible function/QOL, and highest burden of symptoms for symptom domains and single items. The data is presented as percentage of participants with EORTC module QLQ-C13 symptom score achieving clinically significant deterioration on QOL. Participants were considered as deteriorated for a given symptom if the change in score from Baseline was 10 points or higher at any time point after Baseline. The data presented is based on the data cut-off date of 21 January 2014 while the study is still ongoing.	Baseline (Day 1 of Cycle 1 (prior to treatment in Cycle 1)), every 4 weeks during treatment, and 4 weeks after completing treatment or up to approximately 2 years (data cut-off date of 21 January 2014)
Secondary	Pharmacokinetic (PK) Profile of Lenvatinib in Subjects With Non Small Cell Lung Cancer (NSCLC)	Blood samples were collected for lenvatinib PK analysis. Lenvatinib concentrations from sparse PK sampling were measured. The data is presented as mean nanograms per milliliter +/- Standard deviation of lenvatinib serum concentration.	Cycle 1/Day 1 (between 0.5 and 4 hours postdose and 6 and 10 hours postdose), Cycle 1/Day 15 (predose, between 0.5 and 4 hours postdose, and 6 and 10 hours postdose), and Day 1 of Cycles 2 though 4 (predose and between 2 and 12 hours postdose)