A Trial of Lenvatinib (E7080) Plus Pembrolizumab in Participants With Selected Solid Tumors

Sponsor

Eisai Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT02501096

Collaborator

Merck Sharp & Dohme LLC (Industry)

357

Enrollment

Locations

Arm

Actual Duration (Months)

5.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an open-label Phase 1b/2 trial of lenvatinib (E7080) plus pembrolizumab in participants with selected solid tumors. Phase 1b will determine and confirm the maximum tolerated dose (MTD) for lenvatinib in combination with 200 milligrams (mg) (intravenous [IV], every 3 weeks [Q3W]) pembrolizumab in participants with selected solid tumors (i.e. non-small cell lung cancer, renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, or melanoma). Phase 2 (Expansion) will evaluate the safety and efficacy of the combination in 6 cohorts at the MTD from Phase 1b (lenvatinib 20 mg/day orally + pembrolizumab 200 mg Q3W, IV).

Condition or Disease	Intervention/Treatment	Phase
Tumors	Drug: Lenvatinib Drug: Pembrolizumab	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

357 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Multicenter, Open-Label Phase 1b/2 Trial of Lenvatinib (E7080) Plus Pembrolizumab in Subjects With Selected Solid Tumors

Actual Study Start Date :

Jul 22, 2015

Actual Primary Completion Date :

Aug 18, 2020

Actual Study Completion Date :

Apr 21, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lenvatinib + Pembrolizumab Participants with one of the tumors: non-small cell lung cancer, renal cell carcinoma, endometrial cancer, urothelial cancer, squamous cell carcinoma of the head and neck, or melanoma.	Drug: Lenvatinib Lenvatinib will be administered with water orally once a day (with or without food) continuously in 21-day treatment cycle. Other Names: Lenvima E7080 Drug: Pembrolizumab Pembrolizumab will be administered as a dose of 200 mg Q3W, IV in 21-day treatment cycle. Other Names: Keytruda MK-3475

Arm

Intervention/Treatment

Experimental: Lenvatinib + Pembrolizumab

Participants with one of the tumors: non-small cell lung cancer, renal cell carcinoma, endometrial cancer, urothelial cancer, squamous cell carcinoma of the head and neck, or melanoma.

Drug: Lenvatinib

Lenvatinib will be administered with water orally once a day (with or without food) continuously in 21-day treatment cycle.

Other Names:

Lenvima

E7080

Drug: Pembrolizumab

Pembrolizumab will be administered as a dose of 200 mg Q3W, IV in 21-day treatment cycle.

Other Names:

Keytruda

MK-3475

Outcome Measures

Primary Outcome Measures

MTD (Phase 1b) [Cycle 1 (21 Days)]
Objective response rate (ORR) at Week 24 [Week 24]
Dose Limiting Toxicity (DLT) (Phase 1b) [Cycle 1 (21 Days)]

Secondary Outcome Measures

Number of participants with treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (SAEs) [For each participant, from the first dose until 30 days (TEAEs) and 90 days (SAEs) after the last dose, unless participant starts new anticancer drug, then 30 days or up to approximately 2 years]
ORR [From date of first dose of study drug until disease progression, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up, discontinuation of this study by the sponsor, or up to approximately 2 years]
Progression-free survival (PFS) [From the date of first dose of study drug to the date of first documentation of confirmed disease progression or death (whichever occurs first) or up to approximately 2 years)]
Overall survival (OS) [From the date of first dose of study drug until date of death from any cause or up to approximately 2 years]
Duration of response (DOR) [From date of first dose of study drug until disease progression, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up, discontinuation of this study by the sponsor, or up to approximately 2 years]
Disease control rate (DCR) [From date of first dose of study drug until disease progression, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up, discontinuation of this study by the sponsor, or up to approximately 2 years]
Durable stable disease rate (DSDR) [From date of first dose of study drug until disease progression, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up, discontinuation of this study by the sponsor, or up to approximately 2 years]
Clinical benefit rate (CBR) [From date of first dose of study drug until disease progression, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up, discontinuation of this study by the sponsor, or up to approximately 2 years]
Plasma Concentrations of Lenvatinib [Cycle 1 Day 1: 0.5-10 hours post dose; Cycle 1 Day 15: 0-10 hours post dose; Cycle 2 Day 1: 0-12 hours post dose (Cycle length is 21 days)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Phase 1b: Histologically and/or cytologically confirmed metastatic selected solid tumor types that have progressed after treatment with approved therapies or for which there are no standard effective therapies available. If nivolumab or pembrolizumab is an approved therapy for the participant's tumor type, but the participant has not been treated with it, the Investigator may enroll the participant in this study.

Phase 2: Histologically and/or cytologically confirmed metastatic selected solid tumor types with 0-2 prior lines of systemic therapy. If previously treated, participant has progressed after previous treatment. For the non-small cell lung cancer (NSCLC) and melanoma cohorts, participants must have progressed on or after prior treatment with one anti-programmed cell death protein 1 (anti-PD-1), anti-PD-1 ligand 1 (anti-PD-L1), or anti-PD-1 ligand 2 (anti-PD-L2) agent. For the renal cell carcinoma (RCC) cohort, participants must have progressed on treatment with an anti- programmed death receptor-1 /programmed death receptor-ligand 1 monoclonal antibody (anti-PD-1/PD-L1 mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies, the regimen with an anti-PD-1/PD-L1 mAb must be the most recent therapy. Selected tumor types of both phases: NSCLC, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, or melanoma (excluding uveal melanoma)

Life expectancy of 12 weeks or more
Phase 2: Measurable disease meeting the following criteria:
At least 1 lesion of greater than or equal to 10 mm in the longest diameter for a non-lymph node or greater than or equal to 15 mm in the short-axis diameter for a lymph node that is serially measurable according to irRECIST (immune-related Response Evaluation Criteria in Solid Tumors) using computerized tomography/magnetic resonance imaging (CT/MRI)
Lesions that have had external beam radiotherapy (EBRT) or loco-regional therapies such as radiofrequency (RF) ablation must show subsequent evidence of substantial size increase to be deemed a target lesion
Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1
Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than or equal to 150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to the Cycle 1 Day 1
Adequate renal function defined as creatinine less than or equal to 1.5ULN (upper limit of normal) or calculated creatinine clearance greater than or equal to 40 mL/min per the Cockcroft and Gault formula with creatinine levels greater than 1.5ULN
Adequate bone marrow function:
Absolute neutrophil count (ANC) greater than or equal to 1500/mm3 (greater than or equal to 1.5 X 103/uL)
Platelets greater than or equal to 100,000/mm3 (greater than or equal to 100 X 109/L)
Hemoglobin greater than or equal to 9.0 g/dL
Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) less than or equal to 1.5
Adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the ULN and alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3ULN (in the case of liver metastases less than or equal to 5ULN). In case ALP is greater than 3 X ULN (in the absence of liver metastases) or greater than 5 X ULN (in the presence of liver metastases) AND the participant also is known to have bone metastases, the liver specific ALP must be separated from the total and used to assess the liver function instead of the total ALP
Males or females age greater than or equal to 18 years at the time of informed consent
Participants with known brain metastases will be eligible if they have completed the primary brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery or complete surgical resection) and if they have remained clinically stable, asymptomatic and off of steroids for at least 28 days before starting study treatment.
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 Visit and the Baseline Visit. A pregnancy test needs to be performed within 72 hours of the first dose of study drug. Females of childbearing potential must agree to use a highly effective method of contraception for the entire study period and for 120 days after study discontinuation, ie

total abstinence (if it is their preferred and usual lifestyle)
an intrauterine device (IUD) or hormone-releasing system (IUS)
a contraceptive implant
an oral contraceptive** (with additional barrier method) OR
have a vasectomized partner with confirmed azoospermia.

NOTES:

All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
Must be on a stable dose of the same oral hormonal contraceptive product for at least 4 weeks before dosing with study drug and for the duration of the study

Male participants 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 #12) beginning at least 1 menstrual cycle prior to starting study drug(s), throughout the entire study period, and for 120 days after the last dose of study drug, unless the male participants are totally sexually abstinent or have undergone a successful vasectomy with confirmed azoospermia or unless the female partners have been sterilized surgically or are otherwise proven sterile.
Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol
Archival tumor tissue or a newly obtained biopsy must be available prior to the first dose of study drug for biomarker analysis. In the case archival tissue cannot be provided, participants with inaccessible tumors for biopsy specimens can be enrolled without a biopsy upon consultation and agreement by the sponsor Note: In case of submitting unstained cut slides, freshly cut slides should be submitted to the testing laboratory within 14 days from when the slides are cut.

Exclusion Criteria:

Prior anticancer treatment within 28 days (or 5 times the half-life time, whichever is shorter) or any investigational agent within 30 days prior to the first dose of study drugs. All acute toxicities related to prior treatments must be resolved to Grade less than or equal to 1
Participants must have recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy
Participants having greater than 1+ proteinuria on urinalysis will undergo 24-h urine collection for quantitative assessment of proteinuria. Participants with urine protein greater than or equal to 1 g/24-hour will be ineligible.
Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
New York Heart Association congestive heart failure of grade II or above, unstable angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia associated with significant cardiovascular impairment within the past 6 months
Prolongation of corrected QT (QTc) interval to greater than 480 msec
Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug
Active infection (any infection requiring systemic treatment)
Participant is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C
Serious nonhealing wound, ulcer, or bone fracture
Known intolerance to either of the study drugs (or any of the excipients)
History of organ allograft (Participant has had an allogenic tissue/solid organ transplant)
Biologic response modifiers (eg, granulocyte colony-stimulating factor) within 4 weeks before study entry. Chronic erythropoietin therapy is permitted provided that no dose adjustments were made within 2 months before first dose of study treatment
Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial
Females who are pregnant or breastfeeding
Excluding the primary tumor leading to enrollment in this study, any other active malignancy (except for definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the bladder or cervix) within the past 24 months
Prior treatment with lenvatinib or any PD-1, anti-PD-L1, or anti-PD-L2 agent, excluding melanoma and NSCLC where prior treatment with one PD-1, anti-PD-L1, or anti-PD-L2 agent is allowed, and excluding RCC where prior treatment with one regimen containing an anti-PD-1/PD-L1 mAb is required.
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids (up to 7.5mg/d of prednisone or equivalent) may be approved after consultation with the sponsor.
No active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alaska Clinical Research Center	Anchorage	Alaska	United States
2	Arizona Oncology Associates	Oro Valley	Arizona	United States
3	Arizona Oncology Associates, PC - HOPE, Site #1	Tucson	Arizona	United States
4	Arizona Oncology Associates, PC - HOPE, Site #2	Tucson	Arizona	United States
5	Arizona Oncology Associates, PC - HOPE, Site #3	Tucson	Arizona	United States
6	Rocky Mountain Cancer Centers	Aurora	Colorado	United States
7	Rocky Mountain Cancer Centers	Boulder	Colorado	United States
8	Rocky Mountain Cancer Centers	Colorado Springs	Colorado	United States
9	Rocky Mountain Cancer Centers, Site #1	Denver	Colorado	United States
10	Rocky Mountain Cancer Centers, Site #2	Denver	Colorado	United States
11	Rocky Mountain Cancer Centers	Lakewood	Colorado	United States
12	Rocky Mountain Cancer Centers	Littleton	Colorado	United States
13	Rocky Mountain Cancer Centers	Lone Tree	Colorado	United States
14	Rocky Mountain Cancer Centers	Longmont	Colorado	United States
15	Rocky Mountain Cancer Centers	Parker	Colorado	United States
16	Rocky Mountain Cancer Centers	Pueblo	Colorado	United States
17	Rocky Mountain Cancer Centers	Thornton	Colorado	United States
18	Baptist Health Medical Group Oncology, LLC, Site #1	Miami	Florida	United States
19	Baptist Health Medical Group Oncology, LLC, Site #2	Miami	Florida	United States
20	Baptist Health Medical Group Oncology, LLC, Site #3	Miami	Florida	United States
21	Boca Raton Clinical Research Medical Center	Plantation	Florida	United States
22	Piedmont Cancer Institue	Atlanta	Georgia	United States
23	The University of Chicago	Chicago	Illinois	United States
24	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States
25	Mass General Hospital	Boston	Massachusetts	United States
26	University of Minnesota, Masonic Cancer Center	Minneapolis	Minnesota	United States
27	Comprehensive Cancer Centers of Nevada, Site #1	Henderson	Nevada	United States
28	Comprehensive Cancer Centers of Nevada, Site #2	Henderson	Nevada	United States
29	Comprehensive Cancer Centers of Nevada, Site #3	Henderson	Nevada	United States
30	Comprehensive Cancer Centers of Nevada, Site #1	Las Vegas	Nevada	United States
31	Comprehensive Cancer Centers of Nevada, Site #2	Las Vegas	Nevada	United States
32	Comprehensive Cancer Centers of Nevada, Site #3	Las Vegas	Nevada	United States
33	Comprehensive Cancer Centers of Nevada, Site #4	Las Vegas	Nevada	United States
34	New York Hematology Oncology (US Onc)	Albany	New York	United States
35	Memorial Sloan Kettering at Westchester	Harrison	New York	United States
36	Memorial Sloan Kettering Cancer Center	New York	New York	United States
37	Oregon Health & Science University	Portland	Oregon	United States
38	University of Pennsylvania	Philadelphia	Pennsylvania	United States
39	Texas Oncology-Bedford	Bedford	Texas	United States
40	Texas Oncology (US Onc)	Dallas	Texas	United States
41	Texas Oncology	Dallas	Texas	United States
42	Texas Oncology-Denton South	Denton	Texas	United States
43	Texas Oncology-Fort Worth, Site #1	Fort Worth	Texas	United States
44	Texas Oncology-Grapevine	Grapevine	Texas	United States
45	Texas Oncology-Longview Cancer Center	Longview	Texas	United States
46	Texas Oncology-Plano West	Plano	Texas	United States
47	South Texas Accelerated Research Therapeutics, LLC	San Antonio	Texas	United States
48	Texas Oncology-Tyler	Tyler	Texas	United States
49	Texas Oncology-Waco, Site #1	Waco	Texas	United States
50	Texas Oncology-Waco, Site #2	Waco	Texas	United States
51	Haukeland Univerity Hospital	Bergen		Norway
52	Sørlandet Hospital	Kristiansand		Norway	4604
53	Akershus Universitetssykehus HF	Lørenskog		Norway
54	Oslo Univerity Hospital	Oslo		Norway
55	Sykehuset Østfold	Sarpsborg		Norway
56	Hospital Universitari Germans Trias i Pujol	Badalona		Spain
57	Hospital Universitari Vall d'Hebron	Barcelona		Spain
58	Hospital Universitario De Fuenlabrada	Fuenlabrada		Spain
59	Hospital La Paz	Madrid		Spain
60	Hospital Universitario Clinico San Carlos	Madrid		Spain
61	MD Anderson Cancer Center Madrid - España	Madrid		Spain
62	Parc Taulí Sabadell	Sabadell		Spain
63	Hospital Virgen de la Salud	Toledo		Spain
64	Hospital Universitari i Politécnic La Fe.	Valencia		Spain