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

NCT02501096 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: E7080-A001-1112017-000300-26
• Study Type: interventional
• Target: 357
• Locations: 3 countries
• Sites: 64

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, melanoma or leiomyosarcoma). Phase 2 (Expansion) will evaluate the safety and efficacy of the combination in 7 cohorts at the MTD from Phase 1b (lenvatinib 20 mg/day orally + pembrolizumab 200 mg Q3W, IV).

Conditions

Tumors

Keywords

Lenvatinib; Lenvima; E7080; Phase 1b/2; Pembrolizumab; Keytruda; Solid tumors

Outcome Measures

Primary Outcomes (3)

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

  MTD was confirmed if no more than 3 participants experience dose-limiting toxicities(DLTs)during first 3 weeks (Cycle 1) of treatment.If MTD was not confirmed at dose level,then enrollment was proceeded to next lower dose level.Sponsor and investigators reviewed all participants' safety;clinical data to jointly determine RP2D of combination of treatment.DLT may be any of following: hematological/nonhematological toxicities considered to be at least possibly related to Lenvatinib/pembrolizumab occurring during Cycle 1;Failure to administer greater than or equal to (\>=) 75 percent (%) of planned dosage of lenvatinib as result of treatment-related toxicity during Cycle 1;Who discontinue treatment due to treatment-related toxicity.Greater than 2 week delay in starting Cycle 2 because of treatment-related toxicity,even if toxicity does not meet DLT criteria.Toxicity was evaluated as per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03(NCI CTCAE v 4.03).

  Cycle 1 (21 days)

• Phase 1b: Number of Participants With Dose Limiting Toxicities (DLTs) of Lenvatinib

  A DLT was defined as any of the following: any of the hematological or nonhematological toxicities considered to be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1. Failure to administer \>=75% of the planned dosage of lenvatinib as a result of treatment-related toxicity during Cycle 1. Participants who discontinue treatment due to treatment-related toxicity. Greater than 2 week delay in starting Cycle 2 because of a treatment-related toxicity, even if the toxicity does not meet DLT criteria. Toxicity was evaluated as per NCI CTCAE v 4.03.

  Cycle 1 (21 days)

• Objective Response Rate (ORR) Based on Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) Version 1.1 at Week 24

  ORR was defined as the percentage of participants whose best overall response (BOR) was immune related complete response (irCR) or immune related partial response (irPR) based on investigator assessment according to irRECIST version 1.1. irCR was defined as disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to less than (\<) 10 millimeter (mm). irPR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters.

  Week 24

Secondary Outcomes (10)

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

  From date of first dose up to 30 days after the last dose of study drugs (Up to 74 months)

• Objective Response Rate (ORR) Based on irRECIST Version 1.1

  From date of first dose of study drug administration until immune related (irPD), development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor (up to 73 months)

• Progression-free Survival (PFS) Based on irRECIST Version 1.1

  From date of first dose of study drug administration to date of irPD or date of death, whichever occurred first (up to 73 months)

• Overall Survival (OS)

  From the first dose until death from any cause, up to 73 months

• Disease Control Rate (DCR) Based on irRECIST Version 1.1

  From first dose of the study drug until irPD, development of unacceptable toxicity, participant choice, withdrawal of consent, lost to follow up or discontinuation of this study by the sponsor (up to 73 months)

Study Arms (1)

Lenvatinib + Pembrolizumab

EXPERIMENTAL

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, melanoma or leiomyosarcoma.

Drug: Lenvatinib; Drug: Pembrolizumab

Interventions

Lenvatinib DRUG

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

Also known as: Lenvima, E7080

Lenvatinib + Pembrolizumab

Pembrolizumab DRUG

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

Also known as: Keytruda, MK-3475

Lenvatinib + Pembrolizumab

Eligibility Criteria

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

You may qualify if:

• 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 1.5\*ULN (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 1.5\*ULN
• 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 3\*ULN (in the case of liver metastases less than or equal to 5\*ULN). 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Eisai Inc.: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (64)

Alaska Clinical Research Center

Anchorage, Alaska, United States

Location

Arizona Oncology Associates

Oro Valley, Arizona, United States

Location

Arizona Oncology Associates, PC - HOPE, Site #1

Tucson, Arizona, United States

Location

Arizona Oncology Associates, PC - HOPE, Site #2

Tucson, Arizona, United States

Location

Arizona Oncology Associates, PC - HOPE, Site #3

Tucson, Arizona, United States

Location

Rocky Mountain Cancer Centers

Aurora, Colorado, United States

Location

Rocky Mountain Cancer Centers

Boulder, Colorado, United States

Location

Rocky Mountain Cancer Centers

Colorado Springs, Colorado, United States

Location

Rocky Mountain Cancer Centers, Site #1

Denver, Colorado, United States

Location

Rocky Mountain Cancer Centers, Site #2

Denver, Colorado, United States

Location

Rocky Mountain Cancer Centers

Lakewood, Colorado, United States

Location

Rocky Mountain Cancer Centers

Littleton, Colorado, United States

Location

Rocky Mountain Cancer Centers

Lone Tree, Colorado, United States

Location

Rocky Mountain Cancer Centers

Longmont, Colorado, United States

Location

Rocky Mountain Cancer Centers

Parker, Colorado, United States

Location

Rocky Mountain Cancer Centers

Pueblo, Colorado, United States

Location

Rocky Mountain Cancer Centers

Thornton, Colorado, United States

Location

Baptist Health Medical Group Oncology, LLC, Site #1

Miami, Florida, United States

Location

Baptist Health Medical Group Oncology, LLC, Site #2

Miami, Florida, United States

Location

Baptist Health Medical Group Oncology, LLC, Site #3

Miami, Florida, United States

Location

Boca Raton Clinical Research Medical Center

Plantation, Florida, United States

Location

Piedmont Cancer Institue

Atlanta, Georgia, United States

Location

The University of Chicago

Chicago, Illinois, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Location

Mass General Hospital

Boston, Massachusetts, United States

Location

University of Minnesota, Masonic Cancer Center

Minneapolis, Minnesota, United States

Location

Comprehensive Cancer Centers of Nevada, Site #1

Henderson, Nevada, United States

Location

Comprehensive Cancer Centers of Nevada, Site #2

Henderson, Nevada, United States

Location

Comprehensive Cancer Centers of Nevada, Site #3

Henderson, Nevada, United States

Location

Comprehensive Cancer Centers of Nevada, Site #1

Las Vegas, Nevada, United States

Location

Comprehensive Cancer Centers of Nevada, Site #2

Las Vegas, Nevada, United States

Location

Comprehensive Cancer Centers of Nevada, Site #3

Las Vegas, Nevada, United States

Location

Comprehensive Cancer Centers of Nevada, Site #4

Las Vegas, Nevada, United States

Location

New York Hematology Oncology (US Onc)

Albany, New York, United States

Location

Memorial Sloan Kettering at Westchester

Harrison, New York, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Location

Oregon Health & Science University

Portland, Oregon, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Location

Texas Oncology-Bedford

Bedford, Texas, United States

Location

Texas Oncology (US Onc)

Dallas, Texas, United States

Location

Texas Oncology

Dallas, Texas, United States

Location

Texas Oncology-Denton South

Denton, Texas, United States

Location

Texas Oncology-Fort Worth, Site #1

Fort Worth, Texas, United States

Location

Texas Oncology-Grapevine

Grapevine, Texas, United States

Location

Texas Oncology-Longview Cancer Center

Longview, Texas, United States

Location

Texas Oncology-Plano West

Plano, Texas, United States

Location

South Texas Accelerated Research Therapeutics, LLC

San Antonio, Texas, United States

Location

Texas Oncology-Tyler

Tyler, Texas, United States

Location

Texas Oncology-Waco, Site #1

Waco, Texas, United States

Location

Texas Oncology-Waco, Site #2

Waco, Texas, United States

Location

Haukeland Univerity Hospital

Bergen, Norway

Location

Sørlandet Hospital

Kristiansand, 4604, Norway

Location

Akershus Universitetssykehus HF

Lørenskog, Norway

Location

Oslo Univerity Hospital

Oslo, Norway

Location

Sykehuset Østfold

Sarpsborg, Norway

Location

Hospital Universitari Germans Trias i Pujol

Badalona, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Location

Hospital Universitario De Fuenlabrada

Fuenlabrada, Spain

Location

Hospital La Paz

Madrid, Spain

Location

Hospital Universitario Clinico San Carlos

Madrid, Spain

Location

MD Anderson Cancer Center Madrid - España

Madrid, Spain

Location

Parc Taulí Sabadell

Sabadell, Spain

Location

Hospital Virgen de la Salud

Toledo, Spain

Location

Hospital Universitari i Politécnic La Fe.

Valencia, Spain

Location

Related Publications (7)

• Makker V, Taylor MH, Aghajanian C, Cohn AL, Brose MS, Simone CD, Cao ZA, Suttner L, Loboda A, Cristescu R, Jelinic P, Orlowski R, Dutta L, Matsui J, Dutcus CE, Minoshima Y, Messing MJ. Evaluation of potential biomarkers for lenvatinib plus pembrolizumab among patients with advanced endometrial cancer: results from Study 111/KEYNOTE-146. J Immunother Cancer. 2024 Jan 19;12(1):e007929. doi: 10.1136/jitc-2023-007929.

  PMID: 38242717 DERIVED

• Makker V, Aghajanian C, Cohn AL, Romeo M, Bratos R, Brose MS, Messing M, Dutta L, Dutcus CE, Huang J, Schmidt EV, Orlowski R, Taylor MH. A Phase Ib/II Study of Lenvatinib and Pembrolizumab in Advanced Endometrial Carcinoma (Study 111/KEYNOTE-146): Long-Term Efficacy and Safety Update. J Clin Oncol. 2023 Feb 10;41(5):974-979. doi: 10.1200/JCO.22.01021. Epub 2023 Jan 6.

  PMID: 36608305 DERIVED

• Lee CH, Shah AY, Rasco D, Rao A, Taylor MH, Di Simone C, Hsieh JJ, Pinto A, Shaffer DR, Girones Sarrio R, Cohn AL, Vogelzang NJ, Bilen MA, Gunnestad Ribe S, Goksel M, Tennoe OK, Richards D, Sweis RF, Courtright J, Heinrich D, Jain S, Wu J, Schmidt EV, Perini RF, Kubiak P, Okpara CE, Smith AD, Motzer RJ. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021 Jul;22(7):946-958. doi: 10.1016/S1470-2045(21)00241-2. Epub 2021 Jun 15.

  PMID: 34143969 DERIVED

• Lee CH, DiNatale RG, Chowell D, Krishna C, Makarov V, Valero C, Vuong L, Lee M, Weiss K, Hoen D, Morris L, Reznik E, Murray S, Kotecha R, Voss MH, Carlo MI, Feldman D, Sachdev P, Adachi Y, Minoshima Y, Matsui J, Funahashi Y, Nomoto K, Hakimi AA, Motzer RJ, Chan TA. High Response Rate and Durability Driven by HLA Genetic Diversity in Patients with Kidney Cancer Treated with Lenvatinib and Pembrolizumab. Mol Cancer Res. 2021 Sep;19(9):1510-1521. doi: 10.1158/1541-7786.MCR-21-0053. Epub 2021 May 26.

  PMID: 34039647 DERIVED

• Makker V, Taylor MH, Aghajanian C, Oaknin A, Mier J, Cohn AL, Romeo M, Bratos R, Brose MS, DiSimone C, Messing M, Stepan DE, Dutcus CE, Wu J, Schmidt EV, Orlowski R, Sachdev P, Shumaker R, Casado Herraez A. Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer. J Clin Oncol. 2020 Sep 10;38(26):2981-2992. doi: 10.1200/JCO.19.02627. Epub 2020 Mar 13.

  PMID: 32167863 DERIVED

• Taylor MH, Lee CH, Makker V, Rasco D, Dutcus CE, Wu J, Stepan DE, Shumaker RC, Motzer RJ. Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors. J Clin Oncol. 2020 Apr 10;38(11):1154-1163. doi: 10.1200/JCO.19.01598. Epub 2020 Jan 21.

  PMID: 31961766 DERIVED

• Makker V, Rasco D, Vogelzang NJ, Brose MS, Cohn AL, Mier J, Di Simone C, Hyman DM, Stepan DE, Dutcus CE, Schmidt EV, Guo M, Sachdev P, Shumaker R, Aghajanian C, Taylor M. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019 May;20(5):711-718. doi: 10.1016/S1470-2045(19)30020-8. Epub 2019 Mar 25.

  PMID: 30922731 DERIVED

MeSH Terms

Conditions

Neoplasms

Interventions

lenvatinib; pembrolizumab

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: Yes

Study Design

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

Study Record Dates

• First Submitted: July 15, 2015
• First Posted: July 17, 2015
• Study Start: July 22, 2015
• Primary Completion: August 18, 2020
• Study Completion: July 11, 2022
• Last Updated: July 20, 2023
• Results First Posted: July 20, 2023

Record last verified: 2022-06

Locations

US (50); ES (9); NO (5)