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Efficacy and Safety of Pembrolizumab (MK-3475) Plus Lenvatinib (E7080/MK-7902) in Previously Treated Participants With Select Solid Tumors (MK-7902-005/E7080-G000-224/LEAP-005)

NCT03797326

Description:

The purpose of this study is to determine the safety and efficacy of combination therapy with pembrolizumab (MK-3475) and lenvatinib (E7080/MK-7902) in participants with triple negative breast cancer (TNBC), ovarian cancer, gastric cancer, colorectal cancer (CRC), glioblastoma (GBM), or biliary tract cancers (BTC). Participants will be enrolled into initial tumor-specific cohorts which will be expanded if adequate efficacy is determined.

Related Conditions:
  • Breast Carcinoma
  • Colorectal Carcinoma
  • Extrahepatic Cholangiocarcinoma
  • Gallbladder Carcinoma
  • Gastric Carcinoma
  • Glioblastoma
  • Intrahepatic Cholangiocarcinoma
  • Ovarian Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Efficacy and Safety of Pembrolizumab (MK-3475) Plus Lenvatinib (E7080/MK-7902) in Previously Treated Participants With Select Solid Tumors (MK-7902-005/E7080-G000-224/LEAP-005)
  • Official Title: A Multicenter, Open-label Phase 2 Study of Lenvatinib (E7080/MK-7902) Plus Pembrolizumab (MK-3475) in Previously Treated Subjects With Selected Solid Tumors (LEAP-005)

Clinical Trial IDs

  • ORG STUDY ID: 7902-005
  • SECONDARY ID: 2018-003747-37
  • SECONDARY ID: MK-7902-005
  • SECONDARY ID: E7080-G000-224
  • SECONDARY ID: LEAP-005
  • NCT ID: NCT03797326

Conditions

  • Advanced Solid Tumors
  • Triple Negative Breast Cancer
  • Ovarian Cancer
  • Gastric Cancer
  • Colorectal Cancer
  • Glioblastoma
  • Biliary Tract Cancers

Interventions

DrugSynonymsArms
PembrolizumabMK-3475, Keytruda®Pembrolizumab + Lenvatinib
LenvatinibMK-7902, E7080, LENVIMAPembrolizumab + Lenvatinib

Purpose

The purpose of this study is to determine the safety and efficacy of combination therapy with pembrolizumab (MK-3475) and lenvatinib (E7080/MK-7902) in participants with triple negative breast cancer (TNBC), ovarian cancer, gastric cancer, colorectal cancer (CRC), glioblastoma (GBM), or biliary tract cancers (BTC). Participants will be enrolled into initial tumor-specific cohorts which will be expanded if adequate efficacy is determined.

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + LenvatinibExperimentalParticipants receive pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) plus lenvatinib 20 mg via oral capsule once a day (QD). Pembrolizumab will be administered for up to 35 cycles (up to 2 years). Lenvatinib will be administered until progressive disease or unacceptable toxicity (up to at least 2 years).
  • Pembrolizumab
  • Lenvatinib

Eligibility Criteria

        Inclusion Criteria:

          -  Has a histologically or cytologically-documented, advanced (metastatic and/or
             unresectable) solid tumor that is incurable and for which prior standard systemic
             therapy has failed in one of the following cohorts: TNBC, Ovarian Cancer, Gastric
             Cancer, Colorectal Cancer: non-microsatellite instability-High/proficient mismatch
             repair (MSI-H/pMMR) tumor, GBM, BTC: intrahepatic, extrahepatic cholangiocarcinoma and
             gall bladder cancer; excludes Ampulla of Vater

          -  Must have progressed on or since the last treatment

          -  Has measurable disease per RECIST 1.1 (RANO for the GBM cohort) as assessed by the
             local site investigator/radiology and confirmed by BICR

          -  Has provided archival tumor tissue sample or newly obtained core or excisional biopsy
             of a tumor lesion not previously irradiated

          -  Male participants agree to use approved contraception during the treatment period and
             for at least 120 days after the last dose of study treatment, and refrain from
             donating sperm during this period

          -  Female participants are not pregnant or breastfeeding, and are not a woman of
             childbearing potential (WOCBP), OR are a WOCBP that agrees to use contraception during
             the treatment period (or 14 days prior to the initiation of study treatment for oral
             contraception) and for at least 120 days after the last dose of study treatment

          -  Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 7
             days of study treatment initiation

          -  Has adequate organ function

        For Triple Negative Breast Cancer Participants:

          -  Has received one or 2 prior lines of therapy

          -  Has Lactate Dehydrogenase (LDH) <2.0 x Upper Limit of Normal (ULN)

        For Ovarian Cancer Participants:

        - Has received 3 prior lines of therapy

        For Gastric Cancer Participants:

        - Has received 2 prior lines of therapy

        For Colorectal Cancer Participants:

          -  Has received 2 prior lines of therapy

          -  Has a locally determined non-MSI-H/pMMR tumor

        For GBM Participants:

          -  Has failed initial systemic therapy for newly diagnosed GBM

          -  Have the following time periods elapsed before the projected start of scheduled study
             treatment: 1) at least 3 weeks from prior surgical resection, 2) at least 1 week from
             stereotactic biopsy, 3) at least 6 months from completion of prior radiotherapy, 4) at
             least 4 weeks (or 5 half-lives, whichever is shorter) from any investigational agent,
             5) at least 4 weeks from cytotoxic therapy, 6) at least 6 weeks from antibodies, 7) at
             least 4 weeks (or 5 half-lives, whichever is shorter) from other antitumor therapies
             and 1 week for cancer vaccines

          -  Be neurologically stable (e.g. without a progression of neurologic symptoms or
             requiring escalating doses of systemic steroid therapy within last 2 weeks) and
             clinically stable

          -  Has histologically confirmed World Health Organization (WHO) Grade IV GBM

        For Biliary Tract Cancer Participants:

          -  Has received 1 prior line of therapy

          -  Child-Pugh Score, Class A: well-compensated disease. Child-Pugh Score of 5-6

        Exclusion Criteria:

          -  Has presence of gastrointestinal condition including malabsorption that might affect
             the absorption of lenvatinib

          -  Radiographic evidence of major blood vessel invasion/infiltration

          -  Clinical significant hemoptysis or tumor bleeding within 2 weeks prior to the first
             dose of study treatment

          -  Has significant cardiovascular impairment within 12 months of the first dose of study
             treatment: such as history of congestive heart failure greater than New York Heart
             Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular
             accident (CVA), or cardiac arrhythmia associated with hemodynamic instability

          -  Has a history of arterial thromboembolism within 12 months of start of study treatment

          -  Has a known additional malignancy that is progressing or has required active treatment
             within the past 3 years.

          -  Serious nonhealing wound, ulcer or bone fracture

          -  Biologic response modifiers (e.g. granulocyte colony-stimulating factor) within 4
             weeks before study entry.

          -  Has received prior therapy with lenvatinib, an anti-PD-1, anti-PD-L1, or anti PD-L2
             agent or with an agent directed to another stimulatory or co-inhibitory T-cell
             receptor (e.g. cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], Tumor necrosis
             factor receptor superfamily, member 4 [OX 40], tumor necrosis factor receptor
             superfamily member 9 [CD137])

          -  Has received prior systemic anti-cancer therapy including investigational agents
             within 4 weeks or 5 times the half-life time, whichever is shorter prior to study
             treatment start

          -  If participant received major surgery, they must have recovered adequately from the
             toxicity and/or complications from the intervention prior to starting study treatment

          -  Has received prior radiotherapy within 2 weeks of start of study treatment.
             Participants must have recovered from all radiation-related toxicities, not require
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
             for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system
             (CNS) disease

          -  Has received a live vaccine within 30 days prior to the first dose of study treatment

          -  Known intolerance to study treatment (or any of the excipients)

          -  Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study treatment

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior the first dose of study treatment

          -  Has known active CNS metastases and/or carcinomatous meningitis

          -  Has tumors involving the brain stem

          -  Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients

          -  Has an active autoimmune disease that has required systemic treatment in past 2 years

          -  Has a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis

          -  Has an active infection requiring systemic therapy

          -  Has a known history of human immunodeficiency virus (HIV) infection

          -  Has a known history of hepatitis B or known active hepatitis C virus infection

          -  Has a known history of active tuberculosis (TB; Bacillus tuberculosis)

          -  Is pregnant or breastfeeding or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 120 days
             after the last dose of study treatment

          -  Has had an allogenic tissue/solid organ transplant (large organ transplants, stem-cell
             transplant requiring chronic immunosuppressant therapy necessary to prevent graft
             rejection)

        For Colorectal Cancer Participants:

        - Has MSI-H/dMMR disease

        For GBM Participants:

          -  Has carcinomatous meningitis

          -  Has recurrent tumor greater than 6 cm in maximum diameter

          -  Has tumor primarily localized to the brainstem or spinal cord

          -  Has presence of multifocal tumor, diffuse leptomeningeal or extracranial disease

          -  Has evidence of intratumoral or peritumoral hemorrhage on baseline magnetic resonance
             imaging (MRI) scan other than those that are grade ≤ 1 and either post-operative or
             stable on at least 2 consecutive MRI scans
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) or Response Assessment in Neuro-Oncology (RANO) Criteria for Glioblastoma (GBM) by Investigator Assessment in Initial Cohorts
Time Frame:Up to 18 months
Safety Issue:
Description:ORR is defined as the percentage of participants who have a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters [SOD] of target lesions, taking as reference the baseline SOD) as assessed by the investigator per RECIST 1.1, which is modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. For participants with GBM, response will be assessed based on RANO criteria (CR: disappearance of all target lesions, PR: sum of products of diameters [SPD] decreased by ≥ 50% from baseline value).

Secondary Outcome Measures

Measure:Disease Control Rate (DCR) per RECIST 1.1 by Investigator Assessment in Initial Cohorts
Time Frame:Up to 18 months
Safety Issue:
Description:DCR is defined as the percentage of participants who have a best overall response of CR, PR, or stable disease (SD) per RECIST 1.1. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and will be assessed by the investigator for this outcome measure.
Measure:Duration of Response (DOR) per RECIST 1.1 or RANO (GBM) by Investigator Assessment in Initial Cohorts
Time Frame:Up to 18 months
Safety Issue:
Description:DOR is determined by disease assessment and is defined as the time from the earliest date of qualifying response until earliest date of disease progression or death from any cause, whichever comes first. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and will be assessed by the investigator for this outcome measure.
Measure:Progression Free Survival (PFS) per RECIST 1.1 or RANO (GBM) by Investigator Assessment in Initial Cohorts
Time Frame:Up to 18 months
Safety Issue:
Description:PFS is defined as the time from date of study treatment to the first documented disease progression based on RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ (or RANO for GBM participants), or death due to any cause, whichever occurs first, as assessed by the investigator.
Measure:Overall Survival (OS) in Initial Cohorts
Time Frame:Up to 18 months
Safety Issue:
Description:OS is defined as the time from the date of study treatment to the date of death due to any cause.
Measure:DCR per RECIST 1.1 by BICR in Expanded Cohorts (Combined with Initial Cohorts)
Time Frame:Up to 36 months
Safety Issue:
Description:DCR is defined as the percentage of participants who have a best overall response of CR, PR, or (SD) per RECIST 1.1. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and will be assessed by BICR for this outcome measure.
Measure:DOR per RECIST 1.1 or RANO (GBM) by BICR in Expanded Cohorts (Combined with Initial Cohorts)
Time Frame:Up to 36 months
Safety Issue:
Description:DOR is determined by disease assessment and is defined as the time from the earliest date of qualifying response until earliest date of disease progression or death from any cause, whichever comes first. RECIST 1.1 has been modified for this study to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and will be assessed by BICR for this outcome measure.
Measure:PFS per RECIST 1.1 or RANO (GBM) by BICR in Expanded Cohorts (Combined with Initial Cohorts)
Time Frame:Up to 36 months
Safety Issue:
Description:PFS is defined as the time from date of study treatment to the first documented disease progression based on RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ (or RANO for GBM participants), or death due to any cause, whichever occurs first, as assessed by BICR.
Measure:OS in Expanded Cohorts (Combined with Initial Cohorts)
Time Frame:Up to 36 months
Safety Issue:
Description:OS is defined as the time from the date of study treatment to the date of death due to any cause.
Measure:Plasma Concentration of Lenvatinib
Time Frame:Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose and 2-12 hours post-dose; Cycle 2 Day 1: pre-dose, 0.5-4 hours, and 6-10 hours post-dose (up to approximately 23 days). Each cycle is 21 days.
Safety Issue:
Description:Blood samples will be obtained on Day 1 and Day 15 of Cycle 1 (21-day cycle) and Day 1 of Cycle 2 (21-day cycle) for pharmacokinetic (PK) analysis to determine the plasma concentration of lenvatinib.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

  • programmed cell death 1 (PD-1, PD1)
  • programmed cell death ligand 1 (PD-L1, PDL1)
  • programmed cell death ligand 2 (PD-L2, PDL2)
  • tyrosine kinase inhibitor (TKI)
  • multiple TKI
  • Vascular Endothelial Growth Factor Receptor (VEFG)
  • Fibroblast Growth Factor (FGF)
  • Platelet-Derived Growth Factor (PDGF)

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