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)
|
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT03797326 |
|
Recruitment Status :
Active, not recruiting
First Posted : January 9, 2019
Last Update Posted : August 22, 2022
|
Sponsor:
Merck Sharp & Dohme LLC
Collaborator:
Eisai Inc.
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC
- Study Details
- Tabular View
- No Results Posted
- Disclaimer
- How to Read a Study Record
Brief Summary:
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), biliary tract cancers (BTC), or pancreatic cancer.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Advanced Solid Tumors Triple Negative Breast Cancer Ovarian Cancer Gastric Cancer Colorectal Cancer Glioblastoma Biliary Tract Cancers Pancreatic Cancer | Biological: Pembrolizumab Drug: Lenvatinib | Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 590 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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) |
| Actual Study Start Date : | February 12, 2019 |
| Estimated Primary Completion Date : | December 22, 2023 |
| Estimated Study Completion Date : | December 22, 2023 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Breast cancer
| Arm | Intervention/treatment |
|---|---|
|
Experimental: Pembrolizumab + Lenvatinib (Arm 1)
Participants 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).
|
Biological: Pembrolizumab
Administered as an IV infusion on Day 1 Q3W.
Other Names:
Drug: Lenvatinib Administered orally once a day during each 21-day cycle.
Other Names:
|
|
Experimental: Lenvatinib Monotherapy (Arm 2)
Participants receive lenvatinib 24 mg via oral capsule QD, to be administered until progressive disease or unacceptable toxicity (up to at least 2 years).
|
Drug: Lenvatinib
Administered orally once a day during each 21-day cycle.
Other Names:
|
Primary Outcome Measures :
- 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 approximately 72 months ]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 by the investigator based on RANO criteria (CR: disappearance of all target lesions, PR: sum of products of diameters [SPD] decreased by ≥ 50% from baseline value). For participants in the pancreatic cancer cohort, response will be assessed by blinded independent central review (BICR).
- ORR per RECIST 1.1 or RANO (GBM) by Blinded Independent Central Review (BICR) in Expanded Cohorts (Combined with Initial Cohorts) [ Time Frame: Up to approximately 72 months ]ORR is defined as the percentage of participants who have a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD) as assessed by BICR 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: SPD decreased by ≥ 50% from baseline value).
- Percentage of Participants Receiving Pembrolizumab Plus Lenvatinib who Experience an Adverse Event (AE) [ Time Frame: Up to approximately 72 months ]An AE is any untoward medical occurrence in a clinical study participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. The percentage of participants receiving pembrolizumab plus lenvatinib who experience at least one AE will be reported.
- Percentage of Participants Receiving Pembrolizumab Plus Lenvatinib who Discontinue Study Treatment Due to an AE [ Time Frame: Up to approximately 72 months ]An AE is any untoward medical occurrence in a clinical study participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. The percentage of participants receiving pembrolizumab plus lenvatinib who discontinue study treatment due to an AE will be reported.
- Percentage of Participants Receiving Lenvatinib Monotherapy who Experience an AE [ Time Frame: Up to approximately 72 months ]An AE is any untoward medical occurrence in a clinical study participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. The percentage of participants receiving lenvatinib monotherapy who experience at least one AE will be reported.
- Percentage of Participants Receiving Lenvatinib Monotherapy who Discontinue Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 72 months ]An AE is any untoward medical occurrence in a clinical study participant that is temporally associated with the use of study treatment, whether or not considered related to the study treatment. The percentage of participants receiving lenvatinib monotherapy who discontinue study treatment due to an AE will be reported.
Secondary Outcome Measures :
- Disease Control Rate (DCR) per RECIST 1.1 by Investigator Assessment in Initial Cohorts [ Time Frame: Up to approximately 72 months ]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. DCR will be assessed by the investigator for all initial cohorts except for the pancreatic cancer cohort, will be assessed by BICR.
- Duration of Response (DOR) per RECIST 1.1 or RANO (GBM) by Investigator Assessment in Initial Cohorts [ Time Frame: Up to approximately 72 months ]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. DOR will be assessed by the investigator for all initial cohorts except for the pancreatic cancer cohort, will be assessed by BICR.
- Progression Free Survival (PFS) per RECIST 1.1 or RANO (GBM) by Investigator Assessment in Initial Cohorts [ Time Frame: Up to approximately 72 months ]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. PFS will be assessed by the investigator for all initial cohorts except for the pancreatic cancer cohort, will be assessed by BICR.
- Overall Survival (OS) in Initial Cohorts [ Time Frame: Up to approximately 72 months ]OS is defined as the time from the date of study treatment to the date of death due to any cause.
- DCR per RECIST 1.1 by BICR in Expanded Cohorts (Combined with Initial Cohorts) [ Time Frame: Up to approximately 72 months ]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.
- DOR per RECIST 1.1 or RANO (GBM) by BICR in Expanded Cohorts (Combined with Initial Cohorts) [ Time Frame: Up to approximately 72 months ]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.
- PFS per RECIST 1.1 or RANO (GBM) by BICR in Expanded Cohorts (Combined with Initial Cohorts) [ Time Frame: Up to approximately 72 months ]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.
- OS in Expanded Cohorts (Combined with Initial Cohorts) [ Time Frame: Up to approximately 72 months ]OS is defined as the time from the date of study treatment to the date of death due to any cause.
- ORR per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm [ Time Frame: Up to approximately 72 months ]ORR is defined as the percentage of participants who have a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD) as assessed by BICR 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.
- DCR per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm [ Time Frame: Up to approximately 72 months ]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.
- DOR per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm [ Time Frame: Up to approximately 72 months ]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.
- PFS per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm [ Time Frame: Up to approximately 72 months ]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.
- OS in Lenvatinib Monotherapy Arm [ Time Frame: Up to approximately 72 months ]OS is defined as the time from the date of study treatment to the date of death due to any cause.
- 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. ]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.
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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, GBM, BTC (intrahepatic, extrahepatic cholangiocarcinoma and gall bladder cancer; excludes Ampulla of Vater), Pancreatic Cancer
- 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 a PD-L1 evaluable 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 for at least 7 days after the last dose of lenvatinib, or refrain from heterosexual intercourse 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 post pembrolizumab, or 30 days post lenvatinib, whichever occurs last
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 3 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)
- Has locally determined results for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 tumor analyses
For Ovarian Cancer Participants:
- Has primary ovarian cancer and has received 3 prior lines of therapy.
For Gastric Cancer Participants:
- Has received 2 prior lines of therapy. Note: Gastric cancer will include participants with both gastric and gastroesophageal junction (GEJ) adenocarcinoma. Participants with squamous cell carcinoma histology are not eligible
For Colorectal Cancer Participants:
- Has received 2 prior lines of therapy
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
- Has locally determined result for O^6-methylguanine-DNA methyltransferase (MGMT) analysis
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
For Pancreatic Cancer Participants:
- Has pathologically (histologically or cytologically) confirmed pancreatic ductal adenocarcinoma that is metastatic at enrollment
- Has received one or 2 prior lines of therapy
- Has received prior therapy with at least 1 (platinum-containing regimen or gemcitabine-containing regimen) but no more than 2 prior systemic therapies for unresectable or metastatic pancreatic cancer
Exclusion Criteria:
- Has gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib
- Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to enrollment (applies to all cohorts except the ovarian cancer cohort)
- Has radiographic evidence of encasement or invasion of a major blood vessel or of intratumoral cavitation. Participants with portal vein invasion (Vp4), inferior vena cava, or cardiac involvement based on imaging in the BTC cohort are not eligible for enrollment
- Has 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.
- Has a serious nonhealing wound, ulcer or bone fracture
- Has had major surgery within 3 weeks prior to first dose of study interventions
- Has biologic response modifiers therapy (e.g. granulocyte colony-stimulating factor) within 4 weeks before study entry
- Has preexisting ≥Grade 3 gastrointestinal (GI) or non-gastrointestinal fistula
- 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 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
- Has known intolerance to lenvatinib (and/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 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
- Has received Optune® TTFields within 2 weeks of study intervention
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03797326
Locations
Show 88 study locations
Sponsors and Collaborators
Merck Sharp & Dohme LLC
Eisai Inc.
Investigators
| Study Director: | Medical Director | Merck Sharp & Dohme LLC |
Additional Information:
| Responsible Party: | Merck Sharp & Dohme LLC |
| ClinicalTrials.gov Identifier: | NCT03797326 |
| Other Study ID Numbers: |
7902-005 MK-7902-005 ( Other Identifier: Merck Protocol Number ) E7080-G000-224 ( Other Identifier: Eisai Protocol Number ) LEAP-005 ( Other Identifier: Merck ) 2018-003747-37 ( EudraCT Number ) |
| First Posted: | January 9, 2019 Key Record Dates |
| Last Update Posted: | August 22, 2022 |
| Last Verified: | August 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf |
| URL: | http://engagezone.msd.com/ds_documentation.php |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Merck Sharp & Dohme LLC:
|
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) |
Additional relevant MeSH terms:
|
Glioblastoma Triple Negative Breast Neoplasms Biliary Tract Neoplasms Neoplasms Digestive System Neoplasms Neoplasms by Site Digestive System Diseases Astrocytoma Glioma Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms, Glandular and Epithelial |
Neoplasms, Nerve Tissue Breast Neoplasms Breast Diseases Skin Diseases Biliary Tract Diseases Pembrolizumab Lenvatinib Antineoplastic Agents, Immunological Antineoplastic Agents Immune Checkpoint Inhibitors Molecular Mechanisms of Pharmacological Action Protein Kinase Inhibitors Enzyme Inhibitors |