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)

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Advanced Solid Tumors, Triple Negative Breast Cancer, Ovarian Cancer, Gastric Cancer, Colorectal Cancer, Glioblastoma, Biliary Tract Cancers, Pancreatic Cancer

Intervention / Treatment
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* Biological: Pembrolizumab
* Drug: Lenvatinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab + Lenvatinib (Arm 1)<br>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<br>* Administered as an IV infusion on Day 1 Q3W.<br>* Other names: Keytruda®;Drug: Lenvatinib<br>* Administered orally once a day during each 21-day cycle.<br>* Other names: LENVIMA™;|
| Experimental: Lenvatinib Monotherapy (Arm 2)<br>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<br>* Administered orally once a day during each 21-day cycle.<br>* Other names: LENVIMA™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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). | Up to approximately 72 months | 
| ORR per RECIST 1.1 or RANO (GBM) by Blinded Independent Central Review (BICR) in Expanded Cohorts (Combined with Initial Cohorts) | 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). | Up to approximately 72 months | 
| Percentage of Participants Receiving Pembrolizumab Plus Lenvatinib who Experience an Adverse Event (AE) | 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. | Up to approximately 72 months | 
| Percentage of Participants Receiving Pembrolizumab Plus Lenvatinib who Discontinue Study Treatment Due to an AE | 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. | Up to approximately 72 months | 
| Percentage of Participants Receiving Lenvatinib Monotherapy who Experience an AE | 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. | Up to approximately 72 months | 
| Percentage of Participants Receiving Lenvatinib Monotherapy who Discontinue Study Treatment Due to an Adverse Event (AE) | 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. | Up to approximately 72 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) per RECIST 1.1 by Investigator Assessment in Initial Cohorts | 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. | Up to approximately 72 months | 
| Duration of Response (DOR) per RECIST 1.1 or RANO (GBM) by Investigator Assessment in Initial Cohorts | 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. | Up to approximately 72 months | 
| Progression Free Survival (PFS) per RECIST 1.1 or RANO (GBM) by Investigator Assessment in Initial Cohorts | 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. | Up to approximately 72 months | 
| Overall Survival (OS) in Initial Cohorts | OS is defined as the time from the date of study treatment to the date of death due to any cause. | Up to approximately 72 months | 
| DCR per RECIST 1.1 by BICR in Expanded Cohorts (Combined with Initial Cohorts) | 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. | Up to approximately 72 months | 
| DOR per RECIST 1.1 or RANO (GBM) by BICR in Expanded Cohorts (Combined with Initial Cohorts) | 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. | Up to approximately 72 months | 
| PFS per RECIST 1.1 or RANO (GBM) by BICR in Expanded Cohorts (Combined with Initial Cohorts) | 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. | Up to approximately 72 months | 
| OS in Expanded Cohorts (Combined with Initial Cohorts) | OS is defined as the time from the date of study treatment to the date of death due to any cause. | Up to approximately 72 months | 
| ORR per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm | 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. | Up to approximately 72 months | 
| DCR per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm | 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. | Up to approximately 72 months | 
| DOR per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm | 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. | Up to approximately 72 months | 
| PFS per RECIST 1.1 by BICR in Lenvatinib Monotherapy Arm | 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. | Up to approximately 72 months | 
| OS in Lenvatinib Monotherapy Arm | OS is defined as the time from the date of study treatment to the date of death due to any cause. | Up to approximately 72 months | 
| Plasma Concentration of Lenvatinib | 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. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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)