Pembrolizumab in Combination With Lenvatinib in Patients With Advanced Cholangiocarcinoma

  • STATUS
    Recruiting
  • End date
    Dec 26, 2025
  • participants needed
    40
  • sponsor
    Shanghai Jiahui International Hospital
Updated on 26 August 2021

Summary

The prognosis for unresectable and metastatic biliary tract cancers (BTCs) including cholangiocarcinoma is poor with first line gemcitabine and cisplatin offering a median overall survival of 11.7 months. There is no standard second- or third-line therapy for advanced BTC, and this represents an unmet medical need for novel therapies. The immune system plays a critical role in the development of cholangiocarcinoma (CCA) and chronic inflammation is a common underlying risk factor for CCA. Vascular endothelial growth factor (VEGF) signaling in CCA may lead to an immune suppression via inadequate tumor antigen presentation and an impaired T cell-mediated immune response directed against tumor antigens. Lenvatinib significantly decreased the population of immunosuppressive tumor-associated macrophages and increased interferon--producing cluster of differentiation 8+ (CD8+) T cells. Addition of programmed cell death protein 1 (PD-1)/programmed death-ligand (PD-L1) inhibitors helps reverse VEGF-mediated immune suppression, restore T cell function, and promote T cell tumor infiltration. The combination of lenvatinib and pembrolizumab has demonstrated promising activity with manageable adverse events in various solid tumor types.

The investigators will assess the efficacy and safety of the combination of pembrolizumab and lenvatinib in patients with advanced CCA who failed standard therapy in this phase II study.

Description

Title: A Single Arm Phase II Study of Pembrolizumab in combination with Lenvatinib in Patients with Advanced Cholangiocarcinoma after Progression on Standard Systemic Therapy Study Description: The prognosis for unresectable and metastatic biliary tract cancers (BTCs) including cholangiocarcinoma is poor with first line gemcitabine and cisplatin offering a median overall survival of 11.7 months. There is no standard second- or third-line therapy for advanced BTC, and this represents an unmet medical need for novel therapies. The immune system plays a critical role in the development of cholangiocarcinoma (CCA) and chronic inflammation is a common underlying risk factor for CCA. VEGF signaling in CCA may lead to an immune suppression via inadequate tumor antigen presentation and an impaired T cell-mediated immune response directed against tumor antigens. Lenvatinib significantly decreased the population of immunosuppressive tumor-associated macrophages and increased interferon--producing CD8+ T cells. Addition of PD-1/PD-L1 inhibitors helps reverse VEGF-mediated immune suppression, restore T cell function, and promote T cell tumor infiltration. The combination of lenvatinib and pembrolizumab has demonstrated promising activity with manageable adverse events in various solid tumor types.

The investigators will assess the efficacy and safety of the combination of pembrolizumab and lenvatinib in patients with advanced CCA who failed standard therapy in this phase II study.

Objectives and Endpoints:

Primary Objective: Evaluate the objective response rate (ORR) (RECIST1.1) of lenvatinib in combination with pembrolizumab in patients with advanced CCA after progression on standard systemic therapies Secondary Objective: Evaluate the safety and tolerability of lenvatinib+pembrolizumab in this population; Determine the duration of response (DOR), progression free survival (PFS), and overall survival (OS); Determine the ORR, PFS and OS of subgroups stratified by molecular signatures (tumor mutation burden, PD-L1 expression, microsatellite instability (MSI) status, isocitrate dehydrogenase (IDH) or FGFR mutation/fusion status) in a pre-planned post-hoc analysis; Define molecular correlates of response, including circulating biomarkers and tumor tissue biomarkers Study Population: The study will enroll 40 patients who have unresectable or metastatic, histologically-confirmed advanced CCA. Both male and female patients age of 18 years or older who have failed standard systemic therapy for advanced CCA with measurable disease, adequate bone marrow reserve and hepatic/renal function, and ECOG performance status (PS) 0-1 could be eligible to participate in the study after completing the study enrollment screening tests and procedures.

Phase: II Description of Sites/Facilities Enrolling Participants: The study will be conducted at Jiahui International Cancer Center, Shanghai Jiahui International Hospital, in collaboration with Zhongshan Hospital.

Study treatment/Intervention: Each cycle is defined as 21 days treatment of Pembrolizumab in combination with Lenvatinib. Treatment will be administered on an outpatient basis:

Pembrolizumab 200mg IV day 1 of every 21 day-cycles; Lenvatinib 20mg PO once daily for 21-day cycles Study Duration: 24-36 months Participant Duration: up to 24 months

Details
Condition Advanced Cholangiocarcinoma
Treatment Lenvatinib Mesylate, Pembrolizumab Injection [Keytruda]
Clinical Study IdentifierNCT04550624
SponsorShanghai Jiahui International Hospital
Last Modified on26 August 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Patients must meet the following criteria in order to be eligible to participate in the study
Unresectable or metastatic, histologically-confirmed advanced CCA
Failed standard systemic therapy for advanced CCA due to progression of disease or toxicity
Measurable disease
Prior chemoembolization, radiofrequency ablation, or radiation to the liver is allowed as long as the patient has measurable disease outside the chemoembolization or radiation area or measurable progression at the site of chemoembolization or radiation
ECOG Performance status 1
Life expectancy > 3 months
Adequate renal function as defined by Cr 1.5 upper limit of normal (ULN) or glomerular filtration rate (GFR) 60 mL/min/1.73 m2
Adequate hepatic function as defined by bilirubin 2.5 x ULN and alanine transaminase (ALT) and aspartate aminotransferase (AST) 5x ULN
Adequate bone marrow reserve as evidenced by ANC > 1500/mcl, Plts >75,000/mcl, Hgb 9.0g/dl
Prothrombin time / Partial thromboplastin time (PT/PTT) <1.5x ULN
Urine Protein: Creatinine ratio of <1, if protein is > 2+ on urinalysis
Age 18 years
Participants with past or ongoing hepatitis C virus (HCV) infection are eligible for the study. Treated participants must have completed their treatment at least 1 month prior to starting study intervention. Untreated or incompletely treated HCV participants may initiate anti-viral therapy for HCV if liver function remains stable for at least 3 months on study intervention
Participants with controlled hepatitis B are eligible for the study, as long as they meet the following criteria
Participants with chronic hepatitis B virus (HBV) infection, defined as HBsAg
positive and/or detectable HBV DNA, must be given antiviral therapy for HBV
for at least 4 weeks prior to the first dose of study intervention and HBV
viral load must be less than 100 IU/ml. prior to the first dose of study
treatment. Participants on active HBV therapy with viral loads under 100
IU/ml. should stay on the same therapy throughout study intervention
Antiviral therapy after completion of study intervention should follow local
guidelines
\. Participants with clinically resolved HBV infection, defined as HBsAg
negative and anti-hepatitis B core antigen (HBc) positive, and who have an
undetectable HBV viral load at screening should be checked every 6 weeks for
HBV viral load and treated for HBV if viral load is over 100 IU/ml. Antiviral
therapy after completion of study intervention should follow local guidelines

Exclusion Criteria

Patients who exhibit any of the following conditions at screening will not be eligible to be enrolled to the study
Prior treatment with other VEGF-R directed therapies or checkpoint inhibitors
Periampullary cancer or gallbladder cancer
Major surgery or radiation within the 4 weeks prior to enrollment
Uncontrolled hypertension defined by systolic blood pressure (SBP)>150 or diastolic blood pressure (DBP)>90 despite titration of anti-hypertensive medications
Active, known or suspected autoimmune disease
Congestive heart failure or symptomatic coronary artery disease within 3 months prior to enrollment
Cerebrovascular accident within prior 6 months
Clinically significant hemorrhage, bleeding event, or thromboembolic disease within six months
History of bowel perforation
History of (non-infectious) pneumonitis that required steroids or currently has pneumonitis
Known history of HIV infection
Severely impaired lung function or history of interstitial lung disease
Concurrent malignancy (other than adequately treated non-melanoma skin cancer, superficial transitional cell carcinoma of the bladder, and cervical CIS) diagnosed within the past 5 years or any currently active malignancy
Positive serum pregnancy test within 72 hours of first dosing of study treatment
History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
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