Pembrolizumab in Combination With Lenvatinib in Patients With Advanced Cholangiocarcinoma

• Status: Recruiting
• Trial end date: 2025-12-01
• Target enrollment: 0
• Participant gender: All

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-γ-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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Shanghai Jiahui International Hospital
• Collaborator: Shanghai Zhongshan Hospital
• Treatments: Lenvatinib; Pembrolizumab

Criteria

Inclusion Criteria:

• Patients must meet the following criteria in order to be eligible to participate in the study:

1. Unresectable or metastatic, histologically-confirmed advanced CCA

2. Failed standard systemic therapy for advanced CCA due to progression of disease or toxicity

3. Measurable disease

4. 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

5. ECOG Performance status ≤ 1

6. Life expectancy > 3 months

7. 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

8. Adequate hepatic function as defined by bilirubin ≤ 2.5 x ULN and alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 5x ULN

9. Adequate bone marrow reserve as evidenced by ANC > 1500/mcl, Plts >75,000/mcl, Hgb ≥ 9.0g/dl

10. Prothrombin time / Partial thromboplastin time (PT/PTT) <1.5x ULN

11. Urine Protein: Creatinine ratio of <1, if protein is > 2+ on urinalysis

12. Age ≥ 18 years

13. 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

14. 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.

15. 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:

1. Prior treatment with other VEGF-R directed therapies or checkpoint inhibitors

2. Periampullary cancer or gallbladder cancer

3. Major surgery or radiation within the 4 weeks prior to enrollment

4. Uncontrolled hypertension defined by systolic blood pressure (SBP)>150 or diastolic blood pressure (DBP)>90 despite titration of anti-hypertensive medications

5. Active, known or suspected autoimmune disease

6. Congestive heart failure or symptomatic coronary artery disease within 3 months prior to enrollment

7. Cerebrovascular accident within prior 6 months

8. Clinically significant hemorrhage, bleeding event, or thromboembolic disease within six months

9. History of bowel perforation

10. History of (non-infectious) pneumonitis that required steroids or currently has pneumonitis

11. Known history of HIV infection

12. Severely impaired lung function or history of interstitial lung disease

13. 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

14. Positive serum pregnancy test within 72 hours of first dosing of study treatment

15. 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