SSRI Antidepressant Fluoxetine Improving Immunotherapy Efficacy in Advanced Hepatobiliary Malignancy Patients With Depression and Anxiety

NCT ID: NCT07174947

Last Updated: 2025-09-16

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 240 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-10-01
• Study Completion Date: 2027-12-01

Brief Summary

Advanced liver and gallbladder malignancies (including liver cancer, cholangiocarcinoma and gallbladder cancer) are a type of disease that is difficult to treat, and most patients have a short survival period. In recent years, immunotherapy (such as PD-1/PD-L1 inhibitors) has brought new hope to these patients, but still only a small number of patients can benefit.

Research has found that approximately 40% of patients with liver and gallbladder tumors have symptoms of depression and anxiety, which not only affect their quality of life but may also reduce the therapeutic effect by influencing immune function. Fluoxetine is a commonly used antidepressant. The latest research shows that in addition to improving mood, it may also enhance the anti-tumor effect of immunotherapy. This study aims to explore whether fluoxetine combined with immunotherapy can better control tumors than immunotherapy alone, prolong the survival period of patients, and at the same time improve the depressive and anxious symptoms and quality of life of patients.

Conditions

Hepatobiliary Malignancy; Fluoxetine; Anxiety Disorders; Depression Disorders

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Experimental Group

1\. Standard treatment plan For patients with hepatocellular carcinoma, the first-line treatment regimen containing PD-1 inhibitors /PD-L1 inhibitors is adopted: 1) Toripalimab + bevacizumab 2) Tislelizumab 3) Nivolumab + ipilimumab For patients with cholangiocarcinoma, the combination of PD-1 inhibitors /PD-L1 inhibitors and gemcitabine + cisplatin/oxaliplatin (such as pembrolizumab +GEM -CDDP or durvalumab +GEM -CDDP) is adopted. 2. Fluoxetine: Maintain at 20mg per day, orally, until disease progression or intolerance. 3. The use of antiemetic, analgesic and other symptomatic treatment drugs is allowed, and all concurrent medication situations should be recorded.

Group Type: EXPERIMENTAL

Fluoxetine (drug)

Intervention Type: DRUG

Fluoxetine: Maintain at 20mg per day, orally, until disease progression or intolerance

Control Group

1. Standard treatment plan

For patients with hepatocellular carcinoma, the first-line treatment regimen containing PD-1 inhibitors /PD-L1 inhibitors is adopted:

1. Toripalimab + bevacizumab

2. Tislelizumab

3. Nivolumab + ipilimumab For patients with cholangiocarcinoma, the combination of PD-1 inhibitors /PD-L1 inhibitors and gemcitabine + cisplatin/oxaliplatin (such as pembrolizumab +GEM -CDDP or durvalumab +GEM -CDDP) is adopted.

2. Placebo: Take 1 placebo tablet per day for maintenance, orally.

3. The use of antiemetic, analgesic and other symptomatic treatment drugs is allowed, and all concurrent medication situations should be recorded.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo: 1 placebo tablet per day for maintenance, orally.

Interventions

Fluoxetine (drug)

Fluoxetine: Maintain at 20mg per day, orally, until disease progression or intolerance

Intervention Type: DRUG

Placebo

Placebo: 1 placebo tablet per day for maintenance, orally.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age: 18 to 80 years old, both male and female are acceptable.
• The histopathological/cytological diagnosis is hepatocellular carcinoma or cholangiocarcinoma. Hepatocellular carcinoma can be diagnosed by imaging.
• Patients with metastatic advanced or locally advanced liver and gallbladder malignancies;
• No treatment has been received and a first-line treatment regimen including PD-1 inhibitors /PD-L1 inhibitors is planned to be carried out;
• Patients with a PHQ-9 score of ≥10 or a GAD-7 score of ≥8, that is, those with positive screening for depression or anxiety;
• At least one lesion measurable by CT or MRI (with a maximum diameter of ≥0.5cm);
• ECOG: 0-2;
• Child-Pugh score ≤7 points;
• The expected survival period is ≥12 weeks.
• Baseline blood cell count tests and blood biochemistry must meet the following standards:1) White blood cell count ≥3.0×10^9/L; Hemoglobin ≥90 g/L;2) Absolute neutrophil count ≥1.5×10^9/L;3) Platelet count ≥100×10^9/L;4) Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of the normal upper limit (ULN);5) Total bilirubin ≤ twice ULN;6) Serum creatinine ≤ 1.5 times ULN; Albumin ≥30 g/L;
• The subjects voluntarily joined this study, signed the informed consent form, had good compliance and cooperated with the follow-up.

Exclusion Criteria

• Those with uncorrectable coagulation dysfunction and a distinct bleeding tendency;
• Patients who currently have unstable or active ulcers or gastrointestinal bleeding;
• Severe functional insufficiency of vital organs, such as severe cardiopulmonary insufficiency, etc;
• Patients with hepatic encephalopathy or intractable ascites requiring treatment;
• A history of mental disorders such as bipolar disorder, schizophrenia, and active suicidal ideation;
• Patients with active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (active is defined as a viral load > 20,000 IU/mL), or those who are positive for HBV or HCV and refuse to receive standardized antiviral treatment;
• Unable to swallow oral medication;
• Patients allergic to fluoxetine;
• Currently using drugs that may have serious interactions with fluoxetine;
• The researchers assessed that the patient was unable or unwilling to comply with the requirements of the research protocol.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

First Affiliated Hospital of Wenzhou Medical University

OTHER

Sponsor Role: lead

Responsible Party

Gang Chen, MD

M.D., Ph.D.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Other Identifiers

SSRI

Identifier Type: -

Identifier Source: org_study_id