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

NCT07174947 | Recruiting Phase 2 DMC

• 1 other identifier: SSRI
• Study Type: interventional
• Target: 240
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR) by mRECIST (%)

  Proportion of participants achieving complete response (CR) or partial response (PR) based on mRECIST criteria, measured on contrast-enhanced CT/MRI at 4-12 weeks after treatment initiation.

  at 4-12 weeks after treatment initiation

Secondary Outcomes (4)

• Overall Survival (OS) (months)

  5 years

• Progression-Free Survival (PFS) (months)

  5 years

• status of anxiety and depression

  5 years

• Quality of Life Score (EORTC QLQ-C30, 0-100 scale)

  5 years

Study Arms (2)

Experimental Group

EXPERIMENTAL

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.

Drug: Fluoxetine (drug)

Control Group

PLACEBO COMPARATOR

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.

Drug: Placebo

Interventions

Fluoxetine (drug) DRUG

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

Experimental Group

Placebo DRUG

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

Control Group

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• First Affiliated Hospital of Wenzhou Medical University: lead

Study Sites (1)

First Affiliated Hospital of Wenzhou Medical University

Wenzhou, Zhejiang, 325000, China

RECRUITING

MeSH Terms

Conditions

Anxiety Disorders

Interventions

Fluoxetine; Pharmaceutical Preparations

Condition Hierarchy (Ancestors)

Mental Disorders

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: M.D., Ph.D.

Study Record Dates

• First Submitted: September 8, 2025
• First Posted: September 16, 2025
• Study Start: October 1, 2025
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: March 24, 2026

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: The individual participant data (IPD) that underlie the results reported in this article will be made available beginning 6 months after publication and ending 36 months after publication.
• Access Criteria: Data will be shared with researchers who provide a methodologically sound proposal for use in achieving the aims of a specified research project. Proposals should be directed to corresponding author's email. To gain access, data requesters will need to sign a data access agreement.

Locations

CN (1)