Olanzapine plus first-line immunotherapy for advanced EGFR-negative non-small cell lung cancer

An Open-label, Two-arm, Multicenter, Phase II Randomized Controlled Trial Assessing the Impact of Olanzapine on the Efficacy of First-line Immunotherapy in Patients With Advanced EGFR Mutation-negative Non-small Cell Lung Cancer (NSCLC).

This trial will test whether adding the antidepressant olanzapine to first-line PD-1/PD-L1 immunotherapy helps people with advanced EGFR-negative non-small cell lung cancer.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 156 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Second Affiliated Hospital of Nanchang University (other)
• Drugs / interventions: chemotherapy, radiation, Immunotherapy
• Locations: 1 site (Nanchang, Jiangxi)
• Trial ID: NCT06554613 on ClinicalTrials.gov

What this trial studies

This is an open-label, randomized, two-arm Phase II trial comparing first-line PD-1/PD-L1 inhibitor therapy with or without olanzapine in patients with advanced EGFR mutation-negative NSCLC. Participants are randomized to receive nivolumab plus olanzapine or nivolumab alone, receive treatment for about two months, and attend clinic visits every two weeks with follow-up visits every six weeks. The primary endpoint is objective response rate (ORR), with secondary endpoints including interval PFS (iPFS), PFS, duration of response, disease control rate, safety, quality of life, and exploratory immune biomarkers. Eligible patients are adults aged 18–75 with stage IV EGFR-negative NSCLC, ECOG 0–2, adequate organ function, and no prior systemic antitumor therapy.

Who should consider this trial

Good fit: Adults (18–75) with stage IV EGFR mutation-negative non-small cell lung cancer who are treatment-naive for systemic therapy, have ECOG 0–2, and meet organ-function requirements are the intended participants.

Not a fit: Patients with EGFR-mutant tumors, prior systemic antitumor treatment, poor organ function, or ECOG performance status above 2 are unlikely to benefit from this trial.

Why it matters

Potential benefit: If successful, adding olanzapine could increase tumor response rates and prolong disease control for patients receiving first-line immunotherapy.

How similar studies have performed: Preclinical studies and limited retrospective reports suggest psychotropic drugs may influence immune responses, but randomized clinical evidence that olanzapine enhances checkpoint inhibitor efficacy is currently limited and largely novel.

Eligibility criteria

Inclusion Criteria:

1. Participants voluntarily enroll in this study and sign an informed consent form, with good compliance and cooperation with follow-up.
2. Age is over 18 years old (including 18 years old) and under 75 years old (including 75 years old).
3. ECOG score: 0-2 points.
4. Expected survival is no less than 3 months.
5. Staged as Stage IV according to the TNM system.
6. Histologically or cytologically confirmed EGFR mutation-negative non-small cell lung cancer.
7. Has not received systemic antitumor treatment, and is intended to receive monotherapy or combined chemotherapy with a PD-1/PD-L1 inhibitor as first-line treatment.
8. Normal major organ function, that is, meeting the following criteria: (1) Hematological examination criteria must be met: Hb≥90 g/L; ANC≥1.5×10\^9/L; PLT≥80×10\^9/L. (2) Biochemical examination must meet the following criteria: TBIL\<1.5×ULN; ALT and AST\<2.5×ULN; serum Cr≤1.25×ULN or endogenous creatinine clearance \> 45 ml/min (Cockcroft-Gault formula).
9. Women of childbearing age must have taken reliable contraceptive measures and have undergone a pregnancy test (serum or urine) within 7 days before enrollment, with a negative result, and are willing to use appropriate methods of contraception during the trial period and for 8 weeks after the last administration of the trial medication. For men, they must agree to use appropriate methods of contraception during the trial period and for 8 weeks after the last administration of the trial medication or have undergone surgical sterilization.

Exclusion Criteria:

1. Have received any of the following treatments:

   1. Previously used any EGFR tyrosine kinase inhibitors;
   2. Previously received any chemotherapy for lung cancer;
   3. Previously received any radiotherapy for lung cancer (except palliative radiotherapy for bone metastases);
   4. Within 4 weeks prior to the first administration of the study drug, the subject had undergone major surgery;
   5. Within 7 days prior to the first administration of the study drug, used strong inhibitors or inducers of CYP3A4.
2. Subjects with concurrent other malignant tumors, except for basal cell carcinoma of the skin and in situ cancer.
3. Subjects with uncontrollable malignant pleural effusion and pericardial effusion.
4. Subjects allergic to contrast agents for CT and MRI or any subjects who cannot tolerate MRI examination.
5. As judged by the investigator, any serious or poorly controlled systemic diseases, such as uncontrolled hypertension, active bleeding diathesis, or active infection.
6. Clinically severe gastrointestinal functional abnormalities that may affect the intake, transport, or absorption of the drug, such as the inability to take oral medication, uncontrollable nausea or vomiting, history of extensive gastrointestinal resection, unresolved recurrent diarrhea, atrophic gastritis, gastric diseases requiring long-term use of proton pump inhibitors, Crohn's disease, ulcerative colitis, etc.
7. Hepatic encephalopathy, hepatorenal syndrome, or liver cirrhosis.
8. Meet any of the following cardiac examination results:

   1. The average of the corrected QT interval (QTcF) obtained from three ECG examinations at rest is \> 470 msec;
   2. Resting ECG suggests conduction or ECG morphological abnormalities (such as complete left bundle branch block, third-degree atrioventricular block, second-degree atrioventricular block, and PR interval \> 250 msec, etc.);
   3. There are any factors that increase the risk of QTc prolongation or arrhythmic events, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or any concurrent medication of unexplained sudden death in direct relatives under the age of 40 or prolonged QT interval;
   4. Left ventricular ejection fraction (LVEF) \< 50%.
9. Insufficient bone marrow reserve or organ function, reaching any of the following laboratory limits:

   1. Absolute neutrophil count \<1.5×10\^9/L;
   2. Platelet count \<100×10\^9/L;
   3. Hemoglobin \<90 g/L (\<9 g/dL);
   4. If there is no definite liver metastasis, alanine aminotransferase \> 3 times the upper limit of normal (ULN); if there is liver metastasis, alanine aminotransferase \> 5×ULN;
   5. If there is no definite liver metastasis, aspartate aminotransferase \>3×ULN; if there is liver metastasis, aspartate aminotransferase \> 5×ULN;
   6. If there is no definite liver metastasis, total bilirubin \> 1.5×ULN; or with Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastasis, total bilirubin \> 3×ULN;
   7. Creatinine \> 1.5×ULN and creatinine clearance \<50 mL/min (calculated by the Cockcroft-Gault formula); creatinine clearance is only required if creatinine \> 1.5×ULN;
   8. Serum albumin (ALB) \<28 g/L.
10. Active fungal, bacterial, and/or viral infections requiring systemic treatment.
11. Female subjects who are pregnant, breastfeeding, or planning to become pregnant during the study period.
12. History of interstitial lung disease, drug-induced interstitial lung disease, history of radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease.
13. Subjects who, in the judgment of the investigator, may have poor compliance with the procedures and requirements of the study, such as subjects with a clear history of neurological or mental disorders, currently suffering from mental disorders, etc.
14. Subjects whom the investigator judges to have any condition that endangers the safety of the subject or interferes with the evaluation of the study.

Where this trial is running

Nanchang, Jiangxi

• The Second Affiliated Hospital of Nanchang University — Nanchang, Jiangxi, China (RECRUITING)

Study contacts

• Study coordinator: Huang Long, Director

Conditions: Non-Small Cell Lung Cancer