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This observational study evaluates whether vortioxetine - an antidepressant medication with cognitive-enhancing properties - can reduce the neurological and cognitive side effects associated with lorlatinib treatment in patients with non-small cell lung cancer (NSCLC) harboring ALK or ROS1 gene rearrangements.
Lorlatinib is a highly effective third-generation tyrosine kinase inhibitor, but it causes neuropsychological adverse events (NAEs) in approximately 42% of patients, including cognitive impairment, mood changes, and speech disturbances. Vortioxetine has demonstrated cognitive improvement in depressed patients and in preclinical models of androgen deprivation therapy-induced cognitive impairment.
Twenty-four adult patients with ALK/ROS1-positive NSCLC receiving lorlatinib as standard care and prescribed vortioxetine (10-20 mg/day) for NAE management will be enrolled. Comprehensive neuropsychological assessments and quality-of-life questionnaires will be conducted at baseline, week 6, week 12, and month 6 to document changes in cognitive function, depressive symptoms, and quality of life.
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| Measure | Description | Time Frame |
|---|---|---|
| Psychomotor Speed | Digit Symbol Substitution Test (DSST). The DSST measures psychomotor speed and sustained attention. Participants match symbols to digits within a fixed time limit. Score range: 0 to 90 (number of correct substitutions in 90 seconds); higher scores indicate better cognitive performance. Within-subject change from baseline analyzed using ANCOVA. | Baseline, Week 6, Week 12 |
| Processing Speed and Visual Attention | Trail Making Test Part A (TMT-A). The TMT-A measures processing speed and visual scanning. The outcome is time to completion in seconds; lower scores indicate better performance. Clinically meaningful change assessed using the Reliable Change Index (RCI). | Baseline, Week 6, Week 12 |
| Executive Function and Cognitive Flexibility | Trail Making Test Part B (TMT-B). The TMT-B measures executive function and set-shifting ability. The outcome is time to completion in seconds; lower scores indicate better performance. Clinically meaningful change assessed using the Reliable Change Index (RCI). | Baseline, Week 6, Week 12 |
| Selective and Sustained Attention | D2-R Test of Attention. The D2-R Test of Attention measures selective and sustained visual attention. The primary metric is the Total Concentration Performance score (TN-E), calculated as total items processed minus errors. Score range: 0 to 299; higher scores indicate better attentional performance. | Baseline, Week 6, Week 12 |
| Working Memory | Wechsler Adult Intelligence Scale IV (WAIS-IV), Working Memory Index. The WAIS-IV Working Memory Index is a standardized composite score derived from Digit Span and Arithmetic subtests. Score range: 45 to 155 (mean 100, SD 15); higher scores indicate better working memory capacity. Change from baseline analyzed using linear mixed-effects models (LMM). |
| Measure | Description | Time Frame |
|---|---|---|
| Depressive Symptoms | Montgomery-Asberg Depression Rating Scale (MADRS). The MADRS is a clinician-administered scale measuring severity of depressive symptoms across 10 items. Score range: 0 to 60; higher scores indicate greater depression severity. Response defined as >= 50% reduction from baseline; remission defined as score < 10. MCID: >= 50% reduction. | Baseline, Week 6, Week 12, Month 6 |
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Inclusion Criteria:
Exclusion Criteria:
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Adults (>= 18 years) with histologically confirmed advanced (stage IIIB/IV) lung adenocarcinoma harboring ALK or ROS1 fusions, currently receiving lorlatinib as standard care, and initiating vortioxetine for NAE management.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Felipe Canro, MD | Contact | +57 310 8593083 | felipe.canro@gmail.com |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Centro de Tratamiento e Investigación sobre Cáncer Luis Carlos Sarmiento Angulo CTIC | Recruiting | Bogotá | 110131 | Colombia |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31139875 | Background | Sharp AM, Lertphinyowong S, Yee SS, Paredes D, Gelfond J, Johnson-Pais TL, Leach RJ, Liss M, Risinger AL, Sullivan AC, Thompson IM, Morilak DA. Vortioxetine reverses medial prefrontal cortex-mediated cognitive deficits in male rats induced by castration as a model of androgen deprivation therapy for prostate cancer. Psychopharmacology (Berl). 2019 Nov;236(11):3183-3195. doi: 10.1007/s00213-019-05274-4. Epub 2019 May 28. | |
| 37788996 |
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| Baseline, Week 6, Week 12 |
| Processing Speed | Wechsler Adult Intelligence Scale IV (WAIS-IV), Processing Speed Index. The WAIS-IV Processing Speed Index is a standardized composite score derived from Coding and Symbol Search subtests. Score range: 45 to 155 (mean 100, SD 15); higher scores indicate better processing speed. Change from baseline analyzed using LMM. | Baseline, Week 6, Week 12 |
| Verbal Learning and Memory | California Verbal Learning Test (CVLT). The California Verbal Learning Test measures verbal learning and episodic memory across five immediate recall trials plus short- and long-delay recall. Primary metric: Total Learning Trials 1-5 (score range: 0 to 80); higher scores indicate better verbal memory performance. | Baseline, Week 6, Week 12 |
| Language | Phonemic Verbal Fluency Task. Phonemic verbal fluency is measured by the total number of words beginning with a specified letter generated in 60 seconds. There is no fixed maximum; higher scores indicate better phonemic language production and frontal-executive function. The average of three letter trials (F, A, S) will be reported. | Baseline, Week 6, Week 12 |
| Language | Semantic Verbal Fluency Task. Semantic verbal fluency is measured by the total number of words from a specified semantic category generated in 60 seconds. There is no fixed maximum; higher scores indicate better semantic retrieval and language functioning. | Baseline, Week 6, Week 12 |
| Frontal Lobe and Executive Function | INECO Frontal Screening (IFS). The INECO Frontal Screening (IFS) evaluates frontal lobe functions including motor programming, verbal fluency inhibitory control, working memory, abstraction capacity, and reflex suppression. Score range: 0 to 30; higher scores indicate better executive and frontal lobe functioning. | Baseline, Week 6, Week 12 |
| Subjective Cognitive Complaints | Perceived Deficits Questionnaire (PDQ), Attention/Concentration Subscore. The PDQ Attention/Concentration subscore measures self-reported cognitive difficulties in attention and concentration. Subscore range: 0 to 20; higher scores indicate greater perceived cognitive impairment. Analyzed using mixed models for repeated measures (MMRM). | Baseline, Week 6, Week 12 |
| Subjective Cognitive Complaints | Perceived Deficits Questionnaire (PDQ), Planning/Organization Subscore. The PDQ Planning/Organization subscore measures self-reported difficulties in planning and organizational ability. Subscore range: 0 to 20; higher scores indicate greater perceived impairment. Analyzed using MMRM. | Baseline, Week 6, Week 12 |
| Clinical Global Impression of Improvement (CGI-I) | The Clinical Global Impressions-Improvement scale (CGI-I) is a clinician-rated measure of overall clinical improvement relative to baseline. Score range: 1 (very much improved) to 7 (very much worse); lower scores indicate greater improvement. Response is defined as a score of 1 or 2. Analyzed using MMRM. | Baseline, Week 6, Week 12 |
| Depressive Symptoms | Patient Health Questionnaire (PHQ-9). The PHQ-9 is a 9-item self-report scale for depression screening and severity assessment. Score range: 0 to 27; higher scores indicate greater depressive symptom burden. Severity categories: minimal (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), severe (20-27). MCID: >= 5-point reduction. | Baseline, Week 6, Week 12 |
| Health-Related Quality of Life | 36-Item Short Form Health Survey (SF-36), Physical Component Summary (PCS). The SF-36 Physical Component Summary (PCS) is a norm-based composite score derived from four SF-36 subscales (physical functioning, role-physical, bodily pain, general health). Score range: 0 to 100; higher scores indicate better physical health status. MCID: >= 4 points. | Baseline, Month 1, 2, 3, 6, 12 |
| Health-Related Quality of Life | 36-Item Short Form Health Survey (SF-36), Mental Component Summary (MCS). The SF-36 Mental Component Summary (MCS) is a norm-based composite score derived from four SF-36 subscales (vitality, social functioning, role-emotional, mental health). Score range: 0 to 100; higher scores indicate better mental health status. MCID: >= 4 points. | Baseline, Month 1, 2, 3, 6, 12 |
| Life Satisfaction | Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). The Q-LES-Q-SF measures overall enjoyment and satisfaction with daily life across 14 items rated on a 5-point Likert scale (1 = very poor to 5 = very good). Total score range: 14 to 70; higher scores indicate greater life satisfaction. Items 15 and 16 are scored separately and not included in the total. MCID: >= 9 points. | Baseline, Month 1, 2, 3, 6, 12 |
| Health Utility | EuroQol 5-Dimension Questionnaire (EQ-5D), Utility Index. The EQ-5D utility index is derived from five health dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) using the Spanish value set. Score range: -0.654 to 1.0; higher scores indicate better health utility (1.0 = full health, 0 = death). MCID: >= 0.1. | Baseline, Month 1, Month 2, Month 3, Month 6, Month 12 |
| Self-Rated Health | EuroQol Visual Analogue Scale (EQ-VAS). The EQ-VAS is a vertical visual analogue scale for overall self-rated health. Score range: 0 to 100; higher scores indicate better self-rated health (100 = best imaginable health state). MCID: >= 7 points. | Baseline, Month 1, Month 2, Month 3, Month 6, Month 12 |
| Functional Capacity | University of California San Diego Performance-Based Skills Assessment (UPSA), Composite Score. The UPSA composite score combines the UPSA-VIM and UPSA-Brief to measure real-world functional capacity across domains including finance and communication. Score range: 0 to 100; higher scores indicate better functional performance. Analyzed using ANCOVA. | Baseline, Week 6, Week 12 |
| Work Limitations | Work Limitations Questionnaire (WLQ). The WLQ measures the degree to which health problems interfere with job performance across four scales: time management, physical demands, mental-interpersonal demands, and output demands. Each scale is scored 0 to 100; higher scores indicate greater work limitation. An overall WLQ productivity loss score will also be reported. | Baseline, Week 6, Week 12, Month 6 |
| Cognitive and Physical Functioning | Cognitive and Physical Functioning Questionnaire (CPFQ). The CPFQ is a 7-item self-report instrument measuring cognitive and physical energy symptoms relevant to depression and related conditions. Score range: 7 to 42; higher scores indicate greater cognitive and physical impairment. Analyzed only in participants with a baseline score > 25. | Baseline, Week 6, Week 12 |
| Tumor Response to Lorlatinib | Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Tumor response is assessed by contrast-enhanced CT scan per RECIST version 1.1 criteria. Response is classified as: Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD). Best overall response will be documented for each participant. | Month 2, Month 6, Month 12 |
| Adverse Events | Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. All adverse events (AEs) will be graded by type, severity (Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening; Grade 5: death), and causality attribution (unrelated / unlikely / possible / probable / definitely related to vortioxetine). Predefined study suspension thresholds: > 25% Grade 3, > 10% Grade 4, or > 3% Grade 5 AEs attributable to vortioxetine. | All scheduled visits, from baseline through 30 days post-last visit |
| Background |
| Vaiana AM, Chen Y, Gelfond J, Johnson-Pais TL, Leach RJ, Ramamurthy C, Thompson IM, Morilak DA. Effects of vortioxetine on hippocampal-related cognitive impairment induced in rats by androgen deprivation as a model of prostate cancer treatment. Transl Psychiatry. 2023 Oct 3;13(1):307. doi: 10.1038/s41398-023-02600-5. |
| 29189941 | Background | Chen G, Hojer AM, Areberg J, Nomikos G. Vortioxetine: Clinical Pharmacokinetics and Drug Interactions. Clin Pharmacokinet. 2018 Jun;57(6):673-686. doi: 10.1007/s40262-017-0612-7. |
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| ID | Term |
|---|---|
| D002277 | Carcinoma |
| D002289 | Carcinoma, Non-Small-Cell Lung |
| D000077192 | Adenocarcinoma of Lung |
| D060825 | Cognitive Dysfunction |
| D003863 | Depression |
| ID | Term |
|---|---|
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D002283 | Carcinoma, Bronchogenic |
| D001984 | Bronchial Neoplasms |
| D008175 | Lung Neoplasms |
| D012142 | Respiratory Tract Neoplasms |
| D013899 | Thoracic Neoplasms |
| D009371 | Neoplasms by Site |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D000230 | Adenocarcinoma |
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D001526 | Behavioral Symptoms |
| D001519 | Behavior |
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