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.
Study Type
OBSERVATIONAL
Enrollment
24
Centro de Tratamiento e Investigación sobre Cáncer Luis Carlos Sarmiento Angulo CTIC
Bogotá, Colombia
RECRUITINGPsychomotor 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.
Time frame: 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).
Time frame: 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).
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: Baseline, Week 6, Week 12
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.
Time frame: Baseline, Week 6, Week 12, Month 6
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: All scheduled visits, from baseline through 30 days post-last visit