Advanced ALK/ROS1-positive NSCLC, ALK-positive Non-small Cell Lung Cancer (NSCLC), Carcinoma, Non-Small-Cell Lung (NSCLC), Cognitive Dysfunction, Depression, Lung Adenocarcinoma
Conditions
Brief summary
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.
Interventions
None listed
Sponsors
Centro de Tratamiento e Investigación sobre Cáncer, Luis Carlos Sarmiento Angulo
Study design
Observational model
CASE_ONLY
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed diagnosis of ALK/ROS1-positive non-small cell lung cancer (NSCLC), stage IIIB/IV. * Currently receiving lorlatinib as part of the standard therapeutic regimen. * Documented neurocognitive adverse events (NAEs) attributable to lorlatinib. * Age \>= 18 years. * ECOG performance status 0-2. * Ability to understand and sign informed consent. * Expected survival \>= 6 months. * Planned initiation of vortioxetine as part of standard care. * Ability to complete neuropsychological tests and questionnaires in Spanish.
Exclusion criteria
* Prior diagnosis of major cognitive impairment unrelated to cancer treatment. * Current use of another antidepressant that cannot be discontinued. * Uncontrolled major psychiatric disorder. * History of uncontrolled epilepsy or recent seizures. * Severe hepatic or renal impairment. * Known hypersensitivity to vortioxetine. * Participation in another clinical trial within the past 30 days. * Inability to provide informed consent. * Life expectancy \< 3 months. * Contraindications to vortioxetine (e.g., concomitant MAOI use). * Prior vortioxetine use. * Severe psychiatric disorders or significant cognitive impairment unrelated to lorlatinib.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Psychomotor Speed | Baseline, Week 6, Week 12 | 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. |
| Processing Speed and Visual Attention | Baseline, Week 6, Week 12 | 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). |
| Executive Function and Cognitive Flexibility | Baseline, Week 6, Week 12 | 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). |
| Selective and Sustained Attention | Baseline, Week 6, Week 12 | 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. |
| Working Memory | Baseline, Week 6, Week 12 | 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). |
| Processing Speed | Baseline, Week 6, Week 12 | 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. |
| Verbal Learning and Memory | Baseline, Week 6, Week 12 | 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. |
| Language | Baseline, Week 6, Week 12 | 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. |
| Frontal Lobe and Executive Function | Baseline, Week 6, Week 12 | 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. |
| Subjective Cognitive Complaints | Baseline, Week 6, Week 12 | 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). |
| Clinical Global Impression of Improvement (CGI-I) | Baseline, Week 6, Week 12 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Depressive Symptoms | Baseline, Week 6, Week 12, Month 6 | 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. |
| Health-Related Quality of Life | Baseline, Month 1, 2, 3, 6, 12 | 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. |
| Life Satisfaction | Baseline, Month 1, 2, 3, 6, 12 | 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. |
| Health Utility | Baseline, Month 1, Month 2, Month 3, Month 6, Month 12 | 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. |
| Self-Rated Health | Baseline, Month 1, Month 2, Month 3, Month 6, Month 12 | 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. |
| Functional Capacity | Baseline, Week 6, Week 12 | 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. |
| Work Limitations | Baseline, Week 6, Week 12, Month 6 | 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. |
| Cognitive and Physical Functioning | Baseline, Week 6, Week 12 | 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. |
| Tumor Response to Lorlatinib | Month 2, Month 6, Month 12 | 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. |
| Adverse Events | All scheduled visits, from baseline through 30 days post-last visit | 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. |
Countries
Colombia
Contacts
CONTACTFelipe Canro, MD
Outcome results
None listed