| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-small cell lung cancer |
| cáncer de pulmón no microcítico |
|
| E.1.1.1 | Medical condition in easily understood language |
| lung cancer |
| cáncer de pulmón |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The main aim of this trial is to assess the progression-free survival rate at 12 months (PFSR12) to lorlatinib in ALK positive advanced NSCLC patients, who progressed on second generation ALKTKI with the presence of ALK resistance mutations on blood (liquid biopsies) by Independent Central Review (ICR) assessment per RECIST v1.1 |
| Evaluar la tasa de supervivencia sin progresión a los 12 meses (TSSP12) con lorlatinib en pacientes con CPNM avanzado positivo para ALK, que progresaron con inhibidores de la tirosina cinasa (tyrosine kinase inhibitor, TKI) de ALK de segunda generación con la presencia de mutaciones de resistencia de ALK en sangre (biopsias líquidas) en base a la evaluación de la revisión central independiente (RCI) según RECIST v1.1. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate:
• Activity as measured by ORR, Central nervous system response rate (CNS ORR), Duration of the response (DOR), PFS, OS
• Toxicity of lorlatinib in patients previously treated with 2nd generation ALK TKI
• Patient reported outcomes (PRO) of global health-related quality of life (HRQOL), functioning and the impact of lorlatinib on disease/treatment-related symptoms of lung cancer. |
Evaluar:
• La actividad medida por la tasa de respuesta global (TRG), la tasa de respuesta del sistema nervioso central (TRG del SNC), la duración de la respuesta (DR), la supervivencia sin progresión (SSP) y la supervivencia general (SG)
• La toxicidad de lorlatinib en pacientes tratados previamente con TKI de ALK de segunda generación
• Los resultados notificados por el paciente (RNP) de la calidad de vida relacionada con la salud (CdVRS) global, el funcionamiento y el impacto del lorlatinib sobre los síntomas relacionados con la enfermedad/el tratamiento del cáncer de pulmón. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Emergence of ALK and non ALK resistance mutation during response to second generation ALK TKI in blood |
| Aparición de mutaciones de resistencia de ALK y no ALK en sangre durante el tratamiento con inhibidores de tirosina kinasa de ALK de segunda generación |
|
| E.3 | Principal inclusion criteria |
• Age ≥ 18 years old
• Histologically or cytologically confirmed diagnosis of NSCLC with ALK rearrangement, assessed by FISH assay or by Immunohistochemistry approved by FDA
• Stage IIIB (not eligible for local therapy) or stage IV (according to UICC TNM staging v8.0)
• WHO performance status of 0-2
• Previous treatment with at least one 2nd-generation ALK inhibitor. The 2nd-generation ALK TKI (ceritinib, alectinib, brigatinib) should be the latest therapy.
• Progressive disease during treatment with 2nd-generation ALK inhibitor prior to the administration of lorlatinib
• Measurable disease according to RECIST version 1.1 by computed tomography or magnetic resonance imaging (MRI) of Chest/Abdomen/Pelvis and brain MRI performed within 28 days prior to study enrolment
Note: At least one measurable extracranial lesion is required.
• Collection of blood sample for cohort allocation.
• Treated and/or untreated brain or leptomeningeal metastases will be allowed if asymptomatic and/or controlled (stable dose of steroids 7 days before the beginning of lorlatinib treatment)
• Adequate bone marrow and organ function defined as following:
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L;
• Platelets ≥ 100 x 109/L;
• Hemoglobin ≥ 9 g/dL;
• Serum total amylase ≤ 1.5 ULN;
• Serum lipase ≤1.5 ULN;
• Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance > 30 mL/min as calculated using the MDRD formula for subject with serum creatinine levels > 1.5x institutional ULN;
• Total serum bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 x ULN; for patients with Gilbert's disease total bilirubin may be > 1.5 x ULN, however direct bilirubin must be normal;
• Aspartate Aminotransferase (SGOT) and Alanine Aminotransferase (SGPT) ≤ 2.5 x ULN (≤5.0 x ULN if there is liver metastases involvement);
• Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 3 days prior to enrolment.
• Women of childbearing potential must use a highly effective non-hormonal method of contraception during the study treatment period and for at least 35 days after the last dose of lorlatinib. If a hormonal method of contraception is unavoidable, then a condom must be used in combination with the hormonal method.
• Male patients with female partners of childbearing potential must use effective contraception, including a condom, and male patients with pregnant partners must use condoms, during the study treatment period and for at least 14 weeks after the last dose of lorlatinib.
• Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 7 days after the last dose of lorlatinib
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
• Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations
Patient selection criteria for the optional prospective sub-study:
In the optional prospective sub-study, the patient could be enrolled during the ongoing response to second-generation ALK inhibitor if the following conditions are fulfilled:
• Age ≥ 18 years old
• The patient has received at least 6 months of second generation ALK-TKI therapy (if crizotinib-pretreated)
OR
• The patient has received at least 12 months of second generation ALK-TKI therapy (if crizotinib-naïve)
• Patient is willing and able to comply with the sub-study requirements including scheduled visits and examinations
• Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations.
If the patient enrolled in the prospective sub-study presents a PD by RECIST V1.1 while the recruitment in ALKALINE study is still ongoing and all the inclusion/exclusion criteria for the participation in the ALKALINE study are fulfilled, then the patient can be enrolled in the ALKALINE phase II study. |
• Edad ≥18 años.
• Diagnóstico confirmado histológica o citológicamente de CPNM con reordenamiento de ALK, evaluado mediante ensayo FISH (Abbott Molecular Inc) o mediante inmunohistoquímica (IHQ) (Ventana Inc) aprobado por la FDA.
• Estadio IIIB (no apto para tratamiento local) o estadio IV (de acuerdo con la estadificación de TNM de la UICC v8.0).
• Estado funcional 0-2 según la OMS (EF OMS).
• Tratamiento previo con al menos un inhibidor de ALK de segunda generación. El TKI de ALK de segunda generación (ceritinib, alectinib, brigatinib) debe ser el último tratamiento.
• Progresión de la enfermedad durante el tratamiento con inhibidores de ALK de segunda generación antes de la administración de lorlatinib.
• Enfermedad medible según los criterios RECIST versión 1.1 mediante tomografía computarizada (TAC) o resonancia magnética (RM) de tórax/abdomen/pelvis y RM cerebral realizadas en los 28 días previos a la inscripción en el estudio.
Nota: se requiere al menos una lesión extracraneal medible.
•Recogida de muestra de sangre para la asignación de cohortes.
Nota: si no se puede recoger la muestra de sangre (rechazo del paciente o cualquier otro motivo), el paciente no será apto para este estudio.
• Se permitirán metástasis cerebrales o leptomeníngeas tratadas y/o no tratadas si son asintomáticas y/o están controladas (dosis estable de corticosteroides 7 días antes del inicio del tratamiento con lorlatinib).
• Función orgánica y de la médula ósea adecuadas.
• Las mujeres con capacidad de concebir (MCC) deben tener una prueba de embarazo en suero negativa dentro de los 3 días previos a la primera dosis de lorlatinib.
• Las mujeres con capacidad de concebir deben utilizar un método anticonceptivo no hormonal altamente eficaz durante el periodo de tratamiento del estudio y durante al menos 35 días después de la última dosis de lorlatinib. Si un método anticonceptivo hormonal es inevitable, se debe utilizar un preservativo en combinación con el método hormonal.
• Los pacientes varones con parejas femeninas con capacidad de concebir deben utilizar métodos anticonceptivos eficaces, incluido un preservativo, y los pacientes varones con parejas embarazadas deben utilizar preservativos durante el periodo de tratamiento del estudio y durante al menos 14 semanas después de la última dosis de lorlatinib.
• Las pacientes que estén en periodo de lactancia deben interrumpirlo antes de la primera dosis del tratamiento del estudio y hasta 7 días después de la última dosis de lorlatinib.
• El paciente está dispuesto a cumplir con el protocolo durante todo el estudio y es capaz de hacerlo; esto incluye someterse al tratamiento y realizar las visitas y los exámenes programados, incluido el seguimiento.
• Antes del registro del paciente, se debe dar el consentimiento informado por escrito conforme a las directrices de Buena Práctica Clínica (BPC) de la Conferencia Internacional sobre la Armonización (ICH) y a los reglamentos nacionales/locales |
|
| E.4 | Principal exclusion criteria |
• Spinal cord compression. Patients who received adequate treatment (surgery or radiotherapy) and has adequate control of the pain and stabilization and/or recovery of neurological symptoms/function for the 3 weeks prior to study entry are allowed
• Major surgery within 4 weeks prior to study enrolment. Complete wound healing from major surgery must have occurred 3 weeks before the first dose of study treatment.
• Minor surgical procedures (including port insertion, uncomplicated tooth extractions) without complete wound healing at the latest 1 week before the first dose of study reatment.
• Radiation therapy within 2 weeks of study entry. Exception are:
• Palliative radiation (≤10 fractions) is allowed if completed at least 48 hours prior to study enrolment
• Stereotactic or small field brain irradiation is allowed if completed at least 2 weeks prior to study enrolment
• Whole brain radiation is allowed if completed at least 4 weeks prior to study enrolment
• Any systemic anti-cancer therapy or an investigational drug treatment completed within 5 halflives prior to start lorlatinib (in case of clinically meaningful risk of tumour flare according to investigator's assessment, discussion with EORTC is required before enrolment)
• Any unresolved toxicities from prior systemic therapy, including haematological toxicities, greater than CTCAE v5.0 grade 2 at the time of study enrolment
• Active infection requiring therapy
• Known active hepatitis B (HBV) or hepatitis C (HCV). Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA result greater than the lower limits of detection of the assay
• Known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related illness
• Any of the following cardiac criteria:
• Clinically significant cardiovascular disease (that is active or occurred <3 months prior to enrolment): cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), second degree or third-degree AV block (unless paced) or any AV block with PR >220 msec
• Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such as longdistance runners, etc.)
• Abnormal Left Ventricular Ejection Fraction (LVEF): LVEF <50% (assessed by MUGA or ECHO)
• History of interstitial lung disease (ILD) or history of (non-infectious) pneumonitis that required oral or IV steroids (other than COPD exacerbation) or current pneumonitis or current evidence of interstitial lung disease. Patients with history of prior radiation pneumonitis are not excluded
• Any serious or uncontrolled acute or chronic medical or psychiatric condition, including recent(within the past year) or active suicidal ideation or behaviour, chronic alcoholism, drug addiction, or laboratory abnormality that may increase the risk associated with study participation or investigational product dministration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient not eligible for this study
• Hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption
• Inability to swallow and/or retain oral tablets or impaired gastrointestinal function or disease that may significantly alter the absorption of lorlatinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption)
• Evidence of active hematologic or primary solid tumour malignancy (other than completely resected non-melanoma skin cancer, successfully treated in situ carcinoma for example in situ cervical cancer, completely resected and successfully treated papillary thyroid cancer, or localized and presumed cured prostate cancer) within the last 3 years
• History of hypersensitivity to excipients of Lorlatinib (please refer to Summary of Product Characteristics - SmPC)
• Patients currently receiving (or unable to stop use at least 3 plasma half-lives of the strong CYP3A4/5 inducer before lorlatinib treatment is started) medications or herbal supplements known to be strong inducers of cytochrome P450 (CYP) 3A4/5
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial |
• Compresión de la médula espinal. Se permite la entrada de pacientes que recibieron el tratamiento adecuado (cirugía o radioterapia) y que tienen un control adecuado del dolor, así como estabilización y/o recuperación de los síntomas neurológicos/la función neurológica durante las 3 semanas anteriores a la inclusión en el estudio.
• Cirugía mayor en las 4 semanas anteriores a la inclusión en el estudio. La cicatrización completa de la herida de una cirugía mayor debe haberse producido un 3 semanas antes de la primera dosis del tratamiento del estudio.
• Procedimientos quirúrgicos menores (incluida la inserción del puerto, extracciones dentales sin complicaciones) sin cicatrización completa de la herida, como máximo, 1 semana antes de la primera dosis del tratamiento del estudio.
• Radioterapia en el plazo de 2 semanas desde la entrada en el estudio.
• Cualquier tratamiento antineoplásico sistémico o tratamiento con un fármaco en investigación completado en las 5 semividas anteriores al inicio de la administración de lorlatinib (en caso de riesgo clínicamente significativo de exacerbación tumoral según la evaluación del investigador, es necesario comentarlo con EORTC antes de la inscripción).
• Cualquier toxicidad no resuelta del tratamiento sistémico previo.
• Infección activa que requiere tratamiento.
• Infección activa conocida por hepatitis B (VHB) o hepatitis C (VHC).
• Infección conocida por el virus de la inmunodeficiencia humana (VIH) o enfermedad relacionada con el síndrome de inmunodeficiencia adquirida (SIDA).
• Cualquiera de los siguientes criterios cardíacos:
• Enfermedad cardiovascular clínicamente significativa (que está activa o se ha producido <3 meses antes de la inclusión): accidente cerebrovascular/ictus, infarto de miocardio, angina inestable, insuficiencia cardíaca congestiva (clase ≥II según la clasificación de la New York Heart Association), bloqueo AV de segundo o tercer grado (a menos que se haya estimulado) o cualquier bloqueo AV con PR >220 ms.
• Arritmias cardíacas en curso de grado ≥2 según los criterios CTCAE del NCI, fibrilación auricular no controlada de cualquier grado, bradicardia definida como <50 lpm (a menos que, por lo demás, el paciente esté sano, como los corredores de larga distancia, etc.).
• Fracción de eyección del ventrículo izquierdo (FEVI) anómala: FEVI <50 % (evaluada mediante MUGA o ECO)
• Antecedentes de enfermedad pulmonar intersticial (EPI) o antecedentes de neumonitis (no infecciosa) que requirieran corticosteroides orales o i.v. (excepto exacerbación de la EPOC) o bien neumonitis actual o evidencia actual de enfermedad pulmonar intersticial. No se excluye a los pacientes con antecedentes de neumonitis por radiación.
• Cualquier afección médica o psiquiátrica aguda o crónica grave o no controlada, incluidos los casos recientes (en el último año) o activos de pensamientos o conductas suicidas, alcoholismo crónico, adicción a drogas o anomalías analíticas que puedan aumentar el riesgo asociado a la participación en el estudio o la administración del producto en investigación, o que puedan interferir con la interpretación de los resultados del estudio y, a juicio del investigador, hacer que el paciente no sea apto para este estudio.
• Problemas hereditarios raros de intolerancia a la galactosa, deficiencia de lactasa total o malabsorción de glucosa-galactosa.
• Incapacidad para tragar y/o retener comprimidos orales o bien disfunción o enfermedad gastrointestinal que pudiera alterar de manera significativa la absorción de lorlatinib (p. ej., enfermedades ulcerosas, vómitos incontrolados, síndrome de malabsorción, resección del intestino delgado con absorción intestinal reducida).
• Evidencia de neoplasia maligna sólida primaria o hematológica activa (distinta del cáncer de piel no melanoma completamente resecado, carcinoma in situ tratado con éxito, por ejemplo, cáncer de cuello uterino in situ, cáncer papilar de tiroides completamente resecado y tratado con éxito, o cáncer de próstata presuntamente curado y localizado) en los 3 últimos años.
• Antecedentes de hipersensibilidad a los excipientes de lorlatinib.
• Pacientes que reciben actualmente (o no pueden dejar de tomar un inductor potente de CYP3A4/5 al menos 3 semividas plasmáticas antes de iniciar el tratamiento con lorlatinib) medicamentos o suplementos a base de hierbas conocidos por ser inductores potentes del citocromo P450 (CYP) 3A4/5.
• Cualquier afección psicológica o situación familiar, sociológica o geográfica que pudiera potencialmente dificultar el cumplimiento del protocolo del estudio y el calendario de seguimiento; estas situaciones deben comentarse con el paciente antes del registro en el ensayo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS Rate at 12 months |
| tasa de supervivencia sin progresión a los 12 meses |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| disease evaluation at 52 weeks (+/- 2 weeks) is required for all patients who are still alive and without progression |
| La evaluación de la enfermedad a las 52 semanas (+/- 2 semanas) se requiere para todos los pacientes que aún están vivos y sin progresión. |
|
| E.5.2 | Secondary end point(s) |
Overall Survival (OS).
• Progression Free Survival (PFS).
• Overall Response Rate (ORR).
• Duration of Response (DOR).
• CNS Overall Response Rate (CNS-ORR)
• Patient Reported Outcomes (PROs): as assessed by EORTC QLQ- C30, EORTC QLQ-LC13 and study specific Item List.
• Safety profile according to NCI CTCAE v 5.0 |
• la supervivencia general (SG)
• la supervivencia sin progresión (SSP)
• la tasa de respuesta global (TRG)
• la duración de la respuesta (DR)
• la tasa de respuesta del sistema nervioso central (TRG del SNC)
• Resultados notificados por el paciente (RNP): evaluados mediante QLQ-C30 de la EORTC, QLQ-LC13 de la EORTC y una lista de ítems específicos del estudio
• Los acontecimientos adversos se clasificarán según los criterios CTCAE del NCI, versión 5.0. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Follow the primary endpoint |
| Sigue el punto final |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Biobanking, quality of life |
| Biobancos, calidad de vida |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Jordan |
| United Kingdom |
| Belgium |
| France |
| Italy |
| Netherlands |
| Norway |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of study occurs when all of the following criteria have been satisfied:
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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