Clinical trial NCT04790253: PRophylactic Cerebral Irradiation or Active MAgnetic Resonance Imaging Surveillance in Small-cell Lung Cancer Patients (PRIMALung Study)
Official title: PRophylactic Cerebral Irradiation or Active MAgnetic Resonance Imaging Surveillance in Small-cell Lung Cancer Patients (PRIMALung Study)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Limited Stage Small Cell Lung Cancer
Extensive-stage Small-cell Lung Cancer
Keywords: Prophylactic cerebral Irradiation
small cell lung cancer
PCI
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: UNICANCER
First posted: 2021-03-10
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: After eligibility checks, patients will be randomized between the 2 arms, and stratified by stage of disease (limited versus extensive), immunotherapy as part of the first-line treatment (yes/no), and ECOG Performance Status (0 or 1 versus 2).
Primary purpose: TREATMENT

Brief summary: In this phase III study, the primary objective is to test with a one-sided significance of 5% whether for the treatment of small cell lung cancer (SCLC) patients, brain MRI surveillance alone is non-inferior in terms of overall survival compared to prophylactic cranial irradiation (PCI) combined with brain MRI surveillance in the entire study population.

Detailed description: The primary objective is to test with a one-sided significance of 5% whether for the treatment of small cell lung cancer (SCLC) patients, brain MRI surveillance alone is non-inferior in terms of overall survival compared to prophylactic cranial irradiation (PCI) combined with brain MRI surveillance in the entire study population under the treatment policy strategy.

The secondary objectives are:

* To test with a one-sided type I error of 2.5% whether brain MRI surveillance is superior in terms of cognitive failure free survival (CFFS) compared to prophylactic cranial irradiation (PCI) combined with brain MRI surveillance in the study population.
* To test with a one-sided type I error of 2.5% whether brain MRI surveillance is superior in terms of global health status/QoL and cognitive functioning according to EORTC QLQ-C30 questionnaire compared to prophylactic cranial irradiation (PCI) combined with brain MRI surveillance in the study population.
* To evaluate the frequency and severity of toxicities according to CTCAE v5.0 in the two arms in the treated population (i.e. patients who have started treatment).

The exploratory objectives are:

* To compare OS and CFFS between the arms within the subgroups of patients with LS and ES disease.
* To compare OS and CFFS between the arms within the subgroups: HA-PCI or not, first-line immunotherapy or not, memantine or not.
* To compare cognitive failure free survival (CFFS) rate at 12 months after randomization between the arms.
* To compare the cumulative incidence of cognitive failures with death as a competing risk between the arms.
* To compare brain-metastasis-free survival (BMFS) between the arms.
* To compare progression free survival (PFS) between the arms.
* To compare time to brain-metastasis-attributed death (TBMAD) between the arms.
* To compare other QoL scales according to EORTC QLQ-C30 and QLQ-BN20 questionnaires between arms.
* To evaluate the cost-effectiveness of MRI surveillance alone versus MRI surveillance combined with PCI.
* To collect blood for biobanking.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Histologically/cytologically proven diagnosis of SCLC
* Limited and extensive stage
* LS SCLC: Stage I-III (T any, N any, M0, according to UICC TNM staging v8.0) that can be safely treated with definitive radiation doses. Excludes T3-4 due to multiple lung nodules that are too extensive or have tumour/nodal volume that is too large to be encompassed in a tolerable radiation plan.
* ES SCLC: Stage IV (T any, N any, M 1a/b), or T3-4 due to multiple lung nodules that are too extensive or have tumour/nodal volume that is too large to be encompassed in a tolerable radiation plan.
* Completed standard therapy prior to randomization:
* For patients with LS-SCLC, this includes a combination of 4-6 cycles of platinum-based doublet chemotherapy and either definitive thoracic radiotherapy (including SBRT for early-stage T1-2 N0 M0 disease who do not undergo surgery) or definitive surgical resection; thoracic radiation in addition to definitive surgical resection is allowed at the discretion of the treating physician, but is not mandated.
* For patients with ES-SCLC, this includes 4-6 cycles of platinum-based doublet chemotherapy either with or without thoracic radiotherapy

  o Immunotherapy concurrent with and/or adjuvant to standard therapy is allowed at the discretion of the treating physician.
* Absence of progressive disease after completed standard therapy on systemic imaging (computed tomography (CT) or magnetic resonance imaging (MRI) of Chest/Abdomen/Pelvis and brain MRI), 28 days before randomization.
* Absence of brain metastases or leptomeningeal disease after completed standard therapy on systemic imaging (computed tomography (CT) or magnetic resonance imaging (MRI) of Chest/Abdomen/Pelvis and brain MRI), within 28 days before randomization.
* Interval from day 1 of last cycle of chemotherapy to randomization of ≤8 weeks
* ECOG PS ≤ 2
* Estimated creatinine clearance ≥ 30 mL/min as calculated using the MDRD formula
* Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 3 days prior to randomization.

Note: women of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e. females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antioestrogens, low body weight, ovarian suppression or other reasons.

* Patients Women of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the entire period of the radiotherapy treatment study participation and for at least 30 days after the last dose of radiotherapy. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include:
* Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
* Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
* Intrauterine device (IUD)
* Intrauterine hormone-releasing system (IUS)
* Bilateral tubal occlusion
* Vasectomized partner
* Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
* Female subjects who are breast feeding should discontinue nursing prior to the first dose of radiotherapy and during the entire period of the radiotherapy treatmentuntil 30 days after the administration of the last dose of radiotherapy.
* 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/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria:

* Prior radiotherapy to the brain or whole brain radiotherapy. Note: Patients who have undergone prior stereotactic radiosurgery for benign tumours or conditions (e.g., acoustic neuroma, grade I meningioma, trigeminal neuralgia) may be considered on a case-by-case basis. Discussion with EORTC Headquarters is mandatory, before the randomization.
* Known contraindication to imaging tracer or any product of contrast media, such as allergy or insufficient renal function. Known contraindication to MRI, such as implanted metal devices or foreign bodies.
* Other active hematologic or solid tumour malignancy requiring current active treatment.
* Any unresolved toxicities from prior therapy (e.g., chemotherapy, radiotherapy) greater than CTCAE grade 2 (according to CTCAE v5.0) at the time of randomization.
* Patient with severe active comorbidities, defined as follows:
* Unstable angina and/or congestive heart failure requiring hospitalization within 6 months prior to randomization
* Transmural myocardial infarction within 6 months prior to randomization
* Acute infection requiring treatment at the time of randomization
* Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of randomization
* Severe hepatic disease defined as a diagnosis of Child-Pugh class B or C hepatic disease
* HIV positive with CD4 count \< 200 cells/microliter. Note: patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 16 weeks prior to randomization.
* Any severe comorbidity that in the opinion of the Investigator might hamper the participation to the study and/or the treatment administration.
* Severe neurological (including dementia and epilepsy) or psychiatric disorder requiring active treatment.
* 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 randomization in the trial

Primary outcomes:
measure: Overall survival
timeFrame: 12 Months
Secondary outcomes:
measure: cognitive failure free survival
timeFrame: 12 Months
measure: Quality of Life
timeFrame: 12 Months
measure: Safety profiling
timeFrame: 12 Months
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medical University of Graz - Radio-oncology
city: Anderlecht
country: Belgium
facility: Institut Jules Bordet
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Kortrijk
country: Belgium
facility: AZ Groeninge Kortrijk - Campus Kennedylaan
city: Liège
country: Belgium
facility: C.H.U. Sart-Tilman
city: Wilrijk
country: Belgium
facility: Gasthuiszusters van Antwerpen - GasthuisZusters Antwerpen - Sint-Augustinus
city: Avignon
country: France
facility: Institut Sainte Catherine (UNICANCER)
city: Bayonne
country: France
facility: Centre D'Onco. & Radioth. De Haute Energie Du Pays Basque (UNICANCER)
city: Bordeaux
country: France
facility: Institut Bergonie (UNICANCER)
city: Caen
country: France
facility: Centre Francois Baclesse (CLCC) (UNICANCER)
city: Dijon
country: France
facility: CHU de Dijon - Centre Georges-Francois-Leclerc (UNICANCER)
city: La Roche-sur-Yon
country: France
facility: Centre Hospitalier Departemental Vendee (UNICANCER)
city: Marseille
country: France
facility: Institut Paoli-Calmettes (UNICANCER)
city: Montpellier
country: France
facility: Institut du Cancer de Montpellier (UNICANCER)
city: Perpignan
country: France
facility: Centre Catalan d'Oncologie (UNICANCER)
city: Pierre Benite Cedex
country: France
facility: CHU de Lyon - Hopital Lyon Sud (UNICANCER)
city: Rouen
country: France
facility: Centre Henri Becquerel (UNICANCER)
city: Strasbourg
country: France
facility: Institut de Cancerologie Strasbourg Europe (UNICANCER)
city: Villejuif
country: France
facility: Gustave Roussy (UNICANCER)
city: Aachen
country: Germany
facility: Universitaetsklinikum Aachen AOR - Medizinische Fakultaet der RWTH
city: Genova
country: Italy
facility: IRCCS Azienda Ospedaliera Universitaria San Martino "IST" - IRCCS - AUO San Martino - IST
city: Legnago
country: Italy
facility: ULSS 9 Scaligera Veneto - Azienda Unita Locale Socio-Sanitaria N. 9-Mater Salutis Hospital
city: Pavia
country: Italy
facility: Fondazione IRCCS - Policlinico San Matteo
city: Treviglio
country: Italy
facility: ASST-Bergamo Ospedale Treviglio-Caravaggio
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Verona - Ospedale Borgo Roma
city: Gdańsk
country: Poland
facility: Medical University Of Gdansk
city: Olsztyn
country: Poland
facility: Regional Cancer Centre
city: Badajoz
country: Spain
facility: Hospital Universitario Badajoz
city: Las Palmas De Gran Canaria
country: Spain
facility: Hospital Insular De Gran Canaria
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta De Hierro
city: Bern
country: Switzerland
facility: Inselspital
city: La Chaux-de-Fonds
country: Switzerland
facility: Reseau Hospitalier Neuchatelois - RHNe - La Chaux de Fonds
city: Saint Gallen
country: Switzerland
facility: Kantonsspital St Gallen
city: Zürich
country: Switzerland
facility: UniversitaetsSpital Zurich
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS Foundation Trust - Bristol Haematology And Oncology Centre
city: Edinburgh
country: United Kingdom
facility: NHS Lothian - Western General Hospital
city: Maidstone
country: United Kingdom
facility: Maidstone & Tunbridge Wells NHS Trust - Maidstone Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust - City Hospital
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust - Weston Park Hospital
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital - Sutton
Study officials:
affiliation: The Christie NHS Foundation Trust
name: Corinne Faivre-Finn, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Gustave Roussy
name: Antonin Levy, MD
role: PRINCIPAL_INVESTIGATOR
References: