| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| RET fusion-positive, Metastatic Non-Small Cell Lung Cancer |
| carcinoma polmonare non a piccole cellule metastatico positivo alla fusione RET |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lung Cancer |
| Tumore al polmone |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029514 |
| E.1.2 | Term | Non-small cell lung cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025044 |
| E.1.2 | Term | Lung cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To assess whether pralsetinib improves progression-free survival (PFS) as compared to Investigator's choice platinum-containing chemotherapy regimens for patients with RET fusion-positive metastatic NSCLC |
| Valutare se pralsetinib migliora la sopravvivenza libera da progressione (progression-free survival, PFS) rispetto ai regimi chemioterapici a base di platino selezionati dallo sperimentatore per i pazienti affetti da NSCLC metastatico positivo alla fusione di RET |
|
| E.2.2 | Secondary objectives of the trial |
The key secondary objectives are:
•To evaluate objective response rate (ORR) determined by central radiology assessment according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1
•To evaluate overall survival (OS)
To control study-wide Type I error, the key secondary objectives will be tested in the order presented, as part of the sequential testing scheme for the study if the primary analysis is significant |
I principali obiettivi secondari sono:
• Valutare il tasso di risposta obiettiva (objective response rate, ORR), determinato dalla valutazione radiologica centrale secondo i Criteri di valutazione della risposta nei tumori solidi (Response Evaluation Criteria in Solid Tumors, RECIST), versione 1.1.
• Valutare la sopravvivenza globale (overall survival, OS).
Per controllare l’errore di tipo I a livello di studio, gli obiettivi secondari chiave saranno testati nell’ordine presentato, come parte dello schema di analisi sequenziale per lo studio se l’analisi primaria è significativa. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient must be =18 years of age inclusive, at the time of signing the informed consent.
2. Patient has pathologically confirmed, definitively diagnosed, advanced (not able to be treated with surgery or radiotherapy) or metastatic NSCLC and has not been treated with systemic anticancer therapy for metastatic disease.
3. Patient must meet 1 of the following 2 criteria:
a. Have a documented RET fusion using either tissue or plasma as determined by a local test. Refer to laboratory manual for details on acceptable local RET fusion testing methods and tissue requirements. Patient agrees to provide adequate tumor tissue (archived, if available, or a fresh biopsy) for central confirmation of RET fusion using a next generation sequencing (NGS) based assay. If no adequate tumor tissue is available and a new biopsy is not feasible, the patient will not be eligible for enrolment.
b. Have documentation of a RET fusion by a positive result from tumor tissue testing performed at a Sponsor designated central laboratory using an NGS-based assay.
4. Patient has measurable disease based on RECIST 1.1 as determined by the local site Investigator/radiology assessment. Lesions located in a previously irradiated area are considered measurable if progression has been demonstrated after irradiation.
5. Patient has an ECOG PS of 0-1.
6. Patient cannot have received any prior anticancer therapy for metastatic disease.
a. Patients can have received previous anticancer therapy (except a selective RET inhibitor) in the neoadjuvant or adjuvant setting but must have experienced an interval of at least = 6 months from completion of therapy to recurrence.
b. Patients that received previous immune checkpoint inhibitors in the adjuvant or consolidation following chemoradiation are not allowed to receive pembrolizumab if randomized in Arm B
7. Patient is an appropriate candidate for and agrees to receive 1 of the Investigator choice platinum-based chemotherapy regimens if randomized to Arm B.
For the complete list, please refer to Protocol. |
1. Pazienti di età = 18 anni, al momento della firma del consenso informato
2. Il paziente ha ricevuto una diagnosi definitiva con conferma patologica di NSCLC avanzato (non trattabile mediante intervento chirurgico o radioterapia) o metastatico e non è mai stato trattato con terapia antitumorale sistemica per la malattia metastatica.
3. I pazienti devono soddisfare 1 dei 2 criteri seguenti:
a. Avere una fusione di RET documentata utilizzando tessuto o plasma stabilita da un’analisi condotta localmente. Consultare il manuale per il laboratorio per informazioni sui metodi di analisi per la fusione di RET locali accettabili e sui requisiti del tessuto. Il paziente accetta di fornire un adeguato campione di tessuto tumorale (archiviato, se disponibile, o una nuova biopsia) per la conferma centrale della fusione di RET utilizzando un test di sequenziamento di nuova generazione (next generation sequencing, NGS). Se non è disponibile alcun campione di tessuto tumorale adeguato e non è possibile effettuare una nuova biopsia, il paziente non sarà idoneo per l’arruolamento.
b. Avere una fusione di RET documentata da un risultato positivo di un’analisi del tessuto tumorale eseguita presso un laboratorio centrale designato dallo sponsor utilizzando un test NGS.
4. Malattia misurabile secondo i criteri RECIST 1.1 stabilita dalla valutazione dello sperimentatore/radiologica locale del centro.
5. Il paziente presenta un ECOG PS pari a 0-1.
6. I pazienti non devono aver ricevuto alcuna terapia antitumorale precedente per la malattia metastatica.
a. I pazienti possono aver ricevuto una precedente terapia antitumorale (ad eccezione di un inibitore selettivo di RET) nel contesto neoadiuvante o adiuvante, ma devono aver avuto un intervallo di almeno = 6 mesi dal completamento della terapia alla recidiva.
b. I pazienti che hanno ricevuto inibitori del checkpoint immunitario in precedenza in contesto adiuvante o di consolidamento dopo chemioradioterapia non possono ricevere pembrolizumab se randomizzati nel Braccio B
7. Il paziente è un candidato idoneo e accetta di ricevere 1 dei regimi chemioterapici a base di platino scelti dallo sperimentatore, se randomizzato nel Braccio B.
per la lista completa fare riferimento al Protocollo |
|
| E.4 | Principal exclusion criteria |
1. Patient's tumor has any additional known primary driver alterations other than RET, such as targetable mutations of EGFR, ALK, ROS1, MET, and BRAF. Investigators should discuss enrollment with Sponsor designee regarding co-mutations.
2. Patient previously received treatment with a selective RET inhibitor.
3. Patient received radiotherapy or radiosurgery to any site within 14 days before randomization or more than 30 Gy of radiotherapy to the lung in the 6 months before randomization.
4. Patient has a presence of Grade 2 or worse interstitial lung disease or interstitial pneumonitis, including radiation pneumonitis within 28 days before randomization.
5. Patient has CNS metastases or a primary CNS tumor that is associated with progressive neurological symptoms or requires increasing doses of corticosteroids to control the CNS disease. If a patient requires corticosteroids for management of CNS disease, the dose must have been stable for the 2 weeks before C1D1.
For the complete list, please refer to Protocol. |
1. Il tumore del paziente presenta ulteriori alterazioni del driver primario note diverse da RET, quali mutazioni target di EGFR, ALK, ROS1, MET e BRAF. Gli sperimentatori dovranno discutere dell’arruolamento con un incaricato dello sponsor in merito alle co-mutazioni.
2. Il paziente è stato precedentemente sottoposti a trattamento con un inibitore selettivo di RET.
3. Il paziente ha ricevuto radioterapia o radiochirurgia in qualsiasi sito nei 14 giorni precedenti la randomizzazione o più di 30 Gy di radioterapia ai polmoni nei 6 mesi precedenti la randomizzazione.
4. Il paziente presenta malattia polmonare interstiziale di grado 2 o più grave o polmonite interstiziale, inclusa la polmonite da radiazioni nei 28 giorni precedenti la randomizzazione.
5. Il paziente è affetto da metastasi a carico del SNC o da un tumore del CNS primario associato a sintomi neurologici progressivi o richiede dosi incrementali di corticosteroidi per controllare la malattia del SNC. Se un paziente ha bisogno di corticosteroidi per la gestione della malattia a carico del SNC, la dose deve essere stata stabile per le 2 settimane precedenti C1G1.
per la lista completa fare riferimento al Protocollo |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS, defined as the number of weeks from randomization date to the earlier of documented progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 central imaging review or death due to any cause |
| PFS definita come il numero di settimane che intercorrono tra la data della randomizzazione e l’evento che si verifica per primo fra progressione della malattia (progressive disease, PD) documentata da revisione centrale di immagini secondo i criteri RECIST 1.1 e decesso per qualsiasi causa. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Imaging will be performed at the following timepoints, regardless of treatment delays: Screening, at 6 and 12 weeks, then every 9 weeks for the first 48 weeks, and every 12 weeks thereafter |
| Le immagini verranno effettuate ai seguenti timepoints, indipendentemente dai ritardi di trattamento: allo Screening, a 6 e 12 settimane, successivamente ogni 9 settimane per le prime 48 settimane, e ogni successiva periodo di 12 settimane. |
|
| E.5.2 | Secondary end point(s) |
ORR / DOR / Intracranial Progression or Response Rate - "Imaging will be performed at the following timepoints, regardless of treatment delays: Screening, at 6 and 12 weeks, then every 9 weeks for the first 48 weeks, and every 12 weeks thereafter."
OS - "Patients who have confirmed progressive disease at EOT or during follow-up for PFS or those who initiate another antineoplastic therapy will be followed for overall survival by telephone contact that will include questions regarding subsequent antineoplastic therapy and survival status approximately every 3 months from the EOT visit until death, withdrawal of consent, or closure of the study by the Sponsor."
PROs: EORTC-QLQ-LC13, EORTC-QLQ-C30 symptom scores, and EQ-5D-5L assessments will be evaluated as mean change from baseline to Week 12. |
- ORR, definito come la percentuale di pazienti che ottengono una risposta completa (complete response, CR) o parziale (partial response, PR) confermata da revisione centrale di immagini secondo i criteri RECIST 1.1.
- DOR, DCR, CBR secondo i criteri RECIST 1.1
- Progressione intracranica e ORR intracranico secondo i criteri RECIST 1.1
- OS, definita come il numero di settimane dalla data di randomizzazione al decesso per qualsiasi causa.
- Questionari EORTC-QLQ-C30
- Punteggi EORTC-QLQ-LC13
- Valutazione EQ-5D-5L |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR / DOR / Intracranial Progression or Response Rate - "Imaging will be performed at the following timepoints, regardless of treatment delays: Screening, at 6 and 12 weeks, then every 9 weeks for the first 48 weeks, and every 12 weeks thereafter."
OS - "Patients who have confirmed progressive disease at EOT or during follow-up for PFS or those who initiate another antineoplastic therapy will be followed for overall survival by telephone contact that will include questions regarding subsequent antineoplastic therapy and survival status approximately every 3 months from the EOT visit until death, withdrawal of consent, or closure of the study by the Sponsor."
Please refer to protocol for more details. |
- ORR/DOR/progressione intracranica: allo Screening, a 6 e 12 settimane, successivamente ogni 9 settimane per le prime 48 settimane, e ogni successiva periodo di 12 settimane.
- OS: numero di settimane dalla data di randomizzazione al decesso per qualsiasi causa
- Questionari EORTC-QLQ-C30, Punteggi EORTC-QLQ-LC13, Valutazione EQ-5D-5L: dallo screening alla settimana 12.
per favore fare riferimento al protocollo per ulteriori dettagli. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 | Information not present in EudraCT |
| 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 |
| Australia |
| Canada |
| Hong Kong |
| Israel |
| Korea, Republic of |
| Taiwan |
| Turkey |
| Belgium |
| Bulgaria |
| Denmark |
| Finland |
| France |
| Germany |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| Czechia |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The End of trial is defined as the last patient's telephone contact follow up |
| La conclusione della sperimentazione è definita dal contatto telefonico dell’ultimo paziente per il follow-up. |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 6 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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