| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced or Metastatic Non-Small Cell Lung Cancer |
| carcinoma polmonare non a piccole cellule localmente avanzato o metastatico |
|
| E.1.1.1 | Medical condition in easily understood language |
| A specific type of lung cancer called "Non-Small Cell Lung Cancer" |
| un tumore chiamato "tumore polmonare non a piccole cellule" |
|
| 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 | 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 |
| To assess the efficacy of lazertinib, amivantamab, carboplatin, and pemetrexed ( LACP), compared with carboplatin and pemetrexed (CP), in participants with locally advanced or metastatic epidermal growth factor receptor (EGFR) Exon 19del or Exon 21 L858R substitution NSCLC |
| L’obiettivo primario dello studio è valutare l’efficacia di LACP rispetto a CP in partecipanti con NSCLC localmente avanzato o metastatico con Esone 19del di EGFR o sostituzione L858R dell’Esone 21 |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
1. To further assess the clinical benefit of LACP vs CP
2. To assess the safety of LACP vs CP
3. To assess the relationship between pharmacokinetics or immunogenicity and selected endpoints (including but not limited to efficacy, safety, and/or patient-reported outcomes)
4. To assess health-related quality of life and disease-related symptoms in participants treated with LACP vs CP
5.To describe the contribution of lazertinib to the efficacy of LACP (vs ACP)
|
Gli obiettivi secondari sono:
1. Valutare ulteriormente il beneficio clinico di LACP vs CP
2. Valutare la sicurezza di LACP vs CP
3. Valutare la relazione tra farmacocinetica o immunogenicità e gli endpoint selezionati (inclusi, ma non solo, l'efficacia, la sicurezza e/o gli esiti riportati dal paziente)
4. Valutare la qualità della vita correlata alla salute e i sintomi correlati alla malattia nei partecipanti trattati con LACP vs CP
5. Descrivere il contributo di lazertinib all'efficacia di LACP (vs ACP) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. At least 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place).
2. Participant must have histologically or cytologically confirmed, locally advanced or metastatic, non-squamous NSCLC, characterized at or after the time of locally advanced metastatic disease diagnosis by either EGFR Exon 19del or Exon 21 L858R mutation, by an FDA-approved or other validated test of either ctDNA or tumor tissue in a CLIA certified laboratory (sites in the US) or an accredited local laboratory (sites outside of the US). A de-identified copy of the initial test report documenting the EGFR mutation must be included in the participant records and must be submitted to the sponsor during the Screening Phase. If provision of this report is not permitted by the site or local policies, then sponsor-approved equivalent documentation must be provided.
3. Participant must have progressed on or after osimertinib monotherapy as the most recent line of treatment. Osimertinib must have been administered as either the first line treatment for locally advanced or metastatic disease or in the second line setting after prior treatment with first- or second-generation EGFR TKI.
Participants who received either neoadjuvant and/or adjuvant treatment are eligible if progression to locally advanced or metastatic disease occurred at least 12 months after the last dose of such therapy and then the participant progressed on or after osimertinib in the locally advanced or metastatic setting.
Treatment with osimertinib must be discontinued at least 8 days (4 half-lives) prior to randomization (ie, last dose no later than Day -8).
4. Participant must have at least 1 measurable lesion, according to RECIST v1.1, that has not been previously irradiated. Measurable lesions should not have been biopsied during screening, but if only 1 non-irradiated measurable lesion exists, it may undergo the optional diagnostic biopsy and be acceptable as a target lesion, provided the baseline tumor assessment scans are performed at least 14 days after the biopsy.
5. A participant with definitively, locally treated brain metastases must be clinically stable and asymptomatic, with or without low-dose corticosteroid treatment (=10 mg prednisone or equivalent), for at least 14 days prior to randomization.
6. Participant must have Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.
7. Participant must have adequate organ and bone marrow function as follows, without history of red blood cell transfusion or platelet transfusion within 7 days prior to the date of the laboratory test:
• Hemoglobin =10 g/dL
• Absolute neutrophil count =1.5¿109/L, without use of G-CSF within 10 days prior to the date of the test
• Platelets =100¿109/L
• ALT and AST =3×upper limit of normal (ULN)
• Total bilirubin =1.5¿ULN if no liver metastasis, or =3×ULN in the presence of liver metastasis (participants with Gilbert’s syndrome can enroll if conjugated bilirubin is within normal limits)
• Creatinine clearance >50 mL/min as measured or calculated by Cockcroft-Gault formula
8. Any toxicities from prior systemic anticancer therapy must have resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 Grade 1 or baseline level (except for alopecia [any grade], Grade =2 peripheral neuropathy, or Grade <2 hypothyroidism stable on hormone replacement).
9. Participant must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study.
10. A woman of childbearing potential must have a negative serum pregnancy test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study.
Please refer to pages 32- 34 of the protocol for full inclusion criteria. |
Ogni potenziale partecipante deve soddisfare tutti i seguenti criteri per essere arruolato nello studio.
1. Età pari o superiore a 18 anni (o l’età legale del consenso nella giurisdizione in cui si svolge lo studio).
2. Il partecipante deve essere affetto da NSCLC non squamoso, localmente avanzato o metastatico, istologicamente o citologicamente confermato, caratterizzato al momento della diagnosi di malattia metastatica localmente avanzata dall’esone 19del di EGFR o da mutazione L858R dell’esone 21, da un test approvato dall’Ente statunitense preposto al controllo di alimenti e farmaci (Food and Drug Administration, FDA) o da un altro test convalidato del ctDNA o del tessuto tumorale in un laboratorio certificato CLIA [Clinical Laboratory Improvement Amendments (Emendamenti per il miglioramento dei laboratori clinici)] (centri negli Stati Uniti) o in un laboratorio locale accreditato (centri al di fuori degli Stati Uniti). Una copia de-identificata del referto del test iniziale che documenta la presenza della mutazione di EGFR deve essere inclusa nella documentazione del partecipante, nonché trasmessa allo Sponsor durante la Fase di screening. Se la fornitura di questo rapporto non è consentita dal centro o dalle politiche locali, deve essere fornita la documentazione equivalente approvata dallo sponsor.
3. Il partecipante deve aver manifestato progressione durante o dopo la monoterapia con osimertinib come linea di trattamento più recente. Osimertinib deve essere stato somministrato come trattamento di prima linea per la malattia localmente avanzata o metastatica o come trattamento di seconda linea dopo precedente trattamento con TKI di EGFR di prima o seconda generazione.
I partecipanti che hanno ricevuto un trattamento neoadiuvante e/o adiuvante sono idonei se la progressione a malattia localmente avanzata o metastatica si è verificata almeno 12 mesi dopo l’ultima dose di tale terapia e poi il partecipante ha manifestato progressione durante o dopo osimertinib nel contesto localmente avanzato o metastatico.
Il trattamento con osimertinib deve essere interrotto almeno 8 giorni (4 emivite) prima della randomizzazione (ovvero, l’ultima dose non oltre il Giorno -8).
4. Presenza di almeno 1 lesione misurabile secondo i criteri RECIST v1.1, che non sia stata precedentemente irradiata. Le lesioni misurabili non devono essere state sottoposte a biopsia durante lo screening; tuttavia, se è presente solo una lesione misurabile non irradiata, è possibile eseguirne la biopsia diagnostica facoltativa e utilizzarla come lesione target, a condizione che le scansioni basali di valutazione del tumore siano eseguite almeno 14 giorni dopo la biopsia.
5. Un partecipante con metastasi cerebrali trattate localmente in modo definitivo deve essere clinicamente stabile e asintomatico, con o senza trattamento con corticosteroidi a basso dosaggio (=10 mg di prednisone o equivalente) per almeno 14 giorni prima della randomizzazione.
6. Il partecipante deve avere uno stato di 0 o 1 secondo l’Eastern Cooperative Oncology Group (ECOG). Consultare L’Appendice 7 al Protocollo: Stato di validità del Gruppo orientale cooperativo di oncologia (Eastern Cooperative Oncology Group, ECOG).
7. Il partecipante deve avere una funzionalità d’organo e funzione del midollo osseo adeguate, come specificato di seguito, in assenza di un’anamnesi di trasfusione di globuli rossi o trasfusione piastrinica nei 7 giorni precedenti la data del test di laboratorio:
• Emoglobina =10 g/dl
• Conta assoluta dei neutrofili =1,5x109/l, senza supporto con G-CSF nei 10 giorni precedenti la data del test
• Piastrine =100x109/l
• ALT e AST =3 volte il limite superiore della norma (Upper Limit of Normal, ULN)
• Bilirubina totale =1,5xl’ULN se non ci sono metastasi al fegato, o =3×ULN in presenza di metastasi al fegato (i partecipanti con sindrome di Gilbert sono ammessi all’arruolamento se la bilirubina coniugata rientra nei limiti di normalità);
elenco completo pagine 32-34 Protocollo |
|
| E.4 | Principal exclusion criteria |
Any potential participant who meets any of the following criteria will be excluded from participating in the study:
1. Participant has an uncontrolled illness, including but not limited to:
• Uncontrolled diabetes
• Ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics at least 1 week prior to starting study treatment] or diagnosed or suspected viral infection), except as allowed by Exclusion Criterion 17 for HIV
• Active bleeding diathesis
• Impaired oxygenation requiring continuous oxygen supplementation
• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of study treatment
• Psychiatric illness or any other circumstances (including social circumstances) that would limit compliance with study requirements
• Any ophthalmologic condition that is clinically unstable
2. Participant received prior systemic anticancer therapy in the locally advanced or metastatic setting, or in the adjuvant setting, for the same nonsquamous NSCLC intended for treatment now, except as allowed by Inclusion Criterion 3.
3. Participant received radiotherapy for palliative treatment of NSCLC less than 14 days prior to randomization.
4. Participant has active brain metastases not definitively treated with local therapy.
5. Participant previously enrolled in the Sponsor’s study 73841937NSC3003 (NCT04487080).
6. Participant has leptomeningeal disease, or participant has spinal cord compression not definitively treated with surgery or radiation.
7. Participant has known small cell transformation.
8. Participant has uncontrolled tumor-related pain. Symptomatic lesions amenable to palliative radiotherapy (eg, bone metastases, or metastases causing nerve impingement) should be treated at least 14 days prior to randomization.
9. Participant has a medical history of ILD, including drug induced ILD or radiation pneumonitis.
10. Participant has a history of hypersensitivity to carboplatin or pemetrexed, or to any excipient of carboplatin, pemetrexed, amivantamab, or lazertinib.
11. Participant has an active malignancy (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. Exceptions include participants who have undergone curative therapy and have no evidence of disease recurrence since completion of that therapy, and those with local cancers that have been apparently cured such as:
a. Non-muscle invasive bladder cancer (NMIBC) treated within the last 24 months that is considered completely cured.
b. Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured.
c. Non-invasive cervical cancer treated within the last 24 months that is considered completely cured.
d. Localized prostate cancer (N0M0):
• with a Gleason score of 6, treated within the last 24 months or untreated and under surveillance,
• with a Gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence,
• or history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence.
e. Breast cancer:
• lobular carcinoma in situ or ductal carcinoma in situ that is considered completely cured, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence.
f. Other malignancy that is considered cured with minimal risk of recurrence.
Please refer to pages 36- 38 of the protocol for full exclusion criteria. |
Il potenziale partecipante che soddisfi uno qualsiasi dei seguenti criteri sarà escluso dalla partecipazione allo studio:
1. Presenza di malattia non controllata, tra cui, in modo non limitativo:
• Diabete non controllato
• Infezione in atto o attiva (comprese le infezioni che richiedono un trattamento con terapia antimicrobica [la terapia antibiotica dovrà essere completata almeno 1 settimana prima dell’avvio del trattamento dello studio] o le infezioni virali diagnosticate o sospette), tranne nel caso concesso dal Criterio di esclusione 17 per l’HIV [Human Immunodeficiency Virus (virus dell’immunodeficienza umana)]
• Diatesi emorragica attiva
• Deficit di ossigenazione con necessità di supplementazione continua di ossigeno
• Nausea e vomito refrattari, malattie gastrointestinali croniche, incapacità di deglutire il prodotto formulato o pregressa resezione intestinale significativa che potrebbe impedire l’adeguato assorbimento del trattamento in studio
• Malattia psichiatrica o qualsiasi altra circostanza (tra cui circostanze sociali) che potrebbe limitare l’aderenza ai requisiti dello studio
• Qualsiasi condizione oftalmologica che sia clinicamente instabile
2. Il partecipante ha ricevuto una precedente terapia antitumorale sistemica nel contesto localmente avanzato o metastatico, o nel contesto adiuvante, per lo stesso NSCLC non squamoso il cui trattamento è previsto adesso, salvo nei casi consentiti dal Criterio di inclusione 3.
3. Il partecipante ha ricevuto radioterapia per il trattamento palliativo dell’NSCLC meno di 14 giorni prima della randomizzazione.
4. Il partecipante presenta metastasi cerebrali attive non trattate in modo definitivo con terapia locale.
5. Partecipante precedentemente arruolato nello studio dello sponsor 73841937NSC3003/MARIPOSA (NCT04487080).
6. Il partecipante è affetto da malattia leptomeningea o presenta compressione del midollo spinale non trattata in modo definitivo con intervento chirurgico o radioterapia.
7. Il partecipante presenta una trasformazione nota a piccole cellule.
8. Il partecipante presenta dolore correlato al tumore non controllato. Le lesioni sintomatiche suscettibili di radioterapia palliativa (ad es. metastasi ossee o metastasi che causano impingement nervoso) devono essere trattate almeno 14 giorni prima della randomizzazione.
9. Anamnesi di ILD [Interstitial Lung Disease (malattia polmonare interstiziale)], compresa l’ILD da farmaci, o polmonite da radiazioni.
Per l'elenco completo dei Criteri di inclusione si prega di fare riferimento alle pagine 36-38 del Protocollo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) using RECIST v1.1 guidelines, as assessed by blinded independent central review (BICR) |
| PFS in accordo al RECIST 1.1 su valutazione di un revisore centrale in cieco |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The time from randomization until the date of objective disease progression or death, whichever comes first, based on BICR using RECIST v1.1. |
| Il tempo dalla randomizzazione fino alla data della progressione oggettiva della malattia o del decesso, a seconda dell'evento che si verifica per primo, basato su BICR utilizzando RECIST v1.1. |
|
| E.5.2 | Secondary end point(s) |
1. Clinical benefits:
• Objective response (by BICR)
• Overall survival
• Duration of response (by BICR)
• Time to subsequent therapy
• PFS after first subsequent therapy (PFS2)
• Time to symptomatic progression
• Intracranial PFS (by BICR)
2. Safety: Incidence and severity of adverse events and clinical laboratory abnormalities
3. Pharmacokinetics or immunogenicity: Serum amivantamab and plasma lazertinib concentrations, and serum anti-amivantamab antibodies
4. HRQOL and disease related symptoms:
• NSCLC-SAQ
• EORTC-QLQ-C30
• PROMIS-PF
5. Efficacy:
• Intracranial PFS (by BICR)
• Objective response (by BICR)
• Duration of response (by BICR)
• PFS (by BICR)
|
1. Benefici clinici:
• Risposta obiettiva (da BICR)
• Sopravvivenza globale
• Durata della risposta (per BICR)
• Tempo alla terapia successiva
• PFS dopo la prima terapia successiva (PFS2)
• Tempo alla progressione sintomatica
• PFS intracranica (da BICR)
2. Sicurezza: incidenza e gravità di eventi avversi e anomalie cliniche di laboratorio
3. Farmacocinetica o immunogenicità: concentrazioni sieriche di amivantamab e lazertinib plasmatiche e anticorpi sierici anti-amivantamab
4. HRQOL e sintomi correlati alla malattia:
• NSCLC-SAQ
• EORTC-QLQ-C30
• PROMIS-PF
5. Efficacia:
• PFS intracranica (da BICR)
• Risposta obiettiva (da BICR)
• Durata della risposta (per BICR)
• PFS (da BICR) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From randomization until the date of documented progression or death due to any cause, whichever comes first.
2. Throughout the study or as clinically indicated.
3. Arm A- Cycle 1 Day 1 (C1D1): predose, 2 hours (h), 4h; C2D1: predose, 2h, 4h; C3D1, C5D1, C7D1, C9D1, C11D1, C13D1: predose, 30 days after last dose
PK: Arms A and C- C1D1 & C1D2, C2D1 : predose and end of infusion; C3D1, C5D1, C7D1, C10D1, C13D1, C17D1: predose, end of infusion and 30 days after last dose
Immunogenicity: Arms A and C- C1D1, C2D1, C3D1, C5D1, C7D1, C9D1, C11D1, C13D1: predose and 30 days after last dose
4. C1D1, C2D1, C3D1, C4D1, C5+, EOT and follow up
5. From randomization until the date of documented progression or death due to any cause, whichever comes first.
|
1. Da randomizzazione fino alla data di progressione documentata o morte per qualsiasi causa, a seconda di quale si verifica per prima.
2. Durante lo studio o come clinicamente indicato.
3. Arm A- Ciclo 1 Giorno 1 (C1G1): predose, 2 ore (h), 4h; C2G1: predose, 2h, 4h; C3G1, C5G1, C7G1, C9G1, C11G1, C13G1: predose, 30 giorni dopo l'ultima dose
PK: Bracci A e C- C1G1 e C1G2, C2G1: predose e fine dell'infusione; C3G1, C5G1, C7G1, C10G1, C13G1, C17G1: predose, fine infusione e 30 giorni dopo l'ultima dose
Immunogenicità: Bracci A e C- C1G1, C2G1, C3G1, C5G1, C7G1, C9G1, C11G1, C13G1: predose e 30 giorni dopo l'ultima dose
4. C1G1, C2G1, C3G1, C4G1, C5+, EOT e fup
5. Da randomizzazione fino a data di progressione documentata o morte per qualsiasi causa, a seconda di quale si verifica per prima. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 |
| Tolerability, Biomarker evaluation, Immunogenicity assessments, Quality of life |
| Tollerabilità, Valutazione di biomarcatori, Valutazioni di immunogenicità, Qualità di vita |
|
| 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 | Yes |
| 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 | 3 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 |
| Brazil |
| Canada |
| China |
| Hong Kong |
| India |
| Israel |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Puerto Rico |
| Russian Federation |
| Taiwan |
| Turkey |
| United States |
| Belgium |
| Bulgaria |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Sweden |
| United Kingdom |
| Czechia |
| Argentina |
|
| 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 study is considered as the last scheduled study assessment shown in the Schedule of Activities for the last participant in the study. |
| La fine dello studio è considerata come l'ultima valutazione dello studio programmata indicata nel Programma delle attività per l'ultimo partecipante allo studio. |
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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