| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously Treated, Locally-Advanced Unresectable or Metastatic Solid Tumors Driven by HER2 Alterations. |
| Tumori solidi legati ad alterazioni HER2 precedentemente trattati, metastaticio o localmente avanzati non resecabili. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Solid tumors with HER2 alterations. |
| Tumori solidi con alterazioni HER2. |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064467 |
| E.1.2 | Term | Urothelial carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008593 |
| E.1.2 | Term | Cholangiocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10017614 |
| E.1.2 | Term | Gallbladder cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025697 |
| E.1.2 | Term | Malignant neoplasm of ampulla of Vater |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10008342 |
| E.1.2 | Term | Cervix carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10046766 |
| E.1.2 | Term | Uterine cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 evaluate the antitumor activity of tucatinib given in combination with trastuzumab in subjects with previously treated, locally-advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2) overexpressing/amplified or mutated solid tumors. |
| Valutare l'attività antitumorale di tucatinib somministrato in combinazione con trastuzumab in soggetti affetti da tumori solidi, precedentemente trattati, che over-esprimono o con il recettore 2 per il fattore di crescita epidermico umano amplificato o mutato, metastatico o localmente avanzato non resecabile. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability of tucatinib given in combination with trastuzumab with or without fulvestrant. |
| Valutare la sicurezza e la tollerabilità di tucatinib somministrato in combinazione con trastuzumab, con o senza fulvestrant. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Confirmed diagnosis of locally-advanced unresectable or metastatic solid tumor, including primary brain tumors.
2.Subjects with disease types other than breast cancer, biliary tract cancer, non-squamous NSCLC, and cervical cancer: Disease progression on or after the most recent systemic therapy for locally-advanced
unresectable or metastatic disease.
3.Subjects with any breast cancer subtype.
4.Subjects with biliary tract cancer: must have progressed on or after >or=1prior line of treatment (chemotherapy, endocrine therapy, or targeted therapy).
5.Subjects with non-squamous NSCLC: has relapsed from or is refractory to standard treatment or for which no standard treatment is available,
6.Subjects with cervical cancer.
7.Disease demonstrating HER2 alterations (overexpression/amplification or HER2 activating mutations), as determined by local or central testing processed in a Clinical Laboratory Improvement Amendments (CLIA)- or International Organization for Standardization (ISO) accredited laboratory.
8.Have adequate hepatic function as defined by the following:
a. AST and ALT <or=3 × ULN (<or=5 × ULN if liver metastases are present);
b.Total bilirubin <or=1.5 × ULN. Exception: subjects with known history of Gilbert's Syndrome and normal direct bilirubin, AST, and ALT are eligible.
9.Have adequate baseline hematologic parameters as defined by:
a.Absolute neutrophil count (ANC) =1.0 × 109/L;
b.Platelet count =100 × 109/L; subjects with stable platelet count from 75 to 100 × 109/L may be included with approval from Medical Monitor;
c.Hemoglobin =9.0 g/dL; subjects with hemoglobin =8 and <9 g/dL may be included with approval from the Medical Monitor;
d.In subjects transfused before study entry, transfusion must be =14 days prior to start of therapy to establish adequate hematologic parameters independent from transfusion support.
10.Left ventricular ejection fraction (LVEF) >or=50% as assessed by echocardiogram or multiple-gated acquisition scan (MUGA) documented within <or=28 days prior to first dose of study treatment.
Please refer to the protocol for full details. |
1. Diagnosi confermata istologicamente o citologicamente di tumore solido non resecabile localmente avanzato o metastatico, compresi i tumori cerebrali primari.
2. Soggetti con tipi di malattie diversi da carcinoma mammario, cancro del tratto biliare, NSCLC non squamoso e cancro della cervice uterina: progressione della malattia durante o dopo la più recente terapia sistemica per una malattia non resecabile localmente avanzata o metastatica.
3. Soggetti con qualsiasi sottotipo di carcinoma mammario.
4. Soggetti con cancro del tratto biliare: devono aver evidenziato una progressione durante o dopo >o=1 linea di trattamento precedente (chemioterapia, terapia endocrina o terapia mirata).
5. Soggetti con NSCLC non squamoso: hanno evidenziato una recidiva con la terapia standard, sono refrattari alla terapia standard o per essi non è disponibile alcuna terapia standard.
6. Soggetti con cancro della cervice uterina.
7. Malattia che evidenzia alterazioni di HER2 (sovraespressione/amplificazione di HER2 o mutazioni attivanti di HER2), secondo quanto determinato da esami svolti a livello locale o centrale eseguiti presso un laboratorio certificato per Modifiche di miglioramento dei laboratori clinici (Clinical Laboratory Improvement Emendments, CLIA) o accreditato dall’Organizzazione internazionale per la standardizzazione (International Organization for Standardization, ISO).
8. Avere una funzionalità epatica adeguata, definita attraverso i seguenti:
a. AST e ALT <o=3 × ULN (<o=5 × ULN se sono presenti metastasi epatiche)
b. Bilirubina totale <o=1,5 × ULN. Eccezione: i soggetti con anamnesi nota di sindrome di Gilbert e valori normali di bilirubina diretta, AST e ALT sono idonei.
9. Avere parametri ematologici al basale adeguati. |
|
| E.4 | Principal exclusion criteria |
1. Subjects with breast cancer, GEC, or CRC whose disease shows HER2 amplification/overexpression.
2. Previous treatment with HER2-directed therapy; subjects with uterine serous carcinoma may have received prior trastuzumab.
3. Known hypersensitivity to any component of the drug formulation of tucatinib or trastuzumab (drug substance, excipients, murine proteins), or any component of the drug formulation of fulvestrant in subjects with HR+ HER2-mutated breast cancer.
4. History of exposure to a >360 mg/m² doxorubicin-equivalent or >720 mg/m² epirubicin-equivalent cumulative dose of anthracyclines.
5. Treatment with any systemic anti-cancer therapy, radiation therapy, or experimental agent within <or=3 weeks of first dose of study treatment or are currently participating in another interventional clinical trial.
6. Have any toxicity related to prior cancer therapies that has not resolved to <or= Grade 1, with the following some exceptions (please refer to protocol for details).7. Have clinically significant cardiopulmonary disease.
8. Have known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment.
9. Known to be positive for hepatitis B by surface antigen expression. Known to be positive for hepatitis C infection. Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.
10. Presence of known chronic liver disease.
11. Subjects known to be positive for human immunodeficiency virus (HIV) are excluded if they meet specific criteria (please refer to protocol for details).12. Are pregnant, breastfeeding, or planning a pregnancy from time of informed consent until 7 months after the final dose of any study drug, and, if applicable, for at least 2 years after the final dose of fulvestrant.
13. Have inability to swallow pills.
14. Have used a strong cytochrome P450 (CYP) 2C8 inhibitor within 5 half-lives of the inhibitor, or have used a strong CYP3A4 or CYP2C8 inducer within 5 days prior to start of treatment.
15. Have any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures.
16. History of another malignancy within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death, such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
17. Subjects with known CNS lesions must not have any of the following:
a. Any untreated brain lesions >2.0 cm in size, unless approved by the medical monitor,
b. Ongoing use of systemic corticosteroids for control of symptoms of brain lesions at a total daily dose of >2 mg of dexamethasone (or equivalent). However, subjects on a chronic stable dose of <or=2 mg total daily of dexamethasone (or equivalent) may be eligible, following approval by the medical monitor,
c. Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in size or possible treatment-related edema may pose risk to subject. Subjects who undergo local treatment for such lesions identified by screening brain magnetic resonance imaging (MRI) may still be eligible for the study,
d. Known or suspected leptomeningeal disease as documented by the investigator,
e. Have poorly controlled (>1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain lesions notwithstanding CNS-directed therapy.
Please refer to protocol for full details. |
1. Soggetti con carcinoma mammario, GEC o CRC che evidenzia amplificazione/sovraespressione di HER2.
2. Precedente trattamento con terapia mirata a HER2; i soggetti con carcinoma sieroso dell'utero possono aver assunto trastuzumab in precedenza.
3. Nota ipersensibilità a qualsiasi componente della formulazione farmaceutica di tucatinib o trastuzumab o a qualsiasi componente della formulazione farmaceutica di fulvestrant in soggetti affetti da carcinoma mammario HR+ e mutazione di HER2.
4. Anamnesi di esposizione a una dose cumulativa di antracicline equivalente a >360 mg/m² di doxorubicina o a >720 mg/m² di epirubicina.
5. Trattamento con qualsiasi terapia antitumorale sistemica, radioterapia o agente sperimentale entro <o=3 settimane dalla prima dose del trattamento dello studio o attuale partecipazione a un’altra sperimentazione clinica interventistica.
6. Presentano qualsiasi tossicità correlata a precedenti terapie antitumorali che non si sia risolta al Grado <o= 1, con le seguenti eccezioni (fare riferimento al protocollo per i dettagli).
7. Presentano malattia cardiopolmonare clinicamente significativa.
8. Aver avuto noto infarto del miocardio o angina instabile nei 6 mesi precedenti la prima dose del trattamento dello studio.
9. Nota positività al virus dell’epatite B mediante espressione dell’antigene di superficie. Nota positività all’infezione da epatite C. I soggetti che sono stati trattati per l’infezione da epatite C sono ammessi se hanno una risposta virologica sostenuta documentata di 12 settimane.
10. Presenza di nota epatopatia cronica.
11. I soggetti noti per essere positivi al virus HIV sono esclusi se soddisfano criteri specifici (fare riferimento al protocollo per i dettagli).
12. Sono incinte, stanno allattando o stanno programmando una gravidanza dal momento del consenso informato fino a 7 mesi dopo la dose finale di qualsiasi farmaco dello studio e, se applicabile, per almeno 2 anni dopo la dose finale di fulvestrant.
13. Evidenziano incapacità di ingerire le compresse.
14. Hanno assunto un potente inibitore dell'enzima (CYP) 2C8 del citocromo P450 entro 5 emivite dell’inibitore o hanno assunto un potente induttore di CYP3A4 o di CYP2C8 nei 5 giorni precedenti l’inizio del trattamento.
15. Presentano eventuali altri fattori medici, sociali o psicosociali che, a giudizio dello sperimentatore, potrebbero pregiudicare la sicurezza o la conformità con le procedure dello studio.
16. Anamnesi di un altro tumore maligno nei 2 anni precedenti lo screening, con l’eccezione di quelli che presentano un rischio trascurabile di metastasi o di decesso, come nel caso di carcinoma della cervice uterina in situ, tumore della pelle diverso dal melanoma, carcinoma prostatico localizzato, carcinoma duttale in situ o cancro dell’utero allo stadio I adeguatamente trattato.
17. I soggetti con note lesioni al sistema nervoso centrale (SNC) non devono presentare alcune condizioni:
a. Qualsiasi lesione cerebrale non trattata di dimensioni >2,0 cm, salvo approvazione del responsabile del monitoraggio medico (fare riferimento al protocollo per i dettagli). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Confirmed objective response rate (ORR; confirmed complete response [CR] or partial response [PR]) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 per investigator assessment . |
| Tasso di risposta obiettiva confermato (ORR; risposta completa confermata [CR] o risposta pariziale [PR] in accordo ai criteri di valutazione della risposta nei tumori solidi (RECIST) v1.1, in base alla valutazione dello sperimentatore. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to 3 years. |
| Fino a 3 anni. |
|
| E.5.2 | Secondary end point(s) |
Disease control rate (DCR; confirmed CR or PR, or stable disease) per investigator assessment.
Duration of response (DOR; confirmed CR or PR) per investigator assessment.
Progression-free survival (PFS) per investigator assessment .
Overall survival (OS).
Type, incidence, severity, seriousness, and relatedness of adverse events (AEs) Type, incidence, and severity of laboratory abnormalities.
Frequency of treatment interruptions, dose reductions, and treatment discontinuations due to AEs.
Other relevant safety variables including AEs of special interest (AESIs). |
Tasso di controllo della malattia (DCR; CR o PR confermato, o malattia stabile) in base alla valutazione dello sperimentatore.
Durata della risposta (DOR; CR o PR confermata) in base alla valutazione dello sperimentatore.
Sopravvivenza libera da progressione (PFS) in base alla valutazione dello sperimentatore.
Sopravvivenza complessiva (OS)
Tipo, incidenza, gravità e correlazione di eventi avversi (AE).
Tipo, incidenza, gravità e correlazione di anomalie di laboratorio.
Frequenza di interruzione del trattamento, di riduzioni della dose e di sospensione del trattamento a causa di AE.
Altre variabili di sicurezza rilevanti, compresi AE di speciale interesse (AESI). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Up to 3 years. |
| Fino a 3 anni. |
|
| 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 |
| Patient-Reported Outcomes |
| Esiti riportati dal paziente. |
|
| 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 | No |
| 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 | 15 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Japan |
| Korea, Democratic People's Republic of |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
|
| 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
|
The study ends once the last subject completes the last visit, last contact, discontinues from the study, or is lost to follow-up, whichever
occurs first, approximately 3 years after the last subject is enrolled. In addition, the sponsor may terminate the study at any time. |
| Lo studio termina una volta che l'ultimo paziente ha completato l'ultima visita, l'ultimo contatto, interrompe lo studio, o risulta perso al follow up, qualche che si verifichi per primo, a circa 3 anni dopo l'arruolamento dell'ultimo paziente. Inoltre lo sponsor si riserva di terminare lo studio in qualunque momento. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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