| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Small Cell Lung Cancer, Locally Advanced or Metastatic |
| Carcinoma polmonare non a piccole cellule, localmente avanzato o metastatico, |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Small Cell Lung Cancer, Locally Advanced or Metastatic |
| Tumore polmonare non a piccole cellule, localmente avanzato o metastatico |
|
| 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 | 10066490 |
| E.1.2 | Term | Progression of non-small cell 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 evaluate the Objective Response Rate (ORR) to poziotinib in patients with non-small cell lung cancer (NSCLC) |
| • Valutare il tasso di risposta obiettiva (Objective Response Rate, ORR) nei confronti di poziotinib in pazienti affetti da carcinoma polmonare non a piccole cellule (Non-Small Cell Lung Cancer, NSCLC) |
|
| E.2.2 | Secondary objectives of the trial |
• Disease Control Rate (DCR)
• Duration of Response (DoR)
• To evaluate the safety and tolerability of poziotinib
Exploratory Objectives:
• To evaluate Progression-free Survival (PFS)
• To evaluate the Quality of Life,(Coorti 1-4)
- Evaluate alternate poziotinib starting doses (Cohort 5 only)
• Evaluate poziotinib in patients who progressed while on treatment
with first-line osimertinib (Cohort 6 only)
• Evaluate poziotinib in patients with EGFR or HER2 activating mutations
- Evaluate overall survival
• Characterize the PK profile of poziotinib |
- Tasso di controllo della malattia (Disease Control Rate, DCR)
- Durata della risposta (Duration of Response, DoR)
• Valutare la sicurezza e la tollerabilità di poziotinib
Obiettivi esplorativi
• Valutare la Sopravvivenza libera da progressione (Progression-Free Survival, PFS) i
• Valutare la Qualità della vita, (coorti 1-4)
- Valutare dosi iniziali alterne di poziotinib (solo Coorte 5)
- Valutare poziotinib in pazienti andati incontro a progressione durante il trattamento di prima linea con osimertinib (solo Coorte 6)
- Valutare poziotinib in pazienti con mutazioni attivanti di EGFR o HER2
- Valutare la sopravvivenza globale
-Caratterizzare il profilo farmacocinetico di Poziotinib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is at least 18 years of age
2. Patient must be willing and capable of giving written Informed Consent, adhering to dosing and visit schedules, and meeting all study requirements
3. Patient has histologically or cytologically confirmed locally advanced
or metastatic non-small cell lung cancer (NSCLC) that is not amenable to treatment with curative intent
4. Prior treatment status:
• Cohorts 1 and 2: Patient has had at least one prior systemic treatment for locally advanced or metastatic NSCLC
• Cohorts 3 and 4: Patient is treatment-naïve for locally advanced or
metastatic NSCLC and eligible to receive first-line treatment with poziotinib as determined by the Investigator. Adjuvant/neo-adjuvant therapies (chemotherapy, radiotherapy, or investigational agents) are permissible as long as they end at least 15 days prior to study entry.
• Cohort 5: Patients who meet the criteria for enrollment in Cohort 1 to
4, but the enrollment in the respective cohort has been closed
• Cohort 6: Patients with EGFR mutation-positive NSCLC who progressed while on treatment with first-line osimertinib.
• Cohort 7: Patient has had at least one prior systemic treatment for locally advanced or metastatic NSCLC
• Cohorts 1 to 5: Patient has adequate tumor tissue obtained from a biopsy or surgical procedure to enable molecular profiling for retrospective central laboratory confirmation of the mutation. If tissue is not available, the patient must have biopsy accessible disease and must be willing to undergo a biopsy to provide an appropriate tissue sample prior to receiving treatment in the study.
• Cohort 6: Either tissue or plasma samples must be provided after osimertinib progression.
• Cohort 7: Either tissue or plasma samples |
1. Pazienti di almeno 18 anni di età
2. Il paziente deve essere disposto e in grado di fornire il consenso informato scritto, aderire allo schema di
somministrazione e al programma delle visite e rispettare tutte le richieste dello studio.
3. Pazienti con conferma istologica o citologica di carcinoma polmonare non a piccole cellule localmente
avanzato o metastatico (NSCLC) non candidabili a trattamento con intento curativo
4. Trattamenti precedenti:
Coorti 1 e 2: il paziente ha ricevuto in precedenza almeno un trattamento sistemico per il NSCLC
localmente avanzato o metastatico
Coorti 3 e 4: il paziente è naïve al trattamento per il NSCLC localmente avanzato o metastatico ed è
idoneo a ricevere un trattamento di prima linea con poziotinib come stabilito dall'investigatore. Le
terapie adiuvanti / neoadiuvanti (chemioterapia, radioterapia o farmaci sperimentali) sono consentite a
condizione che vengano interrotte almeno 15 giorni prima dell'ingresso nello studio
Coorte 5: il paziente soddisfa i criteri di arruolamento nelle Coorti 1-4, ma non può accedervi in quanto
l’arruolamento nella rispettiva coorte è stato chiuso
Coorte 6: il paziente è affetto da NSCLC positivo per una mutazione di EGFR ed è andato incontro a
progressione durante il trattamento di prima linea con osimertinib
Coorte 7: il paziente ha ricevuto in precedenza almeno un trattamento sistemico per il NSCLC
localmente avanzato o metastatico. |
|
| E.4 | Principal exclusion criteria |
1. Patient has:
• All Cohorts: EGFR T790M
• Cohorts 1 to 5: EGFR exon 20 point mutation
• Cohort 7: EGFR Exon 19 deletion and L858R or HER2 T798I mutations, EGFR and HER2 Exon 20 insertion mutation
2. Patient has had previous treatment with poziotinib or any other EGFR or HER2 exon 20 insertion mutation-selective tyrosine kinase inhibitor (TKI) prior to study participation. The currently approved TKIs (ie, erlotinib, gefitinib, afatinib, osimertinib) are not considered to be exon 20 insertion-selective and are permissible (Cohorts 1 and 2)
3. Patient is concurrently receiving chemotherapy, biologics, immunotherapy for cancer treatment; systemic anti-cancer treatment or investigational treatment should not be used within 2 weeks; or 5 half lives , whichever is longer, local
radiation therapy for bone pain may be allowed.
4. Patient has a history of congestive heart failure (CHF) Class III/IV according to the New York Heart Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring treatment
5. Patient has a high risk of cardiac disease, as determined by the Investigator, may undergo either echocardiogram (ECHO) or multi-gated
acquisition (MUGA) during Screening and has a cardiac ejection fraction <50%.
6. Patient has had other malignancies within the past 3 years, except for stable non-melanoma skin cancer, fully treated and stable early stage prostate cancer or carcinoma in situ of the cervix or breast without need of treatment
7. Patient is confirmed to have clinically significant or recent acute gastrointestinal disease presenting as diarrhea and/or coloenteritis as a main symptom (ie, acute enteritis, malabsorption, or Common
Terminology Criteria for Adverse Events (CTCAE, version 4.03) Grade 2 or above diarrhea due to other etiologies)
8. Patient has an active Grade higher than 2 skin disorder, rash, mucositis, or skin infection that needs medication or therapy or existing Grade =2 skin toxicity from previous therapies; Grade =2 neuropathy, Grade =2pneumonitis.
9. Patient is unable to take drugs orally due to disorders or diseases that may affect gastrointestinal function, such as inflammatory bowel diseases (eg, Crohn's disease, ulcerative colitis) or malabsorption syndrome, or procedures that may affect gastrointestinal function, such as gastrectomy, enterectomy, or colectomy
10. Patient has an active liver disease or biliary tract disease (except for Gilbert's disease, asymptomatic biliary stones, liver metastasis, or stabilized chronic liver diseases)
11. Patient has known hypersensitivity to poziotinib or has a history of allergic reactions attributed to chemically similar compounds or other tyrosine kinase inhibitors (TKIs)
12. Patient has an active uncontrolled infection, underlying medical condition, or other serious illness that would not be appropriate for this study |
1. Pazienti con:
Tutte le coorti: mutazione T790M di EGFR
Coorti 1-5: mutazione puntiforme a carico dell’esone 20 di EGFR
Coorte 7: delezione dell’esone 19 di EGFR e mutazioni L858R di EGFR o T798I di HER2, mutazioni inserzionali a carico dell’esone 20 di EGFR e HER2.
2. Pazienti precedentemente trattati con poziotinib o qualunque altro inibitore tirosin-chinasico (TKI) selettivo per mutazioni inserzionali a carico dell’esone 20 di EGFR o HER2 prima della partecipazione allo studio. I TKI attualmente approvati (cioè erlotinib, gefitinib, afatinib, osimertinib) non sono considerati selettivi per le mutazioni inserzionali a carico dell’esone 20 e sono pertanto permessi (Coorti 1 e 2).
3. Pazienti sottoposti a chemioterapia, terapia con farmaci biologici o immunoterapia concomitante per il trattamento del tumore; i trattamenti antitumorali sistemici o sperimentali non devono essere usati nelle 2 settimane precedenti o per un periodo uguale alle 5 emivite precedenti; la radioterapia localizzata per il trattamento del dolore osseo può essere ammessa.
4. Pazienti con insufficienza cardiaca congestizia (Congestive Heart Failure, CHF) di classe III/IV secondo la classificazione funzionale della NYHA (New York Heart Association) o aritmie cardiache gravi che richiedano trattamento, all’anamnesi.
5. I pazienti ad alto rischio di cardiopatie, in base a quanto determinato dallo sperimentatore, potranno essere sottoposti a ecocardiografia (ECHO) o ad acquisizione a porte multiple (Multi-Gated Acquisition, MUGA) durante lo Screening e, in presenza di una frazione di eiezione cardiaca <50%.
6. Pazienti con altre neoplasie maligne all'anamnesi nei precedenti 3 anni, a eccezione del tumore della cute non melanomatoso stabile, del carcinoma prostatico in fase precoce completamente trattato e stabile, del carcinoma in situ della cervice uterina o del carcinoma della mammella che non necessita di trattamento.
7. Pazienti nei quali siano confermate patologie gastrointestinali acute clinicamente rilevanti o recenti, che si manifestino con diarrea e/o enterocolite come sintomo principale (ossia enterite acuta, malassorbimento o diarrea di altra eziologia di Grado 2 o superiore secondo il CTCAE v4.03. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective Response Rate (ORR, the rate of complete response and partial response) |
| Tasso di risposta obiettivo (ORR, cioè il tasso di risposta completa e risposta parziale) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
ORR is defined as the best response recorded from the start of the study until the end of study in patients who received at least 1 dose of
poziotinib. The ORR will be based on the primary analysis population. The ORR will be determined by an independent radiologic review committee. |
| ORR è definito come la miglior risposta rilevata dall'inizio dello studio alla conclusione dello stesso in pazienti che hanno ricevuto almeno 1 dose di poziotinib. L'ORR sarà basato sulla popolazione di analisi primaria. L'ORR sarà determinato da una commissione indipendente di revisione radiologica |
|
| E.5.2 | Secondary end point(s) |
• Disease Control Rate (DCR, the rate of complete response, partial
response, and stable disease)
• Duration of Response (DoR)
• Safety and Tolerability
Exploratory Endpoint:
• Progression-free Survival (PFS)
• Quality of Life (QoL) (Cohorts 1 to 4 only)
Overall survival (OS) |
• Tasso di controllo della malattia (DCR, cioè il tasso di risposta completa, risposta parziale e malattia stabile)
• Durata della risposta (DoR)
• Sicurezza e tollerabilità
endpoint esploratori
Sopravvivenza libera da progression (progression free survival- PFS)
Qualità della vita ( QoL ) per le coorti 1-4
soppravvivenza globale |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
DCR will be assessed from the first dose of poziotinib to the end of study.
DoR will be measured from the date that measurement criteria are first met for CR-complete response or PR-partial response (whichever status
is recorded first) until the first subsequent date that progressive disease or death is documented.
PFS is defined as the number of days from the treatment start date to the date of documented disease progression or death due to any cause.
QoL will be evaluated in Cohorts 1 to 4 only using the EORTC QLQ-C30 and QLQ-LC13 questionnaire at Cycle 1, Day 1, at every imaging session, and at the Safety Follow-up Visit. The global health status/QoL, functional scales, symptom scales, and lung cancer related symptoms will be summarized for each evaluation time point.
OS: every 3 months |
Il DCR sarà valutato dalla prima dose di poziotinib fino alla fine dello studio. Il DoR sarà misurato dalla data in cui i criteri di misurazione per una CR (risposta completa) o una PR (risposta parziale)vengono rispettati per la prima volta (CR o PR a seconda di quale si verifichi per prima) fino al giorno successivo alla data in cui viene documentata la progressione della malattia o la morte.
PFS è definito come il numero di giorni dalla data di trattamento fino alla data di progressione della malattia documentata o fino alla morte per qualsiasi causa
La QoL verrà valutata solo nelle coorti da 1 a 4 usando l'EORTC QLQ-C30 e il questionario QLQ-LC13 al Ciclo 1, Giorno 1, ad ogni sessione di imaging e alla visita di follow-up sulla sicurezza.
Sopravivenza globale ogni 3 mesi |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Not Applicable |
| Not Applicable |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Canada |
| Israel |
| United States |
| Belgium |
| France |
| Italy |
| Netherlands |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 | 0 |
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