| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| metastatic adenoid cystic carcinomas (ACC) of the salivary glands of the upper aerodigestive tract |
| Carcinoma adenoide cistico delle ghiandole salivari del tratto aerodigestivo superiore, recidivato e/o metastatico |
|
| E.1.1.1 | Medical condition in easily understood language |
| adenoid cystic carcinomas (ACC) of the salivary glands |
| tumore adenoido-cistico della ghiandole salivari |
|
| 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 | 10026121 |
| E.1.2 | Term | Malignant neoplasm of major salivary glands recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Response Rate according to RECIST criteria 1.1. |
| Tasso di risposta secondo RECIST 1.1 |
|
| E.2.2 | Secondary objectives of the trial |
¿ Progression free survival
¿ Overall survival
¿ Duration of response
¿ Acute toxicity according to CTCAE v4.0
¿ PRO Questionnaire: Quality of life (EORTC QLQ C-30, EORTC QLQ-H&N35, EQ-5D)
|
Sopravvivenza libera da progressione
Sopravvivenza globale
Tasso di controllo della malattia (CR, PR, SD)
Valutazione tossicit¿ secondo i criteri CTCAE v4.0
Qualit¿ di vita secondo EORTC QLQ-C30; EORTC QLQ-H&N35 e EQ-5D
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenomics
Version: 1.0
Date: 20/01/2015
Title: Pharmacogenomic study
Objectives: Although currently no biological markers seem to correlate with the anti-angiogenetic drug activity, a correlative studies for translational research will be carried out. Tissue paraffin block from primary lesion or metastasis will be collected for MYB-NFIB translocation analysis. Twenty unstained slides 5¿m are also acceptable. The results of biological data will be correlated with lenvatinib activity. Blood samples (10 mL) will be collected at baseline, at Cycle 2 and at disease progression (type and methods of analyses are still under discussion). Saliva samples will be collected at baseline and at disease progression.
|
Farmacogenomica
Versione: 1.0
Data: 20/01/2015
Titolo: Studio farmacogenomico su marker tessutali prognostici e predittivi di risposta
Obiettivi: Determinazione di biomarcatori sul tessuto tumorale (sezioni di tessuto tumorale gi¿ prelevato in occasione di biopsia diagnostica e/o della recidiva)
|
|
| E.3 | Principal inclusion criteria |
1. Histologically proven relapsed and/or metastatic adenoid cystic carcinoma for which potentially curative options such as surgery or radiotherapy are not indicated.
2. Archival tissue samples or unstained 20 slides from primary tumor or metastasis for translational biological research.
3. Subjects with at least one uni-dimensional measurable lesion by CT-scan or MRI according to RECIST criteria 1.1 (target lesion). A previously treated lesion by radiotherapy or loco-regional therapies such as radiofrequency (RF) can be chosen as target lesion only if progression in the respective lesion has been demonstrated during or following radiotherapy.
4. Clinical or radiological progression of disease within 6 months at study entry. Progression of disease by RECIST is not required.
5. Age = 18 years
6. ECOG Performance Status < 2
7. Life expectancy of > 3 months
8. Adequately controlled blood pressure with or without antihypertensive medications, defined as BP < 150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to Cycle 1 Day 1
9. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening:
¿ Hemoglobin >9.0 g/dl
¿ Neutrophil count (ANC) >1,000/mm3
¿ Platelet count ¿75,000/µl
¿ Total bilirubin <1.5 times the upper limit of normal
¿ ALT and AST <2.5 x upper limit of normal (<5 x upper limit of normal for patients with liver metastases)
¿ Serum creatinine <1.5 x upper limit of normal
¿ Alkaline phosphatase <4 x ULN
¿ PT-INR/PTT <1.5 x upper limit of normal (Patients who are being therapeutically anticoagulated with an agent such as heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists)
10. Previous systemic therapy for metastatic disease is allowed for a maximum of 1 previous line of chemotherapy and/or 1 previous line of TKI
11. Signed written informed consent
|
- Diagnosi di tumore adenoide cistico delle ghiandole salivari istologicamente confermata in pazienti non candidabili a terapia potenzialmente curativa, come chirurgia o radioterapia
- Disponibilità di tessuto tumorale dal tumore primitivo o dalle metastasi per ricerche biologiche (blocchetto d’archivio o 20 slide in bianco)
- Almeno una lesione misurabile secondo criteri RECIST 1.1 con TAC o RMN (lesioni precedentemente trattate con radioterapia o terapie locoregionali quali radiofrequenza (RF) possono essere scelte come lesioni target solo se è stata dimostrata durante o dopo la radioterapia la progressione delle suddette lesioni.
- Progressione clinica o radiologica nei 6 mesi precendenti lo studio. Non è richiesta la progressione secondo i criteri RECIST
- Età maggiore di 18 anni compiuti
- ECOG Performance Status = 2
- Aspettativa di vita superiore a 3 mesi
- Pressione arteriosa adeguatamente controllata con o senza farmaci antipertensivi, definita come BP <150/90 mmHg allo screening e nessun cambiamento nei farmaci antipertensivi entro 1 settimana prima del ciclo 1 giorno 1
- Adeguata funzionalità midollare, epatica e renale valutata rispetto ai seguenti requisiti di laboratorio (esami eseguiti entro 7 giorni dallo screening):
- emoglobina > 9 g/dL
- neutrofili > 1.0 x 109/L,
- piastrine > 75 x 103/µL
- Bilirubina totale sierica < 1.5 x ULN
- Aspartato aminotransferasi (AST) o alanina aminotransferasi (ALT) < 2.5 x ULN (< 5 x ULN per pazienti con metastasi epatiche)
- Creatinina sierica < 1.5 x ULN
- Fosfatasi alcalina < 4 x ULN
- -PT-INR / PTT <1.5 x ULN (saranno ammessi a partecipare allo studio pazienti in terapia con anticoagulanti con agenti come l’eparina a condizione che non ci siano precedenti evidenze di anomalie di fondo di tali parametri)
- Consenso informato scritto
|
|
| E.4 | Principal exclusion criteria |
1. Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry
2. Subjects having > 1+ proteinuria on urine dipstick testing will undergo 24h urine collection for quantitative assessment of proteinuria. Subjects with urine protein = 1 g/24h will be ineligible
3. History of cardiac disease: congestive heart failure >NYHA class 2; active CAD (MI more than 6 mo prior to study entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
4. Gastrointestinal abnormalities (i.e. inability to take oral medication; malabsorption syndrome)
5. Requirement for anticoagulant therapy with oral vitamin K antagonists (LMWH therapy is accepted)
6. Prolongation of QTc interval to > 480 msec
7. Known allergic reaction to any of the components of the treatment
8. Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
9. Legal incapacity or limited legal capacity
10. Active clinically serious infections (> grade 2 NCI-CTC version 4.0)
11. Medical or psychological condition which, in the opinion of the investigator, would not enable the patient to complete the study or knowingly sign the Informed Consent
12. Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and two weeks after the completion of trial
13. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors [Ta, Tis & T1] or any cancer curatively treated > 3 years prior to study entry.
14. Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
15. History of organ allograft.
16. Patients with evidence or history of bleeding diathesis
17. Patients undergoing renal dialysis
18. Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of study entry.
19. Previous therapy with lenvatinib (E7080)
20. Radiotherapy during study or within 3 weeks of start of study drug. (Palliative radiotherapy will be allowed)
21. Major surgery within 2 weeks of start of study
22. Use of biologic response modifiers, such as G-CSF, within 3 week of study entry [G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the investigator, however they may not be substituted for a required dose reduction; patients taking chronic erythropoietin are permitted provided no dose adjustment is undertaken within 2 months prior to the study or during the study]
23. Investigational drug therapy outside of this trial during or within 4 weeks of study entry
|
- Pazienti con metastasi encefaliche o meningee a meno che non siano state trattate oltre i 6 mesi, e siano staibili nelle 4 settimane precedenti l’arruolamento
- Soggetti che hanno proteinuria su test dipstick urine > +1 saranno sottoposti a raccolta delle urine 24 ore per la valutazione quantitativa della proteinuria. I soggetti con proteine nelle urine =1g/24h non saranno arruolabili.
- Anamnesi positiva per malattie cardiache quali insufficienza cardiaca congestizia classe > 2 secondoNYHA; coronaropatia attiva (infarto del miocardio oltre 6 mesi prima dell'ingresso nello studio è consentito); aritmie cardiache che necessitano di una terapia antiaritmica (beta-bloccanti o la digossina sono consentiti)
- Anomalie gastrointestinali (cioè incapacità di assumere farmaci per via orale, sindrome da malassorbimento)
- Necessità di terapia anticoagulante con antagonisti della vitamina K per via orale (terapia EBPM è ammesso)
- Prolungamento dell'intervallo QTc > 480 msec
- Reazione allergica nota a uno qualsiasi dei componenti del trattamento
- Storia di abuso di sostanze, condizioni psicologiche o sociali mediche che possono interferire con la partecipazione del paziente allo studio o valutazione dei risultati dello studio.
- Incapacità legale o limitata capacità giuridica
- Infezioni clinicamente gravi attive (> grado 2 NCI-CTC v. 4.0)
- Condizione medica o psicologica che, a giudizio dello sperimentatore, non consentirebbe al paziente di completare lo studio o firmare il consenso informato
- Pazienti in gravidanza o in allattamento. Le donne in età fertile devono avere un test di gravidanza negativo effettuato entro 7 giorni dall'inizio del trattamento. Sia gli uomini sia le donne arruolate in questo studio devono utilizzare misure barriera di contraccezione adeguate nel corso del trial e due settimane dopo il termine del trattamento.
- Pregressa neoplasia o tumore concomitante in altro sito o altra istologia, eccetto carcinoma cervicale in situ, basalioma trattato; tumore vescicale superficiale [Ta, Tis & T1] o qualsiasi altro tumore trattato in maniera curativa < 3 anni prima dell’ingresso in studio.
- Pazienti con disturbi convulsivi che richiedono farmaci (come gli steroidi o anti-epilettici)
- Storia di trapianto di organo allogenico
- Pazienti con evidenza o anamnesi di diatesi emorragica
- Pazienti sottoposti a dialisi renale
- Chemioterapia o immunoterapia durante lo studio o entro 4 settimane nello studio.
- Precedente terapia con lenvatinib (E7080)
- Radioterapia durante lo studio o entro 3 settimane dall'inizio del farmaco (Sarà consentita radioterapia palliativa)
- Chirurgia maggiore entro 2 settimane dall'inizio dello studio
- Uso di modificatori della risposta biologica, come G-CSF, entro tre settimane dell'ingresso nello studio, pazienti trattati con eritropoietina cronica sono ammessi a condizione che nessun aggiustamento della dose sia condotto entro 2 mesi prima dello studio o durante lo studio
- Terapia farmacologica sperimentale al di fuori di questo studio durante o entro 4 settimane di ingresso nello studio |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Response Rate according to RECIST criteria 1.1. |
| L’obiettivo primario è il tasso di risposta (CR + PR) che sarà calcolato, sulla base dei criteri RECIST (v. 1.1). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
¿ Progression free survival
¿ Overall survival
¿ Duration of response
¿ Acute toxicity according to CTCAE v4.0
¿ PRO Questionnaire: Quality of life (EORTC QLQ C-30, EORTC QLQ-H&N35, EQ-5D)
|
Sopravvivenza libera da progressione
Sopravvivenza globale
Tasso di controllo della malattia (CR, PR, SD)
Valutazione tossicit¿ secondo i criteri CTCAE v4.0
Qualit¿ di vita secondo EORTC QLQ-C30; EORTC QLQ-H&N35 e EQ-5D
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 | 4 |
| 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 | 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 | 0 |
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