| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| R-M Head and Neck Cancer |
| MALATTIA RECIDIVATA O METASTATICA DEL DISTRETTO CERVICO FACCIALE |
|
| E.1.1.1 | Medical condition in easily understood language |
| R-M Head and Neck Cancer |
| MALATTIA RECIDIVATA O METASTATICA DEL DISTRETTO CERVICO FACCIALE |
|
| 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 | PT |
| E.1.2 | Classification code | 10034813 |
| E.1.2 | Term | Pharyngeal cancer recurrent |
| 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 | 10055104 |
| E.1.2 | Term | Pharyngeal cancer metastatic |
| 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 |
a. Assessment of the safety of the combination of avelumab, mCTX and non ablative radiotherapy (phase I).
b. Assessment of activity of avelumab, mCTX and non ablative radiotherapy in a population of heavily pre-treated RM-HNSCC patients (phase II).
|
a. Valutare la tossicità della combinazione (fase I)
b. Determinare l’attività di avelumab, ciclofosfamide metronomica e RT non ablativa in una popolazione pesantemente pretrattata di pazienti con tumori recidivati /metastatici della testa e collo (fase II)
|
|
| E.2.2 | Secondary objectives of the trial |
c. Assessment of the safety of the combination of avelumab, mCTX and non ablative radiotherapy.
d. Description of progression free survival (PFS) and overall survival (OS)
e. Exploratory description of Health-related Quality of Life
|
c. Valutare la tossicità della combinazione
d. Valutare la sopravvivenza libera da progressione (PFS) e la sopravvivenza complessiva (OS)
e. Valutare la qualità di vita
|
|
| 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 |
TRANSLATIONAL STUDY V. 1.0 18/12/2017
OBJECTIVES:
• To identify variations among the major circulating immunological factors during the study CONFRONT.
• To identify the impact of the observed changes (if any) on outcome of the patient.
• To identify the immune status to disease progression.
|
STUDIO TRANSLAZIONALE V. 1.0 18/12/2017
Obiettivi:
- Identificare le variazioni tra i maggiori fattori immunologici circolanti durante lo studio CONFRONT
- Identificare l'impatto dei cambiamenti osservati (se presenti) relativamente all'outcome dei pazienti
- Identificare lo stato immunologico alla progressione
|
|
| E.3 | Principal inclusion criteria |
1. Be willing and able to provide written informed consent for the trial. The subject may also provide consent for the translational study.
2. Be ≥ 18 years of age on day of signing informed consent.
3. ECOG Performance Status 0-2.
4. Have histologically or cytologically-confirmed recurrent or metastatic (disseminated) head and neck squamous cell carcinoma
5. Have a disease progression after treatment with at least one line of therapy including at least Cisplatin, Fluorouracil and Cetuximab for recurrent (disease not amenable to curative treatment)/metastatic disease.
6. Measurable disease by RECIST criteria.
7. At least one metastatic site suitable for irradiation
8. Life expectancy > 3 months.
9. Adequate bone marrow function: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin ≥9 g/dL.
10. Adequate liver function: AST and ALT levels ≤ 2.5 × ULN; bilirubin ≤ 1.5 x ULN.
11. Adequate renal function: creatinine clearance ≥ 30 mL/min (Cockroft-Gault).
12. Fertil men must be using adequate contraceptive measures throughout the study period if their partner are women of childbearing potential.
13. If of childbearing potential, women must use effective contraceptive method (Pearl Index < 1; e.g. oral contraceptive (pill), hormone spiral, hormone implant, transdermal patch, a combination of two barrier methods (condom and diaphragm), sterilisation, sexual abstinence) for the study duration and for at least 30 days after last avelumab treatment administration if the risk of conception exists.
|
1) Consenso informato scritto al trattamento. Consenso informato scritto per lo studio traslazionale.
2) Età ≥ 18 anni
3) ECOG Performance status 0-2
4) Diagnosi istologica o citologica di carcinoma squamo cellulare del distretto cervico facciale.
5) Malattia metastatica o ricorrente non suscettibile di trattamento locoregionale, pretrattata con almeno 1 linea di terapia sistemica comprendente Cisplatino, 5 FU e Cetuximab.
6) Malattia misurabile secondo i criteri RECIST.
7) Almeno una sede di malattia suscettibile di trattamento radioterapico.
8) Aspettativa di vita > 3 mesi.
9) Adeguato profilo ematologico: conta assoluta dei neutrofili (ANC) ≥1,5 x 109/l, piastrine ≥100 x 109/l, emoglobina ≥10 g/dL.
10) Adeguata funzionalità epatica: transaminasi < 2,5 volte il limite superiore di normalità (ULN), bilirubina totale < 1,5 volte l’ULN.
11) Adeguata funzionalità renale: creatinina sierica ≤ULN o clearance della creatinina calcolata (Cockroft-Gault) > 60 mL/min.
12) Gli uomini fertili, se le loro partner sono in età fertile, devono usare un metodo contraccettivo adeguato durante tutto lo studio.
13) Le donne fertili, devono usare un metodo contraccettivo adeguato durante tutto lo studio e per almeno 30 giorni dall’ultima somministrazione di avelumab.
|
|
| E.4 | Principal exclusion criteria |
1. History of malignant disease (with the exception of non-melanoma skin tumours and/or in situ cervical cancer) in the preceding five years.
2. Brain metastases.
3. Autoimmune disorders. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
4. Allergic disorders.
5. Cyclophosphamide treatment contraindications:
a. Cystitis.
b. Urinary Obstruction.
c. Inadequate bone marrow function: WBC <2900 mm3 and/or HCT <30% and/or platelets count <90000 mm3.
d. Active infections.
e. Pregnancy or breast feeding.
6. Prior treatment with inhibitors of the PD-L1 – PD – 1 axis or inhibitors of CTLA-4 (immune check point inhibitors)
7. Previous HBV or HCV infections.
8. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
9. Any active infection requiring specific treatment (Antibiotics, antimicotic, antiviral).
10. Radiotherapy within 6 weeks before enrolment
11. Other non-malignant uncontrolled systemic diseases or social conditions that would preclude trial entry in the opinion of the investigator.
12. Prior organ transplantation including allogenic stem-cell transplantation.
13. Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines.
14. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator’s judgment are acceptable.
15. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behaviour; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
16. Avelumab treatment contraindications:
a. Hypersensitivity to the active ingredient or to any excipient.
b. Inadequate bone marrow function: WBC <2900 mm3 and/or HCT <30% and/or platelets count <90000 mm3.
c. Uncontrolled serous effusions (pleural, pericardic or peritoneal)
d. Blood Pressure <60 mmHg.
e. Pregnancy or breast feeding.
f. Active infections.
Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
g. Brain metastases.
h. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
17. Participation to other concomitant experimental study.
|
1) Pregresse neoplasie maligne d'altra origine nei precedenti 5 anni (esclusi tumori della cute, non melanoma) .
2) Metastasi cerebrali.
3) Patologia autoimmune.
4) Patologia allergica.
5) Controindicazioni al trattamento con Ciclofosfamide:
a. Cistite.
b. Ostruzione flusso urinario.
c. Funzione midollare gravemente compromessa: globuli bianchi totali <2900 mmc e/o Ematocrito <30% e/o Piastrine <90000 mmc.
d. Infezioni in atto.
e. Gravidanza o allattamento.
6) Pregresso trattamento con immunoterapia.
7) Pregresse infezioni da HBV e/o HCV.
8) Trattamento con immunosoppressivi a eccezione di: a. steroidi topici intranasali, steroidi topici cutanei o iniezioni locali (ad esempio intra-articolari). b. Steroidi sistemici a dosi ≤10 mg/die di prednisone o equivalenti. c. steroidi come premedicazione a farmaci per reazione di ipersensibilità.
9) Malattia infettiva in atto che necessita di terapia specifica (antibiotica, antivirale o antimicotica).
10) Radioterapia nelle 6 settimane precedenti l’arruolamento.
11) Presenza di altra condizione non oncologica non controllata o condizioni psico-sociali che precludano l’entrata in studio nell’opinione del clinico.
12) Trapianto d'organo.
13) Vaccinazioni di ogni tipo entro 4 settimane dalla prima dose di Avelumab o con vaccini vivi o attenuati durante il trattamento.
14) Persistente tossicità legata a terapie precedenti NCI CTCAE v. 4.03 G>1 eccetto: Alopecia, Neuropatia e altre G≤2 non ritenute dallo sperimentatore rischiose per il paziente.
15) Comorbilità rilevanti a giudizio del clinico.
16) Partecipazione ad altro concomitante studio sperimentale
17) Controindicazioni al trattamento con Avelumab:
a. Ipersensibilità ai principi attivi o a uno qualsiasi degli eccipienti.
b. Funzione midollare gravemente compromessa: globuli bianchi totali <2900 mmc e/o Ematocrito <30% e/o Piastrine <90000 mmc.
c. Versamenti sierosi non controllati (pleurici, pericardici, peritoneali).
d. Pressione arteriosa < 60 mmHg a riposo.
e. Gravidanza o allattamento.
f. Infezioni in atto.
g. Metastasi cerebrali note.
h. Malattia cardiovascolare clinicamente significativa (attiva): evento cerebro vascolare/ictus (<6 mesi prima dell'arruolamento), infarto miocardico (<6 mesi prima dell'arruolamento), angina instabile, insufficienza cardiaca congestizia (≥ New York Heart Associazione Classificazione Classe II), o gravi aritmie cardiache che richiedono farmaci.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the phase I trial is the absence of unacceptable toxicity. Assessment of the safety profile of the association of avelumab and metronomic cyclophosphamide will be graded using the common toxicity criteria and adverse events (NCI CTC-AE v 4.0). |
L'endpoint dell'attività primaria è il raggiungimento di una risposta oggettiva.
La risposta dell'obiettivo è definita come risposta completa o risposta parziale secondo i criteri di valutazione (RECIST 1.1). Sarà riportato il tasso di risposte obiettive.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 4 weeks |
| Ogni 4 settimane |
|
| E.5.2 | Secondary end point(s) |
• Assessment of the safety profile of the association of avelumab and metronomic cyclophosphamide will be graded using the common toxicity criteria and adverse events (NCI CTC-AE v 4.0).
• Progression free survival is defined as the time from study treatment initiation to the first occurrence of disease progression or death of any cause, whichever occurs first; Overall survival is defined as the time from treatment initiation to death for any cause.
• Quality of Life will be assessed using the EORTC QLQ -30 and EORTC QLQ – H&N35
|
1) La valutazione del profilo di sicurezza dell'associazione di avelumab e della ciclofosfamide metronomica sarà classificata utilizzando i criteri comuni di tossicità e gli eventi avversi (NCI CTC-AE v 4.0).
2) La sopravvivenza libera dalla progressione è definita come il tempo dall'inizio della terapia di studio alla prima comparsa della progressione della malattia o della morte di qualsiasi causa, a seconda di quale occorra prima; la sopravvivenza globale è definita come il tempo dall'inizio della terapia a morte per qualsiasi causa.
3) La qualità della vita sarà valutata utilizzando l'EORTC QLQ -30 e EORTC QLQ-H & N35.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Every 4 weeks |
| Ogni 4 settimane |
|
| 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 | 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Combination (avelumab+ciclofosfamide+radiotherapy) never administered in humans |
|
| 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.8.3 |
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 | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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
|
| After 4,5 years from study start |
| Dopo 4,5 anni dall'inizio della sperimentazione |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
Print
