| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Histologically confirmed advanced Thymoma B3 or Thymic carcinoma inoperable (Masaoka Stage IIIb or IV). |
| Pazienti affetti da timoma avanzato B3 o carcinoma timico inoperabile (stadio IIIb o IV) |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced thymic carcinoma |
| carcinoma timico avanzato |
|
| 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 | 10055108 |
| E.1.2 | Term | Thymic 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Overall response rate (ORR: complete response + partial response) according to the RECIST 1.1 citeria |
| Determinazione del tasso di risposta complessiva (ORR: risposta comleta + risposta parziale) secondo criteri (RECIST 1.1) |
|
| E.2.2 | Secondary objectives of the trial |
• To determine the activity of the combination therapy determined by overall response rate according to modified ITMIG response criteria.
• To determine the activity of combination therapy determined by overall response rate according to immune-related response criteria (irRC).
• To determine six months progression free survival rate of patients treated with combination therapy. |
• valutazione dell’attività ella combinazione in termini di ORR in accordo ai criteri ITMIG modificati
• valutazione dell’attività ella combinazione in termini di ORR in accordo ai criteri immuno correlati irRC
• valutazione della PFS a 6 mesi |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Histologically confirmed advanced Thymoma B3 or Thymic carcinoma
• Inoperable per local Investigator (Masaoka Stage IIIb or IV).
• Progression after treatment with least one platinum containing chemotherapy regimen
• Measurable disease (RECIST 1.1).
• Age =18 years.
• ECOG PS <2.
• Adequate bone marrow function and organ function:
• Hematopoietic function: total white blood cell count (WBC) = 3000/mm³, absolute neutrophil count (ANC) = = 1.5 × 109/L, platelet count = 100 × 109/L , hemoglobin = 9 g/dL
• Hepatic function: Total bilirubin level = 1.5 × the upper limit of normal (ULN) range and AST and ALT levels = 2.5 × ULN or AST and ALT levels = 5 x ULN (for subjects with documented metastatic disease to the liver).
• Estimated creatinine clearance = 30 mL/min according to the Cockcroft-Gault formula
• Negative serum or urine pregnancy test at screening for women of childbearing potential |
• Conferma istologica di Timoma B3 avanzato o carcinoma timico
• Malattia inoperabile (Masaoka Stage IIIb or IV).
• Progressione dopo trattamento con almeno un regime chemioterapico contenente platino
• Malattia misurabile (RECITS 1.1)
• Età=18 anni
• ECOG PS <2.
• Adeguata funzionalità ematopoietica : WBC = 3000/mm³,(ANC) = 1.5, PLT= 100 × 109/L, Hb= 9 g/dL
• Adeguata funzionalità epatica : bilirubina totale = 1.5 × e AST eALT = 2.5 × il limite superiore rispetto al normale o AST and ALT = 5 x il limite superiore rispetto al normale
• creatinine clearance = 30 mL/min in accordo alla formula di Cockcroft-Gault formula
• test di gravidanza negativo su siero o urine per le donne potenzialmente fertili |
|
| E.4 | Principal exclusion criteria |
• Medical illness that in the investigator’s opinion cannot be adequately controlled with appropriate therapy or would compromise the patient’s ability to tolerate this therapy, including
• Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, transient ischemic attack, deep vein thrombosis or symptomatic pulmonary embolism (< 6 months prior to enrolment), congestive heart failure (= New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication
• Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
• Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive
- Active infection requiring systemic therapy;
- Patients with a history of non-infectious pneumonitis that has required a course of oral or intravenous steroids, or interstitial lung disease or pulmonary fibrosis
- inflammatory bowel disease
• Patients with untreated central nervous system disease. Patients with controlled treated CNS lesions who have undergone surgery or stereotactic radiosurgery and stable for 4 weeks are eligible
• Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent, in particular, any autoimmune syndrome typically associated with thymomas (myasthenia gravis, pure red cell aplasia), including patients with positive anti-AChR and/or anti-MuSK antibodies without clinical signs or symptoms of myasthenia gravis. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible
• History of a hematologic or primary solid tumor malignancy, unless in remission for at least 2 years. Patients with pT1-2 prostatic cancer Gleason score < 6, superficial bladder cancer, non melanomatous skin cancer or carcinoma in situ of the cervix are eligible
• Significantly diseased or obstructed gastrointestinal tract, malabsorption, uncontrolled vomiting or diarrhea or inability to swallow oral medications.
• Prior organ transplantation including allogenic stem-cell transplantation.
• Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines
• Serious psychiatric or medical conditions that could interfere with treatment.
• Concurrent therapy with approved or investigational anticancer therapeutics.
• Current use of immunosuppressive medication within 7 days prior to start treatment, 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)
• Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade = 3) |
• Condizione cliniche, a discrezione del medico non tenute adeguatamente sotto controllo e che possono inficiare la corretta partecipazione del paziente allo studio quali;
• malattie cardiovascolari attive
• HIV pos o sindrome da immunodeficienza acquisita.
• Epatite B o epatite C positive allo screening
• infezioni attive che richiedono terapia sistemica
• malattia del SNC non controllata. I pts con lesioni al SNC trattate chirurgicamente o con radiochirurgia stereotattica stabili per almeno 4 settimane sono eleggibili.
• malattie autoimmuni che potrebbero deteriorare con agenti immunostimolanti
• storia di malattia ematologica o tumore solido a mneo che non sia in remssione da almeno 2 anni. Pazienti con pT1-2 carcinoma prostatico Gleason score < 6, carcinoma della vescica superficiale, carcinoma della pelle o carcinoma in situ della cervice sono eleggibili
• patologie che rendano non possibile l’assunzione di farmaci orali
• precedente trapianto di organi compreso trapianto di cellule allogenico
• vaccinazioni entro le 4 settimane dalla prima dose di farmaco, eccetto che per I vaccini inattivi
• condizioni psichiatriche che possano interferire con lo studio
• simultanee terapie anticancro approvate o in sperimentazione
• simultaneo uso di medicamenti immunosoppressivi entro 7 giorni prima del trattaemnto eccetto che per: steroid ad uso topico, inalanti o intranasali, iniezioni di steroid locali, corticosteroidi sisitemici a dosaggio fisiologico = 10 mg/giorno di prednisone o equivalente , steroidi come premedicazioni per reazioni di ipersensibilizzazione (ad es premedicazioni per la CT scan)
• Ipersensibilità nota al trattamento o a qualsiasi suo componente, inclusa ipersensibilità ad anticorpi monoclonali (NCI CTCAE v4.03 Grade = 3) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| to determine the activity of the combination therapy (avelumab + axitinib) determined by overall response rate (RECIST 1.1) in a cohort of patients with advanced Thymoma B3 or Thymic carcinoma. |
| Determinare l’attività della combinazione di avelumab+axitinib valutata tramite percentuale di risposte obiettive valutate con criteri RECIST 1.1 in una coorte di pazienti con timomi B3 e carcinomi timici |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Anti-tumor activity will be assessed through radiological tumor assessments conducted at screening, and then every 8 weeks up to 18 months after start treatment and every 12 weeks thereafter until documented confirmed disease progression by investigator assessment . In addition, radiological tumor assessments will also be conducted whenever disease progression is suspected (eg, symptomatic deterioration) |
| La valutazione dell’attività del trattamento verrà valutata con rivalutazioni radiologiche eseguite ogni 8 settimane nei primi 18 mesi di trattamento e successivamente ogni 12 settimane. Le rivalutazioni radiologiche saranno anticipate rispetto alle tempistiche schedulate a priori, in caso di sintomi o segni sospetti per progressione di malattia. |
|
| E.5.2 | Secondary end point(s) |
| To determine the activity of the combination therapy determined by overall response rate according to modified ITMIG response criteria.; To determine the activity of combination therapy determined by overall response rate according to immune-related response criteria (irRC).; To determine six months progression free survival rate of patients treated with combination therapy.; To evaluate exploratory biomarkers for prediction of response to combination therapy.; To evaluate safety and tolerability of combination therapy. |
| Determinare l’attività della combinazione di avelumab+axitinib valutata tramite percentuale di risposte obiettive valutate con criteri modificati ITMIG; Determinare l’attività della combinazione di avelumab+axitinib valutata tramite percentuale di risposte obiettive valutate con criteri irRC (criteri di risposta immuno-relati); Determinazione della percentuale di progression free survival dopo i primi 6 mesi di trattamento.; Analisi esploratorie condotte sul tessuto tumorale e prelievi ematici dei pazienti per identificare potenziali biomarkers di risposta al trattamento.; Valutare il profilo di tollerabilità e di sicurezza della combinaizone. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Anti-tumor activity according with ITMIG and irRC criteria will be assessed through radiological tumor assessments conducted at screening, and then every 8 weeks up to 18 months after start treatment and every 12 weeks thereafter until documented confirmed disease progression by investigator assessment . In addition, radiological tumor assessments will also be conducted whenever disease progression is suspected (eg, symptomatic deterioration).; Anti-tumor activity according with ITMIG and irRC criteria will be assessed through radiological tumor assessments conducted at screening, and then every 8 weeks up to 18 months after start treatment and every 12 weeks thereafter until documented confirmed disease progression by investigator assessment . In addition, radiological tumor assessmen |
| La valutazione dell’attività del trattamento verrà valutata con rivalutazioni radiologiche eseguite ogni 8 settimane nei primi 18 mesi di trattamento e successivamente ogni 12 settimane. Le rivalutazioni radiologiche saranno anticipate rispetto alle tempistiche schedulate a priori in caso di sintomi o segni sospetti per progressione di malattia.; La valutazione dell’attività del trattamento verrà valutata con rivalutazioni radiologiche eseguite ogni 8 settimane nei primi 18 mesi di trattamento e successivamente ogni 12 settimane. Le rivalutazioni radiologiche saranno anticipate rispetto alle tempistiche schedulate a priori in caso di sintomi o segni sospetti per progressione di malattia.; La valutazione dell’attività del trattamento verrà valutata con rivalutazioni radiologiche eseguite og |
|
| 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 | No |
| 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) | 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 | 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 | 3 |
| 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 | 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 30 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 30 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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