| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Glioblastoma |
| Glioblastoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cerebral cancer |
| Tumore cerebrale |
|
| 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 | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018336 |
| E.1.2 | Term | Glioblastoma |
| 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 role of Regorafenib in prolonging the overall survival of glioblastoma multiforme patients who progressed after surgery and Stupp regimen with or without bevacizumab |
| Valutare il ruolo di Regorafenib nel prolungare la sopravvivenza globale dei pazienti con glioblastoma multiforme che hanno progredito dopo l'intervento chirurgico e il regime Stupp con o senza bevacizumab |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the progression free survival (PFS), safety, objective response rate (ORR), disease control rate (DCR) in the ITT population, and the evaluation of quality of life (QoL) |
| Valutare la sopravvivenza libera da progressione (PFS), la sicurezza, il tasso di risposta obiettiva (ORR), tasso di controllo della malattia (DCR) nella popolazione ITT, e la valutazione della qualità della vita (QoL) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Male or female ≥ 18 years of age
•Histologically confirmed de novo glioblastoma multiforme (grade IV)
•First recurrence after adjuvant treatment (surgery followed by radiotherapy and temozolomide chemotherapy with or without bevacizumab) in patients who have not received further therapeutic interventions
•Documented progression of disease as defined by RANO criteria at least 12 weeks after completion of radiotherapy, unless the recurrence is outside the radiation field or has been histologically documented
•Have adequate bone marrow function, liver function, and renal function, as measured by the following laboratory assessments conducted within 7 days prior to the initiation of study treatment:
-Hemoglobin >9.0 g/dl
-Absolute neutrophil count (ANC) >1500/mm3 without transfusions or granulocyte colony stimulating factor and other hematopoietic growth factors
-Platelet count 100,000/μl
-WBC >3.0 x 109/L
-Total bilirubin <1.5 times the upper limit of normal
-ALT and AST <3 x upper limit of normal (<5 x upper limit of normal for patients with liver involvement of their cancer and/or have bone metastasis)
-Serum creatinine <1.5 x upper limit of normal
-Alkaline phosphatase <2.5 x ULN (<5 x upper limit of normal for patients with liver involvement of their cancer and/or have bone metastasis)
-PT-INR/PTT <1.5 x upper limit of normal (Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists per medical history)
-Lipase ≤ 1.5 x the ULN
•Glomerular filtration rate 30 mL/min/1.73 m2 according to the Modified Diet in Renal Disease abbreviated formula
•Analyses of MGMT methylation status on tumoral tissue at first surgery (at own institution)
•Understand, be willing to give consent, and sign the written informed consent form (ICF) prior to undergoing any study-specific procedure
•If female and of childbearing potential, have a negative result on a pregnancy test performed a maximum of 7 days before initiation of study treatment
•If female and of childbearing potential, or if male, agree to use adequate contraception (eg, abstinence, intrauterine device, oral contraceptive, or double-barrier method) based on the judgment of the investigator or a designated associate from the date on which the ICF is signed until 8 weeks after the last dose of study drug
•WHO Performance status ≤ 1 (or KPS ≥70) within 14 days prior to the initiation of study treatment
•Stable or decreasing dosage of steroids for 7 days prior to the baseline MRI scan.
•Patients may have undergone surgery for the recurrence; the histological report must document a glioblastoma recurrence. If operated:
-at least 28 days and maximum 42 days interval from the surgery is required prior to administration of study drugs and patients should have fully recovered |
•Maschio o femmina ≥ 18 anni di età
•Conferma istologica di glioblastoma multiforme (grado IV)
•Prima recidiva dopo trattamento adiuvante (chirurgia seguita da radioterapia e temozolomide con o senza bevacizumab) in pazienti che non hanno ricevuto ulteriori interventi terapeutici
•Documentata progressione di malattia secondo i criteri RANO almeno 12 settimane dopo il completamento della radioterapia, a meno che la recidiva sia al di fuori del campo di radiazione o sia stata confermata istologicamente
•Adeguata funzionalità epatica, renale e del midollo osseo
•Analisi dello stato di metilazione di MGMT eseguita sul tessuto tumorale
•Comprendere, dare il consenso e firmare il relativo modulo (ICF)
•Sia le donne in età fertile che gli uomini devono accettare di utilizzare un metodo di contraccezione adeguato
•Avere un WHO performance status ≤1 (o KPS ≥70) entro i 14 giorni precedenti l'inizio del trattamento in studio
•Dosaggio stabile o decrescente di steroidi nei 7 giorni prima della RMI basale
•Conferma istologica di recidiva di glioblastoma per i pazienti che eseguono un secondo intervento chirurgico |
|
| E.4 | Principal exclusion criteria |
•Are taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s Wort)
•Radiotherapy within 12 weeks prior to the diagnosis of progression
•Have had systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and/or hormonal therapy within 4 weeks prior to initiation of study treatment
•Positioning of carmustin wafers during first or second surgery
•Other active or inactive malignancy (except for carcinoma in situ of the cervix, of the prostate or basal cell carcinoma). Malignancy will be considered inactive if patients are in complete remission for at least 3 years prior to study entry
•Have had prior treatment with regorafenib or any other VEGFR-targeting kinase inhibitor
•Have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment
•Are pregnant
•Are breastfeeding
•Are unable to swallow oral tablets (crushing of study treatment tablets is not allowed)
•Have congestive heart failure classified as New York Heart Association Class 2 or higher
•Have had unstable angina (angina symptoms at rest) or new-onset angina 3 months prior to screening.
•Have had a myocardial infarction < 6 months prior to initiation of study treatment
•Have cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta blockers or digoxin
•Have uncontrolled hypertension (systolic blood pressure [SBP] > 140 mmHg or diastolic blood pressure [DBP] > 90 mmHg) despite optimal medical management
•Have had arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within 6 months prior to the initiation of study treatment
•Have an ongoing infection with severity of Grade 2 or above (NCI-CTCAE v 4.0)
•Have a known history of human immunodeficiency virus infection
•Have either active or chronic hepatitis B or C requiring treatment with antiviral therapy
•Have a history of organ allograft
•Have evidence or history of any bleeding diathesis (including mild hemophilia), irrespective of severity
•Have had a hemorrhage or a bleeding event Grade 3 (NCI-CTCAE v 4.0) within 4 weeks prior to the initiation of study treatment
•Have a non-healing wound, ulcer, or bone fracture
•Have renal failure requiring hemodialysis or peritoneal dialysis
•Have dehydration Grade 1 (NCI-CTCAE v 4.0)
•Have interstitial lung disease with ongoing signs and symptoms at the time informed consent is obtained
•Have persistent proteinuria > 3.5 g/24 hours measured by urine protein creatinine ratio from a random urine sample ( Grade 3, NCI-CTCAE v 4.0)
•Have any other serious or unstable illness, or medical, psychological, or social condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures, or may interfere with the subject’s participation in the study or evaluation of the study results
•Have a known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
•Have any malabsorbition condition |
•Assumere forti inibitori del citocromo P (CYP) CYP3A4 (ad es. claritromicina, indinavir, itraconazolo, ketoconazolo, nefazodone, nelfinavir, posaconazolo, ritonavir, saquinavir, telitromicina, voriconazolo) o di forti induttori del CYP3A4 (ad es. carbamazepina, fenobarbital, fenitoina, rifampicina, erba di San Giovanni)
•Radioterapia nelle 12 settimane prima della diagnosi di progressione
•Terapia antitumorale sistemica (terapia citotossica, con inibitori della trasduzione del segnale, immunoterapia, e/o terapia ormonale) nelle 4 settimane precedenti l'inizio del trattamento in studio
•Posizionamento di wafer carmustin durante la prima o la seconda chirurgia
•Altra neoplasia attiva o inattiva (ad eccezione del carcinoma in situ della cervice, della prostata o carcinoma basocellulare). La malignità sarà considerata inattiva se in remissione completa da almeno 3 anni
•Precedente trattamento con Regorafenib
•Procedura chirurgica maggiore, biopsia aperta o lesione traumatica significativa nei 28 giorni precedenti l'inizio del trattamento in studio
•Pazienti in gravidanza o allattamento
•Incapacita’ di deglutire le compresse (la frantumazione non è consentita)
•Insufficienza cardiaca congestizia New York Heart Association classe 2
•Angina instabile (sintomi a riposo) o angina di nuova insorgenza (iniziata negli ultimi 3 mesi)
•Infarto del miocardio nei 6 mesi precedenti l’inizio del trattamento in studio
•Aritmie cardiache che necessitano di terapia, sono consentiti i beta-bloccanti o la digossina
•Ipertensione non controllata (pressione sistolica [PAS]>140 mmHg o pressione diastolica [PAD]>90 mmHg) nonostante la terapia anti-ipertensiva
•Eventi trombotici arteriosi o embolici quali cerebrovascolari (inclusi attacchi ischemici transitori), o embolia polmonare nei 6 mesi precedenti l'inizio del trattamento in studio
•Infezione in corso di grado >2 (NCI-CTCAE v 4.0)
•Anamnesi nota di infezione da virus dell'immunodeficienza umana (HIV)
•Epatite B o C attiva o cronica che richiede trattamento con terapia antivirale
•Allotrapianto d’organo
•Pazienti con evidenza o anamnesi di diatesi emorragica (compresa l'emofilia lieve), a prescindere dalla gravità
•Emorragia o evento di sanguinamento di grado 3 (NCI-CTCAE v 4.0) nelle 4 settimane precedenti l'inizio del trattamento in studio
•Ferita, ulcera, o frattura ossea non in guarigione
•Insufficienza renale che richiede emodialisi o dialisi peritoneale
•Disidratazione di grado 1 (NCI-CTCAE v 4.0)
•Malattia polmonare interstiziale con segni e sintomi in corso
•Persistente proteinuria >3,5 g/24 ore (Grado 3, NCI-CTCAE v 4.0)
•Qualsiasi altra malattia grave o instabile, o condizione medica, psicologica o sociale, che potrebbe compromettere la sicurezza del soggetto e/o la sua compliance alle procedure dello studio, o che può interferire con la partecipazione del soggetto allo studio o alla valutazione dei risultati ottenuti
•Ipersensibilità a qualsiasi dei farmaci o classe di farmaci in studio o eccipienti nella formulazione
•Qualsiasi condizione di mal-assorbimento |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall survival, assessed from the date of randomization to the date of death from any cause |
| Valutare la sopravvivenza globale (OS) dalla data di randomizzazione alla data di morte per qualsiasi causa |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 3 years (LP off study: December 2017) |
| 3 anni, (LP off study: Dicembre 2017) |
|
| E.5.2 | Secondary end point(s) |
•Progression free survival, assessed from the date of randomization to the date of disease progression or to the date of death, whichever occurs first
•Objective response rate, as percentage of patients achieving a complete response plus partial response
•Disease control rate, as percentage of patients achieving a complete response plus partial response plus stable disease
•Toxicity during the treatment, graded according to the NCI-Common Terminology Criteria for Adverse Events (CTCAE) v.4
•Quality of Life assessed by EORTC QLQ-C30 and QLQ-BN20 |
• sopravvivenza libera da progressione, valutato dalla data di randomizzazione alla data di progressione della malattia o alla data del decesso, a seconda di quale si verifica prima
• tasso di risposta obiettiva, come la percentuale di pazienti che hanno ottenuto una risposta completa più risposta parziale
• tasso di controllo della malattia, come la percentuale di pazienti che hanno ottenuto una risposta completa più risposta parziale più malattia stabile
• tossicità durante il trattamento, classificati secondo i criteri NCI-Terminologia comune per gli eventi avversi (CTCAE) v.4
• Qualità della vita valutata EORTC QLQ-C30 e QLQ-BN20 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 2 years, (LP off treatment: Dicember 2016) |
| 2 anni, (LP off treatment: Dicembre 2016) |
|
| 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) | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 10 |
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| December 2017 |
| Dicembre 2017 |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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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