| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced urotelial cancer of the bladder, urethra, or the upper urinary tract who are resistant to platinum based therapy |
| carcinoma uroteliale avanzato della vescica, uretra e tratto urinario superiore resistente a treapia a base di platino |
|
| E.1.1.1 | Medical condition in easily understood language |
| urothelial cancer |
| carcinoma uroteliale |
|
| 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 | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10005003 |
| E.1.2 | Term | Bladder cancer |
| 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 |
| Evaluate the activity of Alisertib in patients with relapsed/refractory transitional cell tumors. |
• Response-rate per la fase a singolo braccio.
• Progression-free survival (PFS) per la fase randomizzata.
|
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to:
• To evaluate the safety and tolerability of Alisertib in a population of chemotherapy pretreated patients with UC.
• To evaluate translational correlates of response and outcome.
|
• Valutazione della sicurezza e della tollerabilità del trattamento:
o Numero di pazienti che hanno avuto eventi avversi.
o Tipo, frequenza, severità e correlazione al trattamento degli eventi avversi, valutati secondo i Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
• Valutazione del response-rate (RR) definito secondo i criteri RECIST 1.1 (fase randomizzata).
• PFS nella fase a singolo braccio.
• Sopravvivenza globale (OS) (entrambe le fasi).
• Correlazione della risposta metabolica (PET) con la risposta TC (RECIST) e con la PFS.
• Variazione dello score di qualità della vita durante il trattamento valutato con l’ESAS (Edmonton Symptom Assessment Scale).
• Altri obiettivi di ricerca traslazionale (Biomarkers, vedere per i dettagli nel full protocol).
|
|
| 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 |
| Transaltional study of alisertib in baldder cancer |
| studi traslazionale di alisertib nelle neoplasie uroteliali |
|
| E.3 | Principal inclusion criteria |
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
• Histologically confirmed diagnosis of transitional cell tumors of the bladder or the urothelium. Presence of divergent histologies (ex. squamous-cell histology) may be acceptable provided that there is prevalence (> 50%) of urothelial component.
• Locally advanced or metastatic disease.
• Age 18.
• Measurable disease criteria, defined as ≥ 1 unidimensionally measurable lesion ≥ 2 cm by conventional techniques or ≥ 1 cm by spiral CT scan.
• SINGLE ARM PHASE: Failure of one or two platinum-based (either cisplatin or carboplatin) conventional chemotherapy regimen for metastatic disease (second and third-line setting).
• RANDOMIZED PHASE: Failure of no more than 1 platinum-based (either cisplatin or carboplatin) conventional chemotherapy regimen for metastatic disease (pure second-line setting).
• Neoadjuvant/adjuvant therapy considered if relapse occurred within 6 months of the last cycle of chemotherapy.
• Female subject is either:
o post-menopausal for at least one year before the screening visit, or
o surgically sterilized, or
o willing to use an acceptable method of birth control (ie, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.
• Male subject, even if surgically sterilized (ie, status postvasectomy), agrees to use an acceptable method for contraception during the entire study treatment period through 4 months after the last dose of alisertib.
• Absolute neutrophil count (ANC) > 1500/mm³, platelets > 100,000/mm³, Hgb > 9 g/dL. Values must be obtained without need for myeloid growth factor or platelet transfusion support within 14 days, however, erythrocyte growth factor is allowed as per published ASCO guidelines.
• Total bilirubin ≤ 1.5 x upper limit of nomal (ULN), SGOT (AST) and SGPT (ALT)< 2.5 x ULN. AST and/or ALT may be up to 5X ULN if with known liver mets
• Adequate renal function as defined by: Calculated creatinine clearance must be ≥ 30 mL/minute(see Cockcroft-Gault formula in Section 9.5)
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (refer to Section 9.4) & life expectancy of at least 12 weeks.
• Patients must be accessible for treatment and follow up as well as they must be willing and capable to comply with the requirements of the study.
|
• Consenso informato scritto.
• Età ≥ 18 anni.
• Diagnosi istologicamente confermata di carcinoma a cellule transizionali della vescica o delle vie urinarie.
• Malattia localmente avanzata/metastatica.
• Ricaduta/progressione dopo 1 o 2 linee di trattamento chemioterapico platino (cis- o carboplatino) contenente per malattia metastatica.
• [NB: nella fase randomizzata verrà accettata sono 1 linea di pregressa chemioterapia per malattia metastatica].
• Ricaduta/progressione entro 6 mesi da un precedente trattamento peri-operatorio platino-contenente.
• Malattia misurabile, definita come la presenza di ≥ 1 lesione misurabile uni-dimensionalmente con metodiche convenzionali (TC) di ≥ 2 cm o di ≥ 1 cm se misurata con TC spirale.
• Adeguata funzione midollare, epatica e renale in accordo ai valori riportati in Tabella 3 del full protocol.
• ECOG performance status di 0 o 1.
• Soggetti che accettino di praticare un’effettiva contraccezione durante l’intera durata dello studio, a meno che esista documentazione di infertilità (un test di gravidanza negativo eseguito entro le 2 settimane precedenti l’inizio dello studio è necessario per tutte le donne in età fertile).
• Aspettativa di vita di almeno 12 settimane.
• Possibilità e disponibilità a seguire le procedure previste dal protocollo.
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|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
• Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is considered to be over 25%.
• Known GI disease or GI procedures that could interfere with the oral absorption or tolerance of alisertib. Examples include, but are not limited to partial gastrectomy, history of small intestine surgery, and celiac disease
• Known history of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease; requirement for supplemental oxygen.
• Requirement for constant administration of proton pump inhibitor, H2 antagonist, or pancreatic enzymes. Intermittent uses of antacids or H2 antagonists are allowed as described in Section 3.4.
• Systemic infection requiring IV antibiotic therapy within 14 days preceding the first dose of study drug, or other severe infection.
• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see Section 9.3), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
• Female subject who is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum -human chorionic gonadotropin (-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
• Patient has received other investigational drugs with 14 days before enrollment
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
• Other severe acute or chronic medical or psychiatric condition, including uncontrolled diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement for pancreatic enzymes, any condition that would modify small bowel absorption of oral medications, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this study.
• Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
• Treatment with clinically significant enzyme inducers, such as the enzyme-inducing antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin, rifapentine or St. John's wort within 14 days prior to the first dose of alisertib and during the study.
• Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C. Testing is not required in the absence of clinical findings or suspicion. For guidance in defining active infection for hepatitis B, please refer to the WHO guidelines. (World Health Organization, Global Alert and Response (GAR), Hepatitis B. who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index4.html)
• Prior administration of an Aurora A kinase-targeted agent, including alisertib
• Receipt of corticosteroids within 7 days prior to the first dose of study treatment, unless patient has been taking a continuous dose of no more than 15 mg/day of prednisone for at least 1 month prior to first dose of study treatment. Low dose steroid use for the control of nausea and vomiting will be allowed. Topical steroid use is permitted. Inhaled steroids are permitted.
• Inability to swallow oral medication or inability or unwillingness to comply with the administration requirements related to alisertib.
• Administration of myeloid growth factors or platelet transfusion within 14 days prior to the first dose of study treatment.
• Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study.
|
Co-morbidità escluse:
• Importanti patologie cardiovascolari nei 6 mesi che precedono l’inizio di Alisertib, quali:
o Infarto miocardico (IM), angina instabile (l’IM a più di 6 mesi dall’ingresso nello studio è ammesso), scompenso cardiaco di grado ≥ 2 secondo i criteri NYHA, aritmie di qualsiasi natura che richiedano l’uso di farmaci (beta-bloccanti o digossina sono permessi), ipertensione (PA media > 140/90 mm/Hg) non controllata, prolungamento dell’intervallo QT (QTc) > 450 msec.
o Storia di infarti cerebro-vascolari, embolia polmonare o trombosi venosa profonda non trattata entro i 6 mesi che precedono l’inizio del protocollo.
• Infezione da HIV o epatite cronica attiva di tipo B e C.
• Infezioni clinicamente serie in fase attiva (di grado > 2 dei CTCAE v.4.03).
• Metastasi cerebrali o meningee sintomatiche (a meno di un tempo > 6 mesi da un precedente trattamento curative e malattia clinicamente stabile al momento dell’ingresso nello studio).
• Anamnesi positiva per crisi epilettiche che richiedono specifico trattamento medico (come cortico-steroidi e anti-epilettici).
• Impossibilità ad assumere farmaci orali e/o gravi co-morbidità che pregiudicano il corretto assorbimento del farmaco sperimentale.
• Evidenza o anamnesi positiva per diatesi emorragica.
• Dialisi renale.
• Seconda neoplasia pregressa o concomitante fatta eccezione per il carcinoma in situ della cervice, il carcinoma basocellulare o qualsiasi altra neoplasia trattata in modo radicale ad un tempo > 5 anni rispetto alla data di ingresso nello studio.
• Gravidanza e allattamento.
• Presenza di infezione non controllata.
• Chirurgia maggiore o trauma grave nei 28 giorni precedenti alla prima dose di Pazopanib e/o presenza di ferite aperte, fratture o ulcere.
• Ogni tossicità pre-esistente correlata al precedente trattamento chemioterapico di grado > 1 e/o ingravescente.
• Nota ipersensibilità a farmaci chimicamente correlabili ad Alisertib.
• Presenza di qualsiasi condizione medica, disfunzione metabolica o psichiatrica che possa limitare la piena osservanza delle procedure dello studio o aumentare il rischio associato all’assunzione del farmaco.
Terapie oncologiche e altri farmaci esclusi, pregressi o concomitanti:
• Ogni chemioterapia o immunoterapia sia durante il trattamento che entro i 14 giorni precedenti l’arruolamento nello studio (o 5 volte il tempo dell’emivita del farmaco).
• Radioterapia, chirurgia o embolizzazione tumorale durante o entro 14 giorni dall’arruolamento nello studio (la radioterapia a scopo palliativo è ammessa).
• Uso di modificatori di risposta biologica, come il G-CSF, entro 3 settimane dall’ingresso nello studio. [Il G-CSF e altri fattori di crescita emopoietici possono essere utilizzati nel trattamento della tossicità acuta, come la neutropenia febbrile, quando clinicamente indicato e a discrezione dello sperimentatore, tuttavia non può vicariare l’eventuale riduzione di dose del farmaco in studio].
• [I pazienti che assumono cronicamente eritropoietina possono essere arruolati a patto che non vi sia stato un aggiustamento della dose entro i 2 mesi che precedono l’ingresso nello studio o durante lo stesso].
• Pregresso trattamento con Alisertib.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Response rate, progression free survival |
| tasso di risposte e sopravvivenza libera da progressione |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| overall survival, safety and tolerability |
| sopravvivenza globale, sicurezza e tollerabilità |
|
| 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 | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| 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 | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
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