| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients with
Advanced FIGO Stage IIIB – IV High Grade Serous or Endometrioid Ovarian, Fallopian
Tube, or Peritoneal Cancer treated with standard First-Line Treatment, Combining
Platinum-Taxane Chemotherapy and Bevacizumab Concurrent with Chemotherapy
and in Maintenance |
pazienti affette da carcinoma sieroso ad alto grado o endometrioide
dell’ovaio, della tuba o del peritoneo, avanzato, stadio FIGO IIIB-IV, che
abbiano ricevuto chemioterapia di prima linea con carboplatinopaclitaxel
più bevacizumab. |
|
| E.1.1.1 | Medical condition in easily understood language |
Patients with
Advanced FIGO Stage IIIB – IV High Grade Serous or Endometrioid Ovarian, Fallopian
Tube, or Peritoneal Cancer treated with standard First-Line Treatment, Combining
Platinum-Taxane Chemot |
pazienti affette da carcinoma sieroso ad alto grado o endometrioide
dell’ovaio, della tuba o del peritoneo, avanzato, stadio FIGO IIIB-IV, che
abbiano ricevuto chemioterapia di prima linea con carbopl |
|
| 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 | 10070907 |
| E.1.2 | Term | Ovarian cancer stage III |
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10070908 |
| E.1.2 | Term | Ovarian cancer stage IV |
| 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 determine the efficacy by progression free survival (PFS1) investigator based according to
modified Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) of olaparib
maintenance compared to placebo in high grade epithelial ovarian, fallopian tube, or peritoneal
cancer that are in clinical complete response or partial response following first line platinumtaxane
based chemotherapy plus bevacizumab, and planned to pursue bevacizumab in the
maintenance phase up to a total of 15 months. |
| Sopravivenza libera di malattia (PFS1) fra olaparib e placebo |
|
| E.2.2 | Secondary objectives of the trial |
To determine :
· time to earliest progression by RECIST or Cancer Antigen-125 (CA-125) or death
· time from randomization to first subsequent therapy or death (TFST)
· time from randomization to second progression (PFS2)
· time from randomization to second subsequent therapy or death (TSST)
· overall survival (OS)
2. To assess the safety and tolerability of olaparib maintenance compared to placebo.
3. To compare the effects of olaparib maintenance compared to placebo on
Health-Related Quality of Life (HRQoL) and patient reported outcomes (PROs), with
consideration of patient preference.
4. To evaluate the impact of treatment and disease on resource use. |
1. Determinare :
· Tempo alla progressione secondo RECIST o Cancer Antigen-125 (CA-125) o decesso
· Tempo dalla randomizzazione alla prima terapia successiva o decesso (TFST)
· Tempo dalla randomizzazione alla seconda progressione (PFS2)
· Tempo dalla randomizzazione alla seconda terapia successiva o decesso (TSST)
· Sopravvivenza globale (OS)
2. Valutare la sicurezza e tollerabilità di olaparib in mantenimento versus placebo.
3. Confrontare la qualità di vita (HRQoL) e, gli “patient reported outcomes” (PROs), e la
preferenza dalla paziente di olaparib in mantenimento versus placebo.
4. Valutare l’impatto del trattamento e la malattia sull' impiego di risorse.
|
|
| 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: 3.0
Date: 15/02/2016
Title: PAOLA-1
Objectives: see section 3.3 Exploratory Objectives
|
Farmacogenomica
Versione: 3.0
Data: 15/02/2016
Titolo: PAOLA-1
Obiettivi: see section 3.3 Exploratory Objectives
|
|
| E.3 | Principal inclusion criteria |
I-1. Female Patient must be =18 years of age.
I-2. Signed informed consent and ability to comply with treatment and follow-up.
I-3. Patient with newly diagnosed
I-3-1 Ovarian cancer, primary peritoneal cancer and/or fallopian-tube cancer,
I-3-2 Histologically confirmed (based on local histopathological findings):
• high grade serous (see appendix 2) or
• high grade endometrioid (see appendix 2) or
• other epithelial non mucinous ovarian cancer in a patient with germline BRCA 1 or 2 deleterious mutation
I-3-3 at an advanced stage: FIGO stage IIIB, IIIC, or IV of the 1988 FIGO classification (see appendix 1).
I-4. Patient who has completed prior to randomization first line platinum-taxane chemotherapy:
a. Platinum-taxane based regimen must have consisted of a minimum of 6 treatment cycles and a maximum of 9. However if platinum based therapy must be discontinued early as a result of non hematological toxicity specifically related to the platinum regimen, (i.e. neurotoxicity, hypersensitivity etc.), patient must have received a minimum of 4 cycles of the platinum regimen.
b. Intravenous, intraperitoneal, or neoadjuvant platinum based chemotherapy is allowed; for weekly therapy, three weeks are considered one cycle. Interval debulking is allowed.
I-5. Patient must have received prior to randomization a minimum of 3 cycles of bevacizumab in combination with the 3 last cycles of platinum-based chemotherapy. Only in case of interval debulking surgery, it is allowed to realize only 2 cycles of bevacizumab in combination with the last 3 cycles of platinium-based chemotherapy. Bevacizumab treatment should be administered at a dose 15mg/kg q3 weeks up to a total of 15 months.
I-6. Patient must be prior to randomization without evidence of disease (NED) or in complete response (CR) or partial response (PR) from her first line treatment. There should be no clinical evidence of disease progression (physical exam, imagery, CA 125) throughout her first line treatment and prior to study randomization.
I-7. Patient must be randomized at least 3 weeks and no more than 9 weeks after her last dose of chemotherapy (last dose is the day of the last infusion) and all major toxicities from the previous chemotherapy must have resolved to CTC AE grade 1 or better (except alopecia and peripheral neuropathy).
I-8. Patient must have normal organ and bone marrow function:
a. Hemoglobin = 10.0 g/dL.
b. Absolute neutrophil count (ANC) = 1.5 x 109/L.
c. Platelet count = 100 x 109/L.
d. Total bilirubin = 1.5 x institutional upper limit of normal (ULN).
e. Aspartate aminotransferase /Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT)) and Alanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) = 2.5 x ULN, unless liver metastases are present in which case they must be = 5 x ULN.
f. Serum creatinine = 1.25 x institutional ULN and creatinine clearance > 50 mL/min.
g. Patient not receiving anticoagulant medication who has an International Normalized Ratio (INR) =1.5 and an Activated ProThrombin Time (aPTT) =1.5 x ULN.
The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or APTT is within therapeutic limits (according to site medical standard) the patient is on oral anticoagulants, dose has to be stable for at least two weeks at the time of randomization.
h. Urine dipstick for proteinuria < 2+. If urine dipstick is =2+, 24-hour urine must demonstrate <1 g of protein in 24 hours.
i. Normal blood pressure or adequately treated and controlled hypertension (systolic BP = 140 mmHg and/or diastolic BP = 90 mmHg).
I-9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (see appendix 3)
I-10. Formalin fixed, paraffin embedded (FFPE) tumor sample from the primary cancer must be available for central BRCA testing and test result must be available for stratification.
I-11. Postmenopausal or evidence of non-childbearing status for women of childbearing potential prior to the first dose of study treatment. (see appendix 4)
|
I-1. Sesso femminile con età =18 anni.
I-2. Consenso informato scritto
I-3. Recente diagnosi di:
I-3-1 Carcinoma dell’ovaio, della tuba e/o del peritoneo,
I-3-2 con istologia :
· alto grado sieroso (vedi appendice 2) o
· alto grado endometrioide (vedi appendice 2) o
· altro carcinoma ovarico epiteliale non mucinoso in una paziente con mutazione
germinale BRCA 1 o 2 mutazione deleteria
I-3-3 Stadio avanzato: FIGO IIIB, IIIC, or IV della classificazione FIGO 1988 (vedi appendice 12).
I-4. Chemioterapia a base di platino e taxani completata prima della randomizzazione:
a. Almeno 6 e non più di 9 cicli di terapia a base di platino e taxani. Se la paziente ha
sospeso la terapia platino per una tossicità non ematologica, almeno 4 cicli di
terapia del platino prima della randomizzazione
b. Sono permesse:terapia a base di platino endovenosa o intraperitoneale, terapia
neoadiuvante,chirurgia di intervallo permesso.
I-5. Almeno tre cicli di terapia con bevacizumab in combinazione con gli ultimi 3 cicli di chemioterapia a base di platino. In caso di chirurgia di intervallo, almeno 2 cicli con bevacizumab in combinazione con gli ultimi 3 cicli di chemioterapia a base di platino. Dose di bevacizumab 15mg/kg ogni 3 settimane per fino a 15 mesi.
I-6. Senza evidenza di malattia, o in risposta completa o risposta parziale dopo la prima linea.
Senza evidenza di progressione di malattia durante la terapia di prima linea e prima della
randomizzazione.
I-7. Randomizzazione almeno 3 e non più di 9 settimane dopo l’ultima dose di chemioterapia e
recupero al grado = 1 (secondo CTCAE v4) di tutte le maggiori tossicità dalla precedente
chemioterapia (eccetto: alopecia e neuropatia periferica)
I-8. Normale funzionalità d'organo:
a. Emoglobina = 10.0 g/dL.
b. Valore assoluto Neutrofili (ANC) = 1.5 x 109/L.
c. Piastrine = 100 x 109/L.
d. Bilirubina Totale = 1.5 x il limite alto del range di normalità(ULN).
e. Transaminasi AST/ALT = 2.5 x ULN, eccetto nel caso di metastasi epatiche ove il
valore deve essere = 5 x ULN.
f. Creatinina = 1.25 x ULN e clearance della creatinina > 50 mL/min.
g. Non in trattamento con anticoagulanti che abbia un International Normalized Ratio (INR) =1.5 e un tempo di protrombina attivata (aPTT) =1.5 x ULN.
Il trattamento con anticoagulanti orali o parenterali è consentito se l'INR e l'aPTT sono nei limiti terapeutici (secondo gli standard internazionali accettati) ed il paziente, al momento della randomizzazione, sia in trattamento con una dose stabile di anticoagulanti da almeno 2 settimane.
h. Dipstick delle urine < 2+ per le proteine. In caso di disptick =2+, la proteinuria nelle
24 ore deve essere <1 g.
i. Pressione arteriosa nella norma (sistolica = 140 mmHg e/o diastolica BP = 90
mmHg), o adeguatamente controllata con il trattamento.
I-9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (see appendix 3)
I-10. Campione tissutale in paraffina (Formalin fixed, paraffin embedded, FFPE) del tumore
primitivo per il test di BRCA a livello centralizzato il cui risultato sarà disponibile per la
stratificazione al momento della randomizzazione.
I-11. Evidenza di assenza di gravidanza in corso o possibile o menopausa (naturale o indotta)
prima della prima di dose di trattamento. (vedi appendice 4)
|
|
| E.4 | Principal exclusion criteria |
1-Non-epithelial origin of the ovary, the fallopian tube or the peritoneum(i.e. germ cell tumors).2-Ovarian tumors of low malignant potential (e.g. borderline tumors), ormucinous carcinoma.3-Patients with synchronous primary endometrial cancer unless both of
the following criteria are met:-stage < II,-Less than 60 years old at the time of diagnosis of endometrial cancerwith stage IA or IB grade 1 or 2, or stage IA grade III endometrial carcinoma OR = 60 years old at the time of diagnosis of endometrial cancer withstage IA grade 1 or 2 endometrioid adenocarcinoma.-Patients with serous or clear cell adenocarcinoma or carcinosarcoma of
the endometrium are not eligible.4-Other malignancy within the last 5 years except: adequately treatednon-melanoma skin cancer curatively treated in situ cancer of the cervix,ductal carcinoma in situ .Patients with history of primary triple negative breast cancer may beeligible provided they completed their definitive anticancer treatmentmore than 3 years ago and they remain breast cancer disease free priorto start of study treatment.5-Patients with myelodysplastic syndrome/acute myeloid leukemia
history.6-Patients having experienced a delay > 2 weeks in the chemotherapycourse administration due to prolonged hematological recovery.7-Patients receiving radiotherapy within 6 weeks prior to studytreatment.8-Major surgery within 4 weeks of starting study treatment and patientsmust have recovered from any effects of any major surgery.9-Previous allogenic bone marrow transplant.
10-Any previous treatment with PARP inhibitor, including olaparib.11-Administration of other simultaneous chemotherapy drugs, any otheranticancer therapy or anti-neoplastic hormonal therapy, or simultaneousradiotherapy during the trial treatment period
12-Current or recent (within 10 days prior to randomization) chronic use ofaspirin > 325 mg/day.13-Concomitant use of known potent CYP3A4 inhibitors such asketoconazole, itraconazole, ritonavir, indinavir, saquinavir,telithromycin, clarithromycin and nelfinavir.14-Prior history of hypertensive crisis (CTC-AE grade 4) or hypertensiveencephalopathy.15-Clinically significant cardiovascular disease, including:-Myocardial infarction or unstable angina within = 6 months ofrandomization,-NYH = grade 2 congestive heart failure (CHF),-Poorly controlled cardiac arrhythmia despite medication (patients withrate controlled atrial fibrillation are eligible), or any clinically significantabnormal finding on resting ECG,-Peripheral vascular disease grade = 3 (e.g. symptomatic and interferingwith activities of daily living [ADL] requiring repair or revision).16-Previous Cerebro-Vascular Accident, Transient Ischemic Attack or Sub-Arachnoids Hemorrhage within 6 months prior to randomization.
17-History or evidence of hemorrhagic disorders within 6 months prior torandomization.18-Evidence of bleeding diathesis or significant coagulopathy19-History or clinical suspicion of brain metastases or spinal cordcompression. CT/MRI of the brain is mandatory (within 4 weeks prior torandomization) in case of suspected brain metastases. Spinal MRI ismandatory (within 4 weeks prior to randomization) in case of suspectedspinal cord compression.20-History or evidence upon neurological examination of central nervoussystem disease, unless adequately treated with standard medicaltherapy .21-Significant traumatic injury during 4 weeks prior to randomization.22-Non-healing wound, active ulcer or bone fracture. Patients withgranulating incisions healing by secondary intention with no evidence offacial dehiscence or infection are eligible but require 3 weekly woundexaminations.23-History of VEGF therapy related abdominal fistula or gastrointestinalperforation or active gastrointestinal bleedingwithin 6 months prior tothe first study treatment.24-Current, clinically relevant bowel obstruction, including sub-occlusivedisease, related to underlying disease.25-Patients with evidence of abdominal free air not explained byparacentesis or recent surgical procedure.
26-Evidence of any other disease, metabolic dysfunction, physicalexamination finding or laboratory finding giving reasonable suspicion ofa disease or condition that contraindicates the use of an investigationaldrug or puts the patient at high risk for treatment related complications.27-Pregnant or lactating women. 28-Participation in another clinical study with an investigational product during herchemotherapy course immediately prior to randomization.29-Patients unable to swallow orally administered medication and patientswith gastrointestinal disorders likely to interfere with absorption of thestudy medication.30-Patients with a known hypersensitivity to olaparib or any of therecipients of the product.31-Immunocompromised patients, e.g., with known active hepatitis due torisk of transmitting the infection through blood or other body fluids orpatients who are known to be serologically positive for humanimmunodeficiency virus.
|
1Tumore non epiteliale(i.e.tumore germinale)a origine da ovaio, tuba o peritoneo2Tumore ovarico a basso potenziale di malignita(borderline)o tumore mucinoso3 tumore endometriale sincrono a meno che tutti i seguenti criteri non siano rispettati:a. stadio < II,b. età < 60 anni al momento della diagnosi di carcinoma endometriale stadio IA o IB grado 1 o 2, o stadio IA grado3; ovvero età = 60 anni al momento della diagnosi di carcinoma endometriale I A grado 1 o 2.
Pazienti con tumore endometriale sieroso, a cellule chiare o carcinosarcoma non sono eleggibili.
.Paz con tumore endometriale sieroso, a cellule chiare o carcinosarcoma non sonoeleggibili4Precedenti neoplasie negli ultimi5 anni eccetto: tumori cutanei "non-melanoma", cancrodella cervice in situ e carcinoma duttale della mammella in situ, adeguatamente trattati.Paz con anamnesi di neoplasia localizzata precedente ai5anni dall'inizio deltratt. possono essere eleggibili se hanno completato la terapia adiuvante primadella randomizzazione e sono libere da malattia.Paz con storia di tumore mammario triplo-negativo possono essere eleggibili qualoraabbiano completato il lorotratt. definitivo piu di 3 anni prima e siano liberi daneoplasia prima dell'inizio del tratt. in studio5Paz con anamnesi positiva per sindrome mielodisplastica o leucemia mieloide acuta6Paz che hanno avuto in almeno un ciclo un ritardo di tratt. > 2 settimana acausa di tossicita ematologica prolungata7 Radioterapia nelle 6 settimane precedenti l'inizio del tratt.8Chirurgia maggiore nelle 4 settimane prima dell'inizio del tratt.. La paz deve aver recuperato completamente da ogni effetto della chirurgia maggiore per essere eleggibile.9Precedente trapianto di midollo allogenico10Precedente tratt. con inibitori PARP, incluso olaparib11Somministrazione concomitante di chemioterapia, ogni altro agente antitumorale oradioterapia durante il periodo dello studio. Sono consentiti la terapia ormonale sostitutivae gli steroidi a scopo antiemetico12Utilizzo concomitante o recente (entro 10 giorni precedenti alla randomizzazione) diaspirina a dosi maggiori di 325 mg/die13 Utilizzo simultaneo di potenti inibitori del citocromo CYP3A4 come: ketoconazolo,itraconazolo, ritonavir, indinavir, saquinavir, telithromicina, claritromicina and nelfinavir14Storia di crisi ipertensive(CTCAE G4)o di encefalopatia ipertensiva15Presenza di almeno una malattia cardiovascolare clinicamente significativa (i.e. attiva)incluso:a. Infarto del miocardio o angina instabile nei 6 mesi precedenti alla randomizzazioneb. New York Heart Association(NYHA)=G2scompenso cardiaco congestizio,(vediappendice5).c. Aritmia scarsamente controllata dai farmaci (i Paz con fibrillazione atrialecontrollata sono eleggibili),d. Malattia vascolare periferica = G3(i.e.sintomatiche e che interferisce con lenormali attivita quotidiane(ADL)16Precedente accidente cerebro-vascolare, attacco ischemico transitorio(TIA)o emorragiasubaracnoidea entro i 6 mesi precedenti alla randomizzazione17Storia o evidenza di disordini emorragici nei 6 mesi precedenti la randomizzazione18Evidenza di diatesi emorragica o coagulopatia significativa(in assenza di coagulazione)19Storia o sospetto clinico di metastasi cerebrali o compressione midollare La CT/RMNdell'encefalo e obbligatoria (entro le 4 settimane primadellarandomizzazione) in caso dimetastasi cerebrali sospette. Una RMN della colonna vertebrale e obbligatoria nelle 4settimane precedenti alla randomizzazione in caso di sospetta compressione midollare20Storia o evidenza alla visita neurologica di malattia a a carico del sistema nervoso centralenon adeguatamente controllata con la terapia medica standard (i.e. epilessia noncontrollata)21Trauma significativo nelle 4 settimane precedenti il tratt.22Ferite non rimarginate, ulcere attive, o fratture ossee. Paz con ferite in guarigione perseconda intenzione in assenza di deiscenza della fascia o infezione possono esserearruolabili ma necessitano di controllo trisettimanale della ferita23 Storia di fistola addominale o perforazione gastrointestinale o sanguinamentogastrointestinale attivo legati al tratt. con agenti anti VEGF entro i 6 mesi precedentiall'entrata nello studio24. Occlusione intestinale, inclusa la subocclusione, legata alla patologia di base clinicamente significativa 25Aria libera in addome non spiegabile con una recente paracentesi o procedura chirurgica26Evidenza di qualsiasi altra malattia, disfunzione metabolica, sintomo o segno e qualsiasi altro valore di laboratorio generante il sospetto di una controindicazione all'uso di un agente sperimentale o che ponga il paziente ad alto rischio di complicanze legate al tratt. 27Gravidanza o allattamento28Partecipazione ad altro studio clinico durante il periodo di tratt. chemioterapico immediatamente precedente alla randomizzazione 29 Incapacita della paziente di assumere farmaci per via orale o condizione che possainterferire con il loro assorbimento30Nota ipersensibilita a olaparib o uno degli eccipie |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PFS1 is defined as the time from randomization until the date of the first
objective radiological disease progression according to investigator
assessment of RECIST version 1.1 or death (by any cause in the absence
of progression) regardless of whether the patient withdraws from
randomized study treatment or receives another anti-cancer therapy
prior to progression. Patients who have not progressed or died at the
time of analysis will be censored at the time of the latest date of
assessment from their last evaluable RECIST assessment. However, if
the patient progresses or dies after two or more missed visits, the
patient will be censored at the time of the latest evaluable RECIST
assessment. If the patient has no evaluable visits or does not have a
baseline assessment they will be censored at day 1 unless they die
within two visits of baseline.
The PFS time will always be derived based on imagery assessment dates
not visit dates. RECIST assessments contributing towards a particular
visit may be performed on different dates. The following rules will be
applied:
• Date of progression will be determined based on the earliest date of
the RECIST assessment fulfilling criteria of disease progression.
• When censoring a patient for PFS the patient will be censored at the
latest of the RECIST assessment dates contributing to a particular
overall visit assessment.
The primary analysis will be based on investigator-recorded
assessments. An independent central review (ICR) of the radiological
scans may be carried out. |
PFS1 is defined as the time from randomization until the date of the first
objective radiological disease progression according to investigator
assessment of RECIST version 1.1 or death (by any cause in the absence
of progression) regardless of whether the patient withdraws from
randomized study treatment or receives another anti-cancer therapy
prior to progression. Patients who have not progressed or died at the
time of analysis will be censored at the time of the latest date of
assessment from their last evaluable RECIST assessment. However, if
the patient progresses or dies after two or more missed visits, the
patient will be censored at the time of the latest evaluable RECIST
assessment. If the patient has no evaluable visits or does not have a
baseline assessment they will be censored at day 1 unless they die
within two visits of baseline.
The PFS time will always be derived based on imagery assessment dates
not visit dates. RECIST assessments contributing towards a particular
visit may be performed on different dates. The following rules will be
applied:
• Date of progression will be determined based on the earliest date of
the RECIST assessment fulfilling criteria of disease progression.
• When censoring a patient for PFS the patient will be censored at the
latest of the RECIST assessment dates contributing to a particular
overall visit assessment.
The primary analysis will be based on investigator-recorded
assessments. An independent central review (ICR) of the radiological
scans may be carried out. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS1 is defined as the time from randomization until the date of the first
objective radiological disease progression according to investigator
assessment of RECIST version 1.1 or death |
PFS1 is defined as the time from randomization until the date of the first
objective radiological disease progression according to investigator
assessment of RECIST version 1.1 or death |
|
| E.5.2 | Secondary end point(s) |
Overall Survival (OS) is defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.
Time to earliest progression by RECIST or CA-125 Time to earliest progression by RECIST v. 1.1 or CA-125 or death is
defined as the time from randomization to the earliest date of RECIST or CA-125 progression or death by any cause. Progression according to CA-125 will be assessed according to GCIG (see appendix 8). Patients without a CA-125 progression or a RECIST progression who arestill alive at the time of analysis will be censored at their last evaluable RECIST assessment or their last available CA-125 measurement,whichever is the most recent at the time of the analysis. If a patientprogresses or dies after two or more missed RECIST and CA-125 assessments, then the patient will be censored at the time oftheir last evaluable assessment. If only one assessment is missing during this period, no censoring is required. Second Progression Free Survival (PFS2) Time from randomization to second progression is defined as the time from the date of randomization to the earliest of the progression event subsequent to that used for the primary variable PFS, or date of death.The date of second progression will be recorded by the investigator and defined according to local standard clinical practice and may involve any of; objective radiological, CA-125 or symptomatic progression or death.Second progression status will be reviewed regularly following the progression event used for the primary variable PFS (PFS1) andrecorded. Patients alive and for whom a second disease progression has not been observed should be censored at the last time known to be alive and without a second disease progression, i.e. censored at the latest of the tumor assessment date if the patient has not had a second progression or death).; Time to start of first subsequent therapy or death (TFST) will be assessed. TFST is defined as the time from the date of randomization to the earliest of the date of anti-cancer therapy start date following study treatment discontinuation, or death. Subsequent therapies intended to control ovarian cancer will be reported. Any patient not known to have died at the time of the analysis and not known to have had a furth intervention of this type will be censored at the last known time to havenot received subsequent therapy, i.e. the last follow-up visit where this was confirmed. Safety and tolerability will be assessed in terms of AEs, deaths,laboratory data, vital signs and ECG. AE will be described according to MedDRA terms (version 17.0) and graded according to CTCAE version 4.03. These will be collected for all patients. Appropriate summaries of these data will be presented. Patient reported outcome variables Patient-reported health-related quality of life (HRQoL) will be ossesse using the FACT-O questionnaire 24(Basen-Engquist K et al 2001). The FACT-O is composed of the following subscales: physical, social/family,emotional, and functional well-being as well as the additional concerns scales consisting of specific ovarian cancer symptoms.The total FACT-O score will be calculated which is made up of the sum ofthe individual subscale scores: physical well being (PWB), social well being (SWB), emotional well being (EWB) and functional well being(FWB).
Geriatric assessment will be assessed using the Geriatric Vulnerability Score (GVS). Further details of the analysis based on the geriatric assessment will be outlined in the SAP.Pharmacoeconomy frequency and estimates of resource use, including length of stay and number of hospital admissions, will be derived from the resource use information.
|
Overall Survival (OS) is defined as the time from the date of randomization until death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive.
Time to earliest progression by RECIST or CA-125 Time to earliest progression by RECIST v. 1.1 or CA-125 or death is
defined as the time from randomization to the earliest date of RECIST or CA-125 progression or death by any cause. Progression according to CA-125 will be assessed according to GCIG (see appendix 8). Patients without a CA-125 progression or a RECIST progression who arestill alive at the time of analysis will be censored at their last evaluable RECIST assessment or their last available CA-125 measurement,whichever is the most recent at the time of the analysis. If a patientprogresses or dies after two or more missed RECIST and CA-125 assessments, then the patient will be censored at the time oftheir last evaluable assessment. If only one assessment is missing during this period, no censoring is required. Second Progression Free Survival (PFS2) Time from randomization to second progression is defined as the time from the date of randomization to the earliest of the progression event subsequent to that used for the primary variable PFS, or date of death.The date of second progression will be recorded by the investigator and defined according to local standard clinical practice and may involve any of; objective radiological, CA-125 or symptomatic progression or death.Second progression status will be reviewed regularly following the progression event used for the primary variable PFS (PFS1) andrecorded. Patients alive and for whom a second disease progression has not been observed should be censored at the last time known to be alive and without a second disease progression, i.e. censored at the latest of the tumor assessment date if the patient has not had a second progression or death).; Time to start of first subsequent therapy or death (TFST) will be assessed. TFST is defined as the time from the date of randomization to the earliest of the date of anti-cancer therapy start date following study treatment discontinuation, or death. Subsequent therapies intended to control ovarian cancer will be reported. Any patient not known to have died at the time of the analysis and not known to have had a furth intervention of this type will be censored at the last known time to havenot received subsequent therapy, i.e. the last follow-up visit where this was confirmed. Safety and tolerability will be assessed in terms of AEs, deaths,laboratory data, vital signs and ECG. AE will be described according to MedDRA terms (version 17.0) and graded according to CTCAE version 4.03. These will be collected for all patients. Appropriate summaries of these data will be presented. Patient reported outcome variables Patient-reported health-related quality of life (HRQoL) will be ossesse using the FACT-O questionnaire 24(Basen-Engquist K et al 2001). The FACT-O is composed of the following subscales: physical, social/family,emotional, and functional well-being as well as the additional concerns scales consisting of specific ovarian cancer symptoms.The total FACT-O score will be calculated which is made up of the sum ofthe individual subscale scores: physical well being (PWB), social well being (SWB), emotional well being (EWB) and functional well being(FWB).
Geriatric assessment will be assessed using the Geriatric Vulnerability Score (GVS). Further details of the analysis based on the geriatric assessment will be outlined in the SAP.Pharmacoeconomy frequency and estimates of resource use, including length of stay and number of hospital admissions, will be derived from the resource use information.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| OS OVERALL SURVIVAL; PFS2 SECOND PROGRESSION FREE SURVIVAL |
| OS OVERALL SURVIVAL; PFS2 SECOND PROGRESSION FREE SURVIVAL |
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Quality of life
Geriatric assessment
Biomarkers |
Quality of life
Geriatric assessment
Biomarkers |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | 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
| 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 | 22 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 150 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Japan |
| Austria |
| Belgium |
| Denmark |
| Finland |
| France |
| Germany |
| Norway |
| Spain |
| Sweden |
|
| 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
|
The end of the study is defined as 'the last visit of the last patient
undergoing the study'.
The study is expected to start in Quarter 1 2015 and to end by Quarter
1 2022. The study may be terminated at individual centers if the study
procedures are not being performed according to GCP, or if recruitment
is slow. ARCAGY-GINECO may also terminate the entire study
prematurely if concerns for safety arise within this study or in any
other study with olaparib. |
The end of the study is defined as 'the last visit of the last patient
undergoing the study'.
The study is expected to start in Quarter 1 2015 and to end by Quarter
1 2022. The study may be terminated at individual centers if the study
procedures are not being performed according to GCP, or if recruitment
is slow. ARCAGY-GINECO may also terminate the entire study
prematurely if concerns for safety arise within this study or in any
other study with olaparib. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| 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 | 7 |
| 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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