| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Platinum-resistant or refractory, high-grade serous ovarian cancer with no germline BRCA mutation |
|
| E.1.1.1 | Medical condition in easily understood language |
| High-grade serous ovarian cancer without hereditary BRCA mutation that did not respond to prior platinum-based chemotherapy or recurred within six months after such therapy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
| Primary objective: To determine whether treatment with alpelisib in combination with olaparib prolongs PFS compared to single agent cytotoxic chemotherapy |
| L’objectif de cette étude est d'évaluer l'efficacité et la sécurité d'emploi de l'association alpelisib et olaparib comparé à une chimiothérapie standard. |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objective: To determine whether treatment with alpelisib in combination with olaparib prolongs OS compared to single agent cytotoxic chemotherapy
Secondary objectives:
1. To assess safety and tolerability of alpelisib in combination with olaparib
2. To evaluate alpelisib in combination with olaparib compared to single agent cytotoxic chemotherapy with respect to time to deterioration of ECOG (Eastern Cooperative Oncology Group) performance status
3. To assess additional efficacy parameters
4. To characterize the PK of alpelisib and olaparib when administered in combination in patients with platinum-resistant or refractory, gBRCAnm HGSOC
5. To evaluate patient reported-outcomes of alpelisib in combination with olaparib compared to single agent cytotoxic chemotherapy |
Déterminer si le traitement par alpelisib en association avec olaparib prolonge la survie globale (SG) comparé à une mono-chimiothérapie cytotoxique.
Autres objectifs secondaires
1. Evaluer la sécurité d'emploi et la tolérance de l’association alpelisib - olaparib
2. Evaluer alpelisib en association avec olaparib comparé à une mono-chimiothérapie cytotoxique, par rapport à la détérioration de l'indice de performance ECOG (Eastern Cooperative Oncology Group)
3. Evaluer des paramètres d'efficacité additionnels
4. Caractériser la pharmacocinétique d’alpelisib etolaparib lorsqu'ils sont administrés en association , à des patientes atteintes de COSHG gBRCAnm résistant ou réfractaire au platine.
5. Evaluer l’état de santé rapporté par les patientes recevant alpelisib en association avec olaparib,comparé à une mono-chimiothérapiechez. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participant has histologically confirmed diagnosis of high-grade serous or high-grade endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
Measurable disease, i.e., at least one measurable lesion per RECIST 1.1 criteria (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation).
If no measurable disease is present, the disease should be assessable by Gynecologic Cancer Intergroup criteria (GCIC) for CA-125.
Participant has no germline BRCA1/2 mutation as determined by an FDA-approved assay.
Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
Participant has platinum-resistant (progression within one to six months after completing platinum-based therapy) or platinum refractory disease (progression during treatment or within 4 weeks after the last dose), where platinum-based therapy is not an option, according to the GCIG 5th Ovarian Cancer Consensus Conference definitions (Wilson et al 2016). The platinum-based chemotherapy regimen does not necessarily need to be the last regimen the participant received prior to study entry.
Participant must have received at least one but no more than three prior systemic treatment regimens and for whom single-agent chemotherapy is appropriate as the next line of treatment.
Participant has adequate bone marrow and organ function. |
Diagnostic histologiquement confirmé de cancer de l'ovaire séreux de haut grade ou endométrioïde de haut grade, de cancer de la trompe de Fallope ou de cancer péritonéal primitif.
D’une maladie mesurable, c.-à-d., au moins une lésion mesurable conformément aux critères RECIST v1.1 (une lésion sur un site précédemment irradié ne peut être comptabilisée en tant que lésion cible que s'il existe des signes manifestes d'une progression de la lésion depuis son irradiation).
Ou si aucune maladie mesurable n'est présente, la maladie doit pouvoir être évaluée d’après les critères du GCIG (Gynecologic Cancer InterGroup) pour le CA-125.
Aucune mutation germinale BRCA1/2.
Remarque : Si un résultat négatif de mutation germinale BRCA avec le test Myriad BRACAnalysis CDx approuvé par la FDA est fourni par un laboratoire local, ces données peuvent servir pour la confirmation d’absence de mutation BRCA. Si le test Myriad BRACAnalysis CDx approuvé par la FDA n'est pas disponible localement, un résultat négatif de recherche de mutation germinale BRCA doit être confirmé par le laboratoire désigné par Novartis (NVS).
Indice de performance ECOG (Eastern Cooperative Oncology Group) de 0 ou 1.
Maladie résistante au platine (progression dans un délai d’un à six mois après la fin du traitement à base de platine) ou maladie réfractaire au platine (progression sous traitement ou dans les 4 semaines après la dernière dose), pour laquelle le traitement à base de platine n'est pas une option, d’après les définitions de la 5e Conférence de consensus sur les cancers de l'ovaire du GCIG.
Un traitement par chimiothérapie à base de platine ne doit pas nécessairement être le dernier traitement reçu par la patiente avant son entrée dans l'étude.
La patiente doit avoir reçu au moins un mais pas plus de trois schémas de traitements systémiques antérieurs, et pour qui la mono-chimiothérapie est appropriée comme ligne de traitement suivante.
Une fonction adéquate de la moelle osseuse et des organes. |
|
| E.4 | Principal exclusion criteria |
Participant has received prior treatment with any PI3K, mTOR or AKT inhibitor. Participant is concurrently using other anti-cancer therapy.
Participant is in a state of small or large bowel obstruction or has other impairment of gastrointestinal (GI) function or GI disease.
Participant has had surgery within 14 days prior to starting study drug or has not recovered from major side effects.
Participant has not recovered from all toxicities related to prior anticancer therapies to baseline or NCI CTCAE Version 4.03 Grade ≤1. Exception to this criterion: participants with any grade of alopecia are allowed to enter the study.
Participants with liver impairment and Child Pugh score B or C
Participant has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to randomization, and who has not recovered to baseline, grade 1 or better from related side effects of such therapy (with the exception of alopecia).
Participant has a known hypersensitivity to any of the study drugs or excipients. |
Les patientes remplissant l'un des critères suivants ne sont pas éligibles pour inclusion dans cette étude traitement antérieur par un inhibiteur de PI3K, mTOR ou AKT.Utilisation concomitante d’un autre traitement anticancéreux.
Obstruction de l’intestin grêle ou du gros intestin ou autre altération de la fonction gastro-intestinale (GI) ou pathologie GI susceptible.
Intervention chirurgicale dans les 14 jours précédant l'instauration du médicament à l'étude ou absence de récupération des principaux effets secondaires de l'intervention.
Absence de récupération de la totalité des toxicités liées aux traitements anticancéreux antérieurs à la baseline ou de grade ≤ 1 (Common Terminology Criteria for Adverse Events, CTCAE v 4.03). Exception à ce critère : les patientes présentant une alopécie, quelle qu'en soit le grade, sont autorisées à participer à l’étude.
Insuffisance hépatique et score de Child-Pugh B ou C.
Radiothérapie dans un délai de ≤ 4 semaines ou radiothérapie palliative à champ limité dans un délai ≤ 2 semaines avant la randomisation, et absence de récupération de l’état de baseline, grade 1 ou mieux, des effets secondaires associés de ce traitement (sauf alopécie).
Le participant présente une hypersensibilité connue à l'un des médicaments à l'étude ou excipients. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival based on blinded independent review committe assessment using RECIST 1.1 criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Futility analysis based on progression-free survival: approximately after 90 progression-free survival events (first documented progression or death due to any cause), approximately 14 months after randomization of the first subject
Final analysis for progression-free survival: approximately after 224 progression-free survival events, approximately 22 months after randomization of the first subject |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoint: To determine whether treatment with alpelisib in combination with olaparib prolongs OS compared to single agent cytotoxic chemotherapy in participants with platinum-resistant or refractory, gBRCAnm HGSOC
Secondary endpoints: To assess safety and tolerability of alpelisib in combination with olaparib with administered to participants with platinum-resistant or refractory gBRCAnm HGSOC. To Evaluate alpelisib in combination with olaparib compared to single agent cytotoxic chemotherapy in participants with platinum-resistant or refractory, gBRCAnm HGSOC with respect to time to deterioration of ECOG performance status. To assess additional efficacy parameter, such as ORR, CBR, DOR and TTR based on BIRC assessment using RECIST 1.1. To characterize alpelisib when administered in combination with olaparib in participants with platinum- resistant or refractory gBRCAnm HGSOC. To evaluate patient report outcomes of alpelisib in combination with olaparib compared to single agent cytotoxic chemotherapy in participants with platinum-resistant or refractory, gBRCAnm HGSOC. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key secondary endpoint: OS will only be tested if final analysis of PFS is statistically significant.
• The time point for the first OS interim analysis will be at the time of final PFS analysis after approximately 50% of deaths (126 deaths) are expected to have been recorded in the clinical database.
• If OS is not statistically significant at the first interim analysis, the second OS analysis will be planned after approximately 75% of deaths (189 deaths) have been recorded in the clinical database (approximately 31 months after randomization of the first subject). If OS is not statistically significant at this stage, a final analysis is planned at the time approximately 252 deaths have been recorded (approximately 44 months after randomization of the first subject). |
|
| 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 | Yes |
| 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) | 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 52 |
| 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 | No |
| 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 |
| Australia |
| Brazil |
| Canada |
| China |
| India |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Russian Federation |
| Singapore |
| Taiwan |
| Turkey |
| United States |
| Austria |
| Belgium |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Netherlands |
| Portugal |
| Slovakia |
| Spain |
| United Kingdom |
| Czechia |
| Argentina |
|
| 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
|
| Study completion is defined as when the last subject finishes their safety and efficacy follow-up periods (as applicable) and any repeat assessments associated with this visit have been documented and followed-up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision. |
|
| 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 | 3 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
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