Platine, Avastin and OLAparib in 1st Line

Ovarian Cancer Clinical Trial

— PAOLA-1  

Official title:

Randomized, Double-Blind, Phase III Trial Olaparib vs. Placebo Patients With Advanced FIGO Stage IIIB-IV High Grade Serious or Endometrioid Ovarian, Fallopian Tube, or Peritoneal Cancer Treated Standard First-Line Treatment

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02477644
• Other study ID #: GINECO-OV125b
• Status: Completed
• Phase: Phase 3
• Start date: May 6, 2015
• Est. completion date: March 22, 2022

Study information

• Verified date: August 2022
• Source: Arcagy Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Randomized, Double-Blind, Phase III Trial of Olaparib vs. Placebo in 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 806
• Est. completion date: March 22, 2022
• Est. primary completion date: March 22, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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 or

• high grade endometrioid 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.

I-4. Patient who has completed prior to randomization first line platinum-taxane chemotherapy:

1. 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.

2. 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:

1. Hemoglobin = 10.0 g/dL.

2. Absolute neutrophil count (ANC) = 1.5 x 109/L.

3. Platelet count = 100 x 109/L.

4. Total bilirubin = 1.5 x institutional upper limit of normal (ULN).

5. 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.

6. Serum creatinine = 1.25 x institutional ULN and creatinine clearance > 50 mL/min.

7. 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). If the patient is on oral anticoagulants, dose has to be stable for at least two weeks at the time of randomization.

8. Urine dipstick for proteinuria < 2+. If urine dipstick i s =2+, 24-hour urine must demonstrate <1 g of protein in 24 hours.

9. 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. 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-12. For France only: In France, a subject will be eligible for randomization in this study only if either affiliated to, or a beneficiary of, a social security category.

Exclusion Criteria:

E-1. Non-epithelial origin of the ovary, the fallopian tube or the peritoneum (i.e. germ cell tumors).

E-2. Ovarian tumors of low malignant potential (e.g. borderline tumors), or mucinous carcinoma.

E-3. Patient with synchronous primary endometrial cancer unless both of the following criteria are met:

1. stage < II,

2. Less than 60 years old at the time of diagnosis of endometrial cancer with stage IA or IB grade 1 or 2, or stage IA grade III endometrioid adenocarcinoma OR = 60 years old at the time of diagnosis of endometrial cancer with stage IA grade 1 or 2 endometrioid adenocarcinoma.

Patient with serous or clear cell adenocarcinoma or carcinosarcoma of the endometrium is not eligible.

E-4. Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS). Patient with a history of localized malignancy diagnosed over 5 years ago may be eligible provided she completed her adjuvant systemic therapy prior to randomization and that the patient remains free of recurrent or metastatic disease.

Patient with history of primary triple negative breast cancer may be eligible provided she completed her definitive anticancer treatment more than 3 years ago and she remains breast cancer disease free prior to start of study treatment.

E-5. Patient with myelodysplastic syndrome/acute myeloid leukemia history E-6. Patient having experienced for at least one cycle, a delay > 2 weeks due to prolonged hematological recovery during the first line chemotherapy E-7. Patient receiving radiotherapy within 6 weeks prior to study treatment E-8. Major surgery within 4 weeks of starting study treatment and patient must have recovered from any effects of any major surgery E-9. Previous allergenic bone marrow transplant. E-10. Any previous treatment with PARP inhibitor, including olaparib. E-11. Administration of other simultaneous chemotherapy drugs, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period (hormonal replacement therapy is permitted as are steroidal antiemetics).

E-12. Current or recent (within 10 days prior to randomization) chronic use of aspirin > 325 mg/day.

E-13. Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.

E-14. Prior history of hypertensive crisis (CTC-AE grade 4) or hypertensive encephalopathy.

E-15. Clinically significant (e.g. active) cardiovascular disease, including:

1. Myocardial infarction or unstable angina within = 6 months of randomization,

2. New York Heart Association (NYHA) = grade 2congestive heart failure (CHF).

3. Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled atrial fibrillation are eligible), or any clinically significant abnormal finding on resting ECG,

4. Peripheral vascular disease grade = 3 (e.g. symptomatic and interfering with activities of daily living [ADL] requiring repair or revision).

E-16. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub- Arachnoids Hemorrhage (SAH) within 6 months prior to randomization.

E-17. History or evidence of hemorrhagic disorders within 6 months prior to randomization.

E-18. Evidence of bleeding diathesis or significant coagulopathy (in the absence of coagulation).

E-19. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory (within 4 weeks prior to randomization) in case of suspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to randomization) in case of suspected spinal cord compression.

E-20. History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).

E-21. Significant traumatic injury during 4 weeks prior to randomization. E-22. Non-healing wound, active ulcer or bone fracture. Patient with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection is eligible but require 3 weekly wound examinations.

E-23. History of VEGF therapy related abdominal fistula or gastrointestinal perforation or active gastrointestinal bleeding within 6 months prior to the first study treatment.

E-24. Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease.

E-25. Patient with evidence of abdominal free air not explained by paracentesis or recent surgical procedure.

E-26. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications.

E-27. Pregnant or lactating women. E-28. Participation in another clinical study with an investigational product during her chemotherapy course immediately prior to randomization.

E-29. Patient unable to swallow orally administered medication and patient with gastrointestinal disorders likely to interfere with absorption of the study medication.

E-30. Patient with a known hypersensitivity to olaparib or any of the recipients of the product.

E-31. Immunocompromised patient, e.g., with known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids or patient who is known to be serologically positive for human immunodeficiency virus (HIV).

Related Conditions & MeSH terms

• Carcinoma, Ovarian Epithelial
• Ovarian Cancer
• Ovarian Neoplasms

Intervention

Drug:
• Olaparib
Tablets, per os, 300 mg twice daily;
• Placebo
Tablets, per os, 300 mg twice daily.

Locations

Country	Name	City	State
Austria	KH der Barmherzigen Brüder Graz	Graz
Austria	Medical University of Graz	Graz
Austria	Medical University of Innsbruck	Innsbruck
Austria	Landeskrankenhaus Salzburg	Salzburg
Austria	Krankenhaus Hietzing	Vienna
Austria	Medical University of Vienna	Vienna
Belgium	Institut Jules Bordet	Bruxelles
Belgium	Antwerp University Hospital	Edegem
Belgium	UZ Gasthuisberg	Leuven
Belgium	Hôpital de la Citadelle	Liège
Belgium	Clinique et maternité Sainte Elisabeth	Namur
Belgium	CHU Dinant Godinne	Yvoir
Denmark	Rigshospitalet	Copenhagen
Denmark	Herlev Hospital	Herlev
Finland	Kuopio University Hospital	Kuopio
Finland	Oulu University Hospital	Oulu
Finland	Tampere University Hospital	Tampere
Finland	Turku University Hospital	Turku
France	ICO Paul Papin	Angers
France	Institut Sainte-Catherine	Avignon
France	Hôpital Jean Minjoz	Besancon
France	Institut Bergonié	Bordeaux
France	Polyclinique Bordeaux Nord	Bordeaux
France	Centre François Baclesse	Caen
France	Centre Jean Perrin	Clermont-ferrand
France	Centre Georges François Leclerc	Dijon
France	Groupe Hospitalier Mutualiste de Grenoble	Grenoble
France	Centre Hospitalier Départemental Les Oudairies	La Roche-sur-yon
France	Hôpital Michallon - Centre Hospitalier Universitaire de Grenoble	La Tronche
France	Centre Jean Bernard - Clinique Victor Hugo	Le Mans
France	Centre Hospitalier Régional Universitaire de Lille - Hôpital Huriez	Lille
France	Centre Oscar Lambret	Lille
France	Centre Léon Bérard	Lyon
France	Institut Paoli Calmettes	Marseille
France	Hôpital de Mont-de-Marsan	Mont-de-marsan
France	ICM Val d'Aurelle	Montpellier
France	Centre Azuréen de Cancérologie	Mougins
France	Centre Catherine de Sienne - Group confluent	Nantes
France	Centre Antoine Lacassagne	Nice
France	Centre Hospitalier Régional d'Orléans	Orleans
France	Groupe Hospitalier Saint-Joseph	Paris
France	Hôpital Cochin	Paris
France	Hôpital des Diaconesses	Paris
France	Hôpital Européen Georges Pompidou	Paris	Ilhe De France
France	Hopital Tenon	Paris
France	Institut Curie - Hopital Claudius Régaud	Paris
France	Clinique Francheville	Perigueux
France	Centre Hospitalier Lyon Sud	Pierre-benite
France	Centre CARIO - HPCA	Plérin
France	Hôpital de la Milétrie - CHU de Poitiers - Pôle Régional de Cancérologie	Poitiers
France	Centre Eugène Marquis	Rennes
France	Centre Henri Becquerel	Rouen
France	Hôpital René Huguenin, Institut Curie	Saint-cloud
France	ICO Centre René Gauducheau	Saint-herblain
France	Centre de Radiothérapie - Clinique Sainte-Anne	Strasbourg
France	Centre Paul Strauss	Strasbourg
France	Hôpitaux Universitaires de Strasbourg	Strasbourg
France	Clinique Pasteur - ONCOSUD	Toulouse
France	Institut Claudius Regaud	Toulouse
France	ICL Institut de Cancérologie de Lorraine	Vandoeuvre-les-nancy
France	Institut Gustave Roussy	Villejuif
Germany	Klinikum Aschaffenburg	Aschaffenburg
Germany	Klinikum Augsburg	Augsburg
Germany	Hochtaunus-Kliniken	Bad Homburg
Germany	Charité - Universitätsmedizin Berlin (CVK)	Berlin
Germany	HELIOS Klinikum Berlin-Buch	Berlin
Germany	Praxisklinik Krebsheilkunde für Frauen	Berlin
Germany	Onkologie Bottrop	Bottrop
Germany	GYNAEKOLOGICUM Bremen	Bremen
Germany	Städtisches Klinikum Dessau	Dessau
Germany	Universitätsklinikum Carl Gustav Carus	Dresden
Germany	Evangelisches Krankenhaus Düsseldorf	Düsseldorf
Germany	Universitätsklinikum Düsseldorf	Düsseldorf
Germany	Universitätsfrauenklinik Erlangen	Erlangen
Germany	Kliniken Essen Mitte	Essen
Germany	Universitätsklinikum Essen	Essen
Germany	Klinikum Esslingen	Esslingen
Germany	Klinikum der Johann Wolfgang Goethe-Universität	Frankfurt
Germany	Klinikum Frankfurt Höchst	Frankfurt
Germany	Universitätsfrauenklinik Freiburg	Freiburg
Germany	Universitäts-Frauenklinik Göttingen	Göttingen
Germany	Universitätsmedizin Greifswald	Greifswald
Germany	Klinkum Gütersloh	Gütersloh
Germany	Universitätsklinikum Halle	Halle
Germany	Albertinen Krankenhaus	Hamburg
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	Gynäkologisch-Onkologische Praxis Hannover	Hannover
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätsklinikum Jena	Jena
Germany	St. Vincentius Kliniken	Karlsruhe
Germany	Klinikum Kassel	Kassel
Germany	Universitätsklinikum Schleswig-Holstein	Kiel
Germany	St. Elisabeth Krankenhaus	Köln
Germany	Universitätsfrauenklinik Köln	Köln
Germany	Klinikum Konstanz	Konstanz
Germany	HELIOS Klinikum Krefeld	Krefeld
Germany	Universitätsklinikum Schleswig-Holstein	Lübeck
Germany	Klinikum Ludwigsburg	Ludwigsburg
Germany	Universitätsklinikum Gießen und Marburg	Marburg
Germany	Johannes Wesling Klinikum	Minden
Germany	Klinikum der Universität München	München
Germany	Klinikum rechts der Isar	München
Germany	Universitätsklinikum Münster	Münster
Germany	Kliniken des Landkreises Neumarkt	Neumarkt
Germany	Sana Klinikum Offenbach	Offenbach
Germany	Ortenau Klinikum	Offenburg
Germany	Onkologie Ravensburg	Ravensburg
Germany	Universitätsfrauenklinik Regensburg	Regensburg
Germany	Klinikum am Steinenberg	Reutlingen
Germany	ROMed Klinikum Rosenheim	Rosenheim
Germany	Klinikum Südstadt	Rostock
Germany	Robert-Bosch-Krankenhaus	Stuttgart
Germany	Universitäts-Frauenklinik Tübingen	Tübingen
Germany	Universitätsklinikum Ulm	Ulm
Germany	HELIOS Dr. Horst Schmidt Kliniken	Wiesbaden
Germany	Marien Hospital Witten	Witten
Germany	amO Wolfsburg	Wolfsburg
Germany	Klinikum Worms	Worms
Germany	Universitätsklinikum Würzburg	Würzburg
Italy	Centro Riferimento Oncologico	Aviano
Italy	Policlinico S.Orsola-Malpighi	Bologna
Italy	Spedali Civili-Università di Brescia	Brescia
Italy	Ospedale Senatore Antonio Perrino	Brindisi
Italy	EO Ospedali Galliera	Genova
Italy	Ospedale San Luca	Lucca
Italy	Istituto Europeo di Oncologia	Milano
Italy	Istituto Nazionale Tumori	Milano
Italy	Istituto Nazionale Tumori - IRCCS Pascale	Napoli
Italy	Istituto Oncologico Veneto	Padova
Italy	Ospedale Santa Maria della Misericordia	Perugia
Italy	Ospedale Santa Chiara	Pisa
Italy	AO ASL 4 - Ospedale di Prato	Prato
Italy	Arcispedale S. M. Nuova	Reggio Emilia
Italy	Istituto Regina Elena	Roma
Italy	Policlinico Umberto I La Sapienza	Roma
Italy	Policlinico Universitario Gemelli Università Cattolica del Sacro Cuore	Roma
Italy	Ospedale Mauriziano	Torino
Italy	Ospedale S. Anna	Torino
Italy	Ospedale Santa Chiara	Trento
Japan	Ehime University Hospital	Ehime
Japan	Hyogo Cancer Center	Hyogo
Japan	University of Tsukuba Hospital	Ibaraki
Japan	Kagoshima University Medical And Dental Hospital	Kagoshima
Japan	Saitama Medical University International Medical Center	Saitama
Japan	Jichi Medical University Hospital	Tochigi
Japan	National Cancer Center Hospital	Tokyo
Monaco	Centre Hospitalier Princesse Grace	Monaco
Spain	H. U. Fundación Alcorcón	Alcorcón
Spain	C.S. Parc Taulí	Barcelona
Spain	H. de la Santa Creu i Sant Pau	Barcelona
Spain	H. U. Reina Sofía	Córdoba
Spain	H.U. Arnau de Vilanova	Lleida
Spain	H. U. 12 de Octubre	Madrid
Spain	H. U. Ramón y Cajal	Madrid
Spain	MD Anderson Cancer Center Madrid	Madrid
Spain	H.U. Central de Asturias	Oviedo
Spain	Complejo Hospitalario de Navarra	Pamplona
Spain	H. General Universitario de Valencia	Valencia
Spain	H. U. P. La Fe	Valencia
Spain	Instituto Valenciano de Oncología	València
Spain	H. U. Miguel Servet	Zaragoza
Sweden	Linköping University Hospital	Linköping

Sponsors (9)

Lead Sponsor

Collaborator

Arcagy Research

Arbeitsgemeinschaft Gynaekologische Onkologie Austria, Arbeitsgemeinschaft Gynaekologishe Onkologie Germany, Belgian Gynaecological Oncology Group, Grupo Español de Investigación en Cáncer de Ovario, Gynecologic Oncology Trial & Investigation Consortium, Mario Negri Gynecologic Oncology group (MaNGO), Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies, Nordic Society of Gynaecological Oncology - Clinical Trials Unit

Countries where clinical trial is conducted

Austria,  Belgium,  Denmark,  Finland,  France,  Germany,  Italy,  Japan,  Monaco,  Spain,  Sweden, 

References & Publications (1)

Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martín A, Berger R, Fujiwara K, Vergote I, Colombo N, Mäenpää J, Selle F, Sehouli J, Lorusso D, Guerra Alía EM, Reinthaller A, Nagao S, Lefeuvre-Plesse C, Canzler U, Scambia G, Lortholary A, Marmé F, — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Efficacy by progression free survival (PFS1)		phase up to a total of 15 months
Secondary	Overall survival	Overall survival is defined as the time from the date of randomization until death due to any cause.	Study end
Secondary	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.	Study end
Secondary	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.	Study end
Secondary	Time to start of first subsequent therapy or death (TFST)	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.	Study end
Secondary	Time to start of second subsequent therapy or death (TSST)	Time to start of second subsequent therapy or death (TSST) will be assessed. TSST is defined as the time from the date of randomization to the earliest of the date of second subsequent anti-cancer therapy start date following study treatment discontinuation, or death.	Study end
Secondary	Safety and Tolerability		Study end
Secondary	Patient reported outcome		2 years after last patient included

External Links

•   Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer