Clinical trial NCT01802749: Bevacizumab Beyond Progression in Platinum Sensitive Ovarian Cancer
Official title: Multicenter Phase III Randomized Study With Second Line Chemotherapy Plus or Minus Bevacizumab in Patients With Platinum Sensitive Epithelial Ovarian Cancer Recurrence After a Bevacizumab/Chemotherapy First Line
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Recurrent Ovarian Cancer
Keywords: second line
platinum sensitive
first line bevacizumab
biologic factors
clinical factors
Lead sponsor: National Cancer Institute, Naples
Sponsor class: OTHER
Collaborators: name: Mario Negri Institute for Pharmacological Research
First posted: 2013-03-01
Enrollment: 406
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Bevacizumab has been found to prolong progression free survival in first line, and more recently, in second line treatment for platinum sensitive ovarian cancer patients who had not received prior treatment with bevacizumab.

Recently reported data suggest that patients with colon cancer who receive bevacizumab in more than one line of therapy (beyond progression) have better results. In ovarian cancer, the role of bevacizumab administered in both first and second-line therapies needs to be defined.

This study aims to evaluate whether administering bevacizumab in combination with chemotherapy in second-line therapy to patients with recurrent ovarian cancer who have received first-line bevacizumab will be more effective than chemotherapy alone.


Eligibility criteria: Inclusion Criteria:

* Female patients ≥18 years of age.
* Patients with histologically confirmed epithelial ovarian or fallopian tube carcinoma or primary peritoneal carcinoma, including mixed Mullerian Tumours
* Recurrence or progression at least 6 months after the last chemotherapy cycle of a first line carboplatin + paclitaxel chemotherapy including bevacizumab (recurrence or progression might occur either during or after bevacizumab as maintenance)
* Patients can be included if they have a RECIST progression, with either measurable or non-measurable disease
* ECOG (Eastern Cooperative Oncology Group Performance) Status of 0-2.
* Life expectancy of at least 12 weeks.
* Signed informed consent obtained prior to initiation of any study-specific procedures and treatment as confirmation of the patient's awareness and willingness to comply with the study requirements including blood samples for molecular analyses.
* Availability of tumour samples for molecular analyses from primary surgery (mandatory) and secondary surgery (when available)

Exclusion Criteria:

Cancer related

* Ovarian tumours with low malignant potential (i.e. borderline tumours)
* History or evidence of synchronous primary endometrial carcinoma, unless all of the following criteria related to the endometrial carcinoma are met:

  * stage ≤Ia
  * no more than superficial myometrial invasion
  * no lymphovascular invasion
  * not poorly differentiated (grade 3 or papillary serous or clear cell carcinoma).
* Other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer.

Prior current or planned treatment:

* More than one previous chemotherapy line
* Previous therapy with other anti-angiogenetic agents different from bevacizumab.
* Any prior radiotherapy to the pelvis or abdomen.
* Surgery (including open biopsy) within 4 weeks prior to the first bevacizumab dose.Current or recent (within 10 days prior to the first study drug dose) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes (except for line patency, in which case international normalized ratio \[INR\] must be maintained below 1.5). Post operative prophylaxis with low molecular weight heparin sc is allowed.
* Current or recent (within 30 days of first study dosing) treatment with any other investigational drug.

Laboratory:

* Inadequate bone marrow function: ANC (absolute neutrophil count): \<1500/mm3, or platelet count \<100,000/mm3 or Haemoglobin \<9 g/dl. Patients may be transfused to maintain haemoglobin values ≥9 g/dl.
* Inadequate coagulation parameters:

  * activated partial thromboplastin time (APTT) \>1.5 x upper limit of normal (ULN) or
  * INR (international normalized ratio) \>1.5
* Inadequate liver function, defined as:

  * serum (total) bilirubin \>1.5 x ULN for the institution
  * AST/SGOT or ALT/SGPT \> 2.5 x ULN.
* Inadequate renal function, defined as:

  * serum creatinine \>2.0 mg/dl or \>177 micromol/l
  * urine dipstick for proteinuria \>2+. Patients with ≥ 1+ proteinuria at baseline dipstick analysis should undergo a 24-hour urine collection and must demonstrate ≤1g of protein in their 24-hour urine collection.

Prior or concomitant conditions or procedures:

* History or evidence of brain metastases or spinal cord compression.
* Pregnant or lactating females.
* History or evidence of thrombotic or haemorrhagic disorders; including cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA) or sub-arachnoid haemorrhage within ≤6 months prior to the first study treatment).
* Uncontrolled hypertension (sustained systolic \>150 mm Hg and/or diastolic \>100 mm Hg despite antihypertensive therapy) or clinically significant (i.e. active) cardiovascular disease, including:
* myocardial infarction or unstable angina within ≤6 months prior to the first study treatment
* New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF)
* serious cardiac arrhythmia requiring medication (with the exception of atrial fibrillation or paroxysmal supraventricular tachycardia)
* peripheral vascular disease ≥grade 3 (i.e. symptomatic and interfering with activities of daily living requiring repair or revision).
* History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess, or with signs of impending bowel obstruction within 6 months prior to the first study treatment.
* Non-healing wound, ulcer or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require three weekly wound examinations.
* Evidence of any other medical conditions (such as psychiatric illness, peptic ulcer, etc.), physical examination or laboratory findings that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment-related complications.

Primary outcomes:
measure: progression free survival
timeFrame: 12 months
Secondary outcomes:
measure: overall survival
timeFrame: 12 months
measure: number of complete or partial responses
timeFrame: 6 months
measure: worst grade toxicity per patient
timeFrame: evaluated every 3 weeks up to 12 months
measure: number of patients taking oral antidiabetic therapy
timeFrame: at baseline
measure: number of patients taking antithrombotic therapy
timeFrame: at baseline
measure: progression free survival
timeFrame: 12 months
Other outcomes:
measure: predictive clinical factors for efficacy of bevacizumab
timeFrame: 12 months
measure: correlation of baseline plasma biomarker expression and clinical outcome
timeFrame: 12 months
Locations:
city: Aix-en-Provence
country: France
facility: Centre Hospitalier d'Aix-en-Provence
city: Bayonne
country: France
facility: Hôpital de la Côte Basque
city: Bordeaux
country: France
facility: Institut Bergoniè
city: Bourg-en-Bresse
country: France
facility: Hôpital Fleyriat
city: Caen
country: France
facility: Centre François Baclesse
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal de Créteil
city: Dijon
country: France
facility: Centre d'Oncologie et de Radiothérapie
city: Dijon
country: France
facility: Centre Georges Francois Leclerc
city: Le Mans
country: France
facility: Centre Hospitalier du Mans
city: Limoges
country: France
facility: Centre Hospitalier Universitaire Dupuytren
city: Lyon
country: France
facility: Centre Léon Bérard
city: Lyon
country: France
facility: Clinique de la Sauvegarde
city: Marseille
country: France
facility: Hôpital Nord
city: Marseille
country: France
facility: Hôpital Saint-Joseph
city: Metz
country: France
facility: Clinique Claude Bernard
city: Mougins
country: France
facility: Centre Azuréen de Cancérologie
city: Paris
country: France
facility: Centre Hospitalier Général de Pau
city: Paris
country: France
facility: Hopital Cochin
city: Paris
country: France
facility: Hôpital des Diaconesses
city: Paris
country: France
facility: Hôpital Tenon
city: Pau
country: France
facility: Centre Hospitalier Général de Pau
city: Pringy
country: France
facility: Centre Hospitalier de la Région d'Annecy
city: Reims
country: France
facility: Institut Jean Godinot
city: Saint Cloud
country: France
facility: Hopital Renè Huguenin, Institut Curie
city: Saint Mande
country: France
facility: Hôpital Inter Armées de Begin (HIA Begin),
city: Senlis
country: France
facility: GHPSO
city: Strasbourg
country: France
facility: Centre de Radiothèrapie - Clinique Sainte-Anne
city: Valenciennes
country: France
facility: Clinique des Dentellières,
city: Villejuif
country: France
facility: Institut de Cancérologie Gustave Roussy
city: Athens
country: Greece
facility: Anticancer Hospital Agio Savvas
city: Athens
country: Greece
facility: General Hospital of Athens Alexandra
city: Athens
country: Greece
facility: General Oncology Hospital Agii Anargiri
city: Thessaloniki
country: Greece
facility: General Hospital of Thessaloniki Papageorgiou
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico
city: Benevento
country: Italy
facility: A.O. G. Rummo
city: Brescia
country: Italy
facility: Spedali Civili Università di Brescia
city: Brindisi
country: Italy
facility: Ospedale Senatore Antonio Perrino
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per l'Oncologia IRCCS
city: Catania
country: Italy
facility: Osp. Cannizzaro
city: Faenza
country: Italy
facility: Ospedale Civile di Faenza
city: Genova
country: Italy
facility: I.R.C.C.S. San Martino IST
city: Genova
country: Italy
facility: Ospedale Galliera
city: La Spezia
country: Italy
facility: ASL 5 Spezzino Ospedale Felettino
city: Lecce
country: Italy
facility: A.O. Vito Fazzi
city: Lecco
country: Italy
facility: Ospedale Manzoni di Lecco
city: Meldola
country: Italy
facility: Istituto Romagnolo per lo Studio e la Cura dei Tumori
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Milano
country: Italy
facility: Istituto Nazionale Tumori
city: Mirano
country: Italy
facility: U.L.S.S. 13
city: Napoli
country: Italy
facility: A.O.U. Federico II
city: Napoli
country: Italy
facility: A.O.U. Seconda Università di Napoli
city: Napoli
country: Italy
facility: Istituto Nazionale dei Tumori , Oncologia Medica - Dipartimento Uro-Ginecologico
city: Negrar
country: Italy
facility: Ist. Sacro Cuore Don Calabria
city: Novara
country: Italy
facility: NO AOU Maggiore della Carità
city: Padova
country: Italy
facility: Istituto Oncologico Veneto
city: Palermo
country: Italy
facility: Casa di Cura La Maddalena
city: Perugia
country: Italy
facility: Osp Silvestrini
city: Pisa
country: Italy
facility: Ospedale Santa Chiara
city: Pordenone
country: Italy
facility: A.O. S. Maria degli Angeli
city: Prato
country: Italy
facility: AO ASL 4
city: Ravenna
country: Italy
facility: Ospedale S. Maria delle Croci AUSL di Ravenna
city: Reggio Emilia
country: Italy
facility: Arcispedale S. Maria Nuova
city: Rimini
country: Italy
facility: Ospedale Civile Rimini
city: Roma
country: Italy
facility: Ospedale S. Giovanni Calibita Fatebenefratelli
city: Roma
country: Italy
facility: Policlinico Universitario Gemelli Università Cattolica del Sacro Cuore
city: Roma
country: Italy
facility: Policlinico Università Campus Biomedico
city: Sondrio
country: Italy
facility: Ospedale di Sondrio
city: Torino
country: Italy
facility: A.O. Ordine Mauriziano
city: Udine
country: Italy
facility: A.O. di Udine S. Maria della Misericordia
city: Monaco
country: Monaco
facility: Centre Hospitalier Princesse Grace
city: Aarau
country: Switzerland
facility: Zentrum fùr Onkologie/ Hamat. und Transf
city: Basel
country: Switzerland
facility: Universitatsspital,Frauenklinik
city: Bellinzona
country: Switzerland
facility: IOSI
city: Bern
country: Switzerland
facility: Klinik Engeried
city: Chur
country: Switzerland
facility: Kantonsspital
city: Frauenfeld
country: Switzerland
facility: Kantonsspital
city: Geneva
country: Switzerland
facility: HUG Breast Center
city: Luzern
country: Switzerland
facility: Kantonsspital
city: Munsterlingen
country: Switzerland
facility: Kantonsspital
city: Olten
country: Switzerland
facility: Kantonsspital
city: St. Gallen
country: Switzerland
facility: Klinische Forschung Onkologie
city: Winterthur
country: Switzerland
facility: Kantonsspital
Study officials:
affiliation: National Cancer Institute, Naples
name: Sandro Pignata, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: European Institute of Oncology
name: Nicoletta Colombo, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: National Cancer Institute, Naples
name: Francesco Perrone, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: National Cancer Institute, Naples
name: Gennaro Daniele, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Mario Negri Institute
name: Roldano Fossati, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Campania Luigi Vanvitelli
name: Ciro Gallo, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Mario Negri Institute
name: Irene Floriani, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pignata S, Lorusso D, Joly F, Gallo C, Colombo N, Sessa C, Bamias A, Salutari V, Selle F, Frezzini S, De Giorgi U, Pautier P, Bologna A, Orditura M, Dubot C, Gadducci A, Mammoliti S, Ray-Coquard I, Zafarana E, Breda E, Favier L, Ardizzoia A, Cinieri S, Largillier R, Sambataro D, Guardiola E, Lauria R, Pisano C, Raspagliesi F, Scambia G, Daniele G, Perrone F; MITO16b/MANGO-OV2/ENGOT-ov17 Investigators. Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):267-276. doi: 10.1016/S1470-2045(20)30637-9.
citation: Arend R, Westin SN, Coleman RL. Decision analysis for secondline maintenance treatment of platinum sensitive recurrent ovarian cancer: a review. Int J Gynecol Cancer. 2020 May;30(5):684-694. doi: 10.1136/ijgc-2019-001041. Epub 2020 Feb 19.