Clinical trial NCT01462890: Evaluation of Optimal Treatment Duration of Bevacizumab Combination With Standard Chemotherapy in Patients With Ovarian Cancer
Official title: A Prospective Randomised Phase III Trial to Evaluate Optimal Treatment Duration of First-line Bevacizumab in Combination With Carboplatin and Paclitaxel in Patients With Primary Epithelial Ovarian, Fallopian Tube or Peritoneal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Genital Diseases, Female
Ovarian Diseases
Ovarian Neoplasms
Fallopian Tube Neoplasms
Peritoneal Neoplasms
Keywords: Ovarian Carcinoma
Bevacizumab
Paclitaxel
Carboplatin
Lead sponsor: AGO Study Group
Sponsor class: OTHER
Collaborators: name: ARCAGY/ GINECO GROUP
name: Nordic Society of Gynaecological Oncology - Clinical Trials Unit
First posted: 2011-11-01
Enrollment: 927
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized Phase III study
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether the early and continuous addition of bevacizumab for up to 30 months to the standard chemotherapy is more effective than the early and continuous addition of bevacizumab for up to 15 months.

Detailed description: Determination whether the early and continuous addition of bevacizumab for up to 30 months to the standard chemotherapy is more effective than the early and continuous addition of bevacizumab for up to 15 months

Eligibility criteria: Inclusion Criteria:

* Signed written informed consent obtained prior to initiation of any study specific procedures and treatment as confirmation of the patients awareness and willingness to comply with the study requirements
* Primary diagnosis is confirmed by specialized pathology review (Germany only)
* Females aged ≥ 18 years
* Histologically confirmed, newly diagnosed

  * Epithelial ovarian carcinoma
  * Fallopian tube carcinoma
  * Primary peritoneal carcinoma AND FIGO stage IIb - IV (all grades and all histological types)
* Patients should have already undergone surgical debulking, by a surgeon experienced in the management of ovarian cancer, with the aim of maximal surgical cytoreduction according to the GCIG Conference Consensus Statement. There must be no planned surgical debulking prior to disease progression. Patients with stage III and IV disease in whom initial surgical debulking was not appropriate or possible will still be eligible providing

  * the patient has a histological diagnosis and
  * debulking surgery prior to disease progression is not foreseen
* Patients must be able to commence cytotoxic chemotherapy within 8 weeks of cytoreductive surgery. The first dose of bevacizumab can be omitted in both arms if the investigator decides to start chemotherapy within 4 weeks of surgery.
* ECOG 0-2
* Life expectancy \> 3 months
* Adequate bone marrow function (within 14 days prior to randomization)

  * ANC ≥ 1.5 x 10\^9/L
  * PLT ≥ 100 x 10\^9/L
  * Hb ≥ 9 g/dL (can be post-transfusion)
* Adequate coagulation parameters (within 14 days prior to randomization)

  * Patients not receiving anticoagulant medication who have an INR ≤ 1.5 and an aPTT ≤ 1.5 x ULN
  * The use of full-dose oral or par-enteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to institution medical standard) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of randomization.
* Adequate liver function (within 14 days prior to randomization)

  * Serum bilirubin ≤ 1.5 x ULN
  * Serum transaminases ≤ 2.5 x ULN
* Urine dipstick for proteinuria \< 2+. If urine dipstick is ≥ 2+, 24 hour urine must demonstrate ≤ 1 g of protein in 24 hours
* Adequate postoperative GFR \> 40 ml/min (estimates based on the Cockroft-Gault or Jelliffe formula are sufficient)

Exclusion Criteria:

* Non-epithelial origin of the ovary, the fallopian tube or the peritoneum
* Borderline tumours (tumours of low malignant potential) and FIGO stage Ia - IIa tumours
* Planned intraperitoneal cytotoxic chemotherapy
* Prior systemic anti-cancer therapy for ovarian cancer (for example chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy or hormonal therapy)
* Surgery (including open biopsy) within 4 weeks prior to anticipated first dose of bevacizumab (allowing for the fact that bevacizumab can be omitted from the first cycle of chemotherapy). It is strongly recommended that an interval of 7 days is left between the insertion of any central venous access devices (CVADs) and the onset of bevacizumab treatment.
* Any planned surgery during the study treatment period plus 4 additional weeks to allow for bevacizumab clearance
* Uncontrolled hypertension (sustained elevation of BP systolic \> 150mmHg and/or diastolic \> 100mmHg despite antihypertensive therapy)
* Any previous radiotherapy to the abdomen or pelvis
* Significant traumatic injury during 4 weeks preceding the potential first dose of bevacizumab
* 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.
* History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy e.g. uncontrolled seizures
* Previous Cerebro-Vascular Accident (CVA), Transient Ischaemic Attack (TIA) or Sub-Arachnoid Haemorrhage (SAH) within 6 months prior to randomization
* Fertile woman of childbearing potential not willing to use adequate contraception (oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for the study duration and at least 6 months afterwards
* Pregnant or lactating women
* Treatment with other investigational agents, or participation in another clinical trial testing a drug within the past 4 weeks before start of therapy concomitantly with this trial
* Malignancies other than ovarian cancer within 5 years prior to randomization, except for adequately treated

  * carcinoma in situ of the cervix
  * and/or basal cell skin cancer
  * and/or non-melanomatous skin cancer
  * carcinoma in situ of the breast
  * and/or early endometrial carcinoma as specified below. Patients may have received previous adjuvant chemotherapy for other malignancies e.g. breast or colorectal carcinoma if diagnosed over 5 years ago with no evidence of subsequent recurrence.
* Patients with synchronous primary endometrial carcinoma, or a past history of primary endometrial carcinoma, are excluded unless ALL of the following criteria for describing the endometrial carcinoma are met

  * Disease stage FIGO stage ≤ IA (tumour invades less than one half of the myometrium)
* Known hypersensitivity to bevacizumab and its excipients, Chinese hamster ovary cell products or other recombinant human or humanised antibodies
* Non healing wound, active ulcer or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require 3 weekly wound examinations
* History or evidence of thrombotic or hemorrhagic disorders within 6 months prior to randomization
* Clinically significant cardiovascular disease, including

  * Myocardial infarction or unstable angina within 6 months of randomization
  * NYHA ≥ Grade 2 Congestive Heart Failure (CHF)
  * Poorly controlled cardiac arrhythmia despite medication (patients with rate-controlled atrial fibrillation are eligible)
  * Grade ≥ 3 peripheral vascular disease (i.e. symptomatic and interfering with activities of daily living requiring repair or revision)
* Current or recent (within 10 days prior to randomization) chronic use of aspirin \> 325 mg/day
* Pre-existing sensory or motor neuropathy ≥ Grade 2
* Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug or puts the patient at high risk for treatment-related complications

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: every 12 weeks until progression or up to 30 months, thereafter every 6 months
Secondary outcomes:
measure: Objective response rate (ORR)
timeFrame: every 12 weeks until progression or up to 30 months, thereafter every 6 months
measure: Overall survival (OS)
timeFrame: every 3 weeks, 31 months after start of treatment, thereafter every 6 months
measure: Health related Quality of life (QoL)
timeFrame: baseline, then every 12 weeks until progression, 31 months after start of treatment or if applicable 4 weeks after last dose of bevacizumab (whichever occurs later)
measure: Safety and tolerability, i.e. type, frequency, severity and duration of adverse reactions
timeFrame: every 3 weeks, 31 months after start of treatment or if applicable 4 weeks after last dose of bevacizumab (whichever occurs later)
measure: Translational Research - Tumor Tissue Block
timeFrame: Assessment at end of study planned
measure: Translational Research - Complementary and Alternative Treatment Questionnaires
timeFrame: baseline, 6 months and 12 months after start of treatment, if required at timepoint of treatment termination
Other outcomes:
Locations:
city: Aalborg
country: Denmark
city: Copenhagen
country: Denmark
city: Herlev
country: Denmark
city: Kuopio
country: Finland
city: Oulu
country: Finland
city: Tampere
country: Finland
city: Turku
country: Finland
city: Angers
country: France
city: Besancon
country: France
city: Blois
country: France
city: Bordeaux
country: France
city: Caen
country: France
city: Cahors
country: France
city: Clamart
country: France
city: Clermont-Ferrand
country: France
city: Creteil
country: France
city: Dax
country: France
city: Draguignan
country: France
city: Grenoble
country: France
city: Limoges
country: France
city: Lyon
country: France
city: Mougins
country: France
city: Nancy
country: France
city: Nantes
country: France
city: Nice
country: France
city: Nimes
country: France
city: Orleans
country: France
city: Paris
country: France
city: Pau
country: France
city: Plérin
country: France
city: Poitiers
country: France
city: Quimper
country: France
city: Reims
country: France
city: Rouen
country: France
city: Saint-Herblain
country: France
city: Strasbourg
country: France
city: Toulouse
country: France
city: Vandoeuvre-Les-Nancy
country: France
city: Vannes
country: France
city: Villejuif
country: France
city: Aachen
country: Germany
city: Arnsberg
country: Germany
city: Aschaffenburg
country: Germany
city: Augsburg
country: Germany
city: Bad Homburg vor der Höhe
country: Germany
city: Berlin
country: Germany
city: Bochum
country: Germany
city: Bonn
country: Germany
city: Bottrop
country: Germany
city: Brandenburg
country: Germany
city: Bremen
country: Germany
city: Chemnitz
country: Germany
city: Coburg
country: Germany
city: Deggendorf
country: Germany
city: Dessau
country: Germany
city: Dresden
country: Germany
city: Düsseldorf
country: Germany
city: Ebersberg
country: Germany
city: Eggenfelden
country: Germany
city: Erlangen
country: Germany
city: Essen
country: Germany
city: Esslingen
country: Germany
city: Flensburg
country: Germany
city: Frankfurt/M.
country: Germany
city: Freiburg
country: Germany
city: Fürstenfeldbruck
country: Germany
city: Fürth
country: Germany
city: Georgsmarienhütte
country: Germany
city: Gera
country: Germany
city: Greifswald
country: Germany
city: Göttingen
country: Germany
city: Gütersloh
country: Germany
city: Halle (Saale)
country: Germany
city: Hamburg
country: Germany
city: Hanau am Main
country: Germany
city: Hannover
country: Germany
city: Heidelberg
country: Germany
city: Henstedt-Ulzburg
country: Germany
city: Hildesheim
country: Germany
city: Jena
country: Germany
city: Kaiserslautern
country: Germany
city: Karlsruhe
country: Germany
city: Kassel
country: Germany
city: Kiel
country: Germany
city: Krefeld
country: Germany
city: Köln
country: Germany
city: Lich
country: Germany
city: Limburg
country: Germany
city: Lübeck
country: Germany
city: Lüneburg
country: Germany
city: Magdeburg
country: Germany
city: Mainz
country: Germany
city: Mannheim
country: Germany
city: Marburg
country: Germany
city: Minden
country: Germany
city: München
country: Germany
city: Neumarkt
country: Germany
city: Neuss
country: Germany
city: Nordhausen
country: Germany
city: Offenbach
country: Germany
city: Offenburg
country: Germany
city: Oldenburg
country: Germany
city: Osnabrück
country: Germany
city: Ravensburg
country: Germany
city: Regensburg
country: Germany
city: Reutlingen
country: Germany
city: Rosenheim
country: Germany
city: Rostock
country: Germany
city: Rottweil
country: Germany
city: Saalfeld
country: Germany
city: Salzgitter
country: Germany
city: Schweinfurt
country: Germany
city: Schwäbisch Hall
country: Germany
city: Sigmaringen
country: Germany
city: Solingen
country: Germany
city: Stralsund
country: Germany
city: Stuttgart
country: Germany
city: Torgau
country: Germany
city: Trier
country: Germany
city: Tübingen
country: Germany
city: Ulm
country: Germany
city: Viersen
country: Germany
city: Wiesbaden
country: Germany
city: Witten
country: Germany
city: Wolfsburg
country: Germany
city: Worms
country: Germany
city: Bergen
country: Norway
city: Oslo
country: Norway
city: Trondheim
country: Norway
city: Falun
country: Sweden
city: Uppsala
country: Sweden
Study officials:
affiliation: AGO Study Group
name: Jacobus Pfisterer, MD PhD
role: STUDY_CHAIR
References:
citation: Pfisterer J, Joly F, Kristensen G, Rau J, Mahner S, Pautier P, El-Balat A, Kurtz JE, Canzler U, Sehouli J, Heubner ML, Hartkopf AD, Baumann K, Hasenburg A, Hanker LC, Belau A, Schmalfeldt B, Denschlag D, Park-Simon TW, Selle F, Jackisch C, Burges A, Luck HJ, Emons G, Meier W, Gropp-Meier M, Schroder W, de Gregorio N, Hilpert F, Harter P. Optimal Treatment Duration of Bevacizumab as Front-Line Therapy for Advanced Ovarian Cancer: AGO-OVAR 17 BOOST/GINECO OV118/ENGOT Ov-15 Open-Label Randomized Phase III Trial. J Clin Oncol. 2023 Feb 1;41(4):893-902. doi: 10.1200/JCO.22.01010. Epub 2022 Nov 4.