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Bevacizumab Beyond Progression in Platinum Sensitive Ovarian Cancer (MITO16MANGO2b)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01802749
Recruitment Status : Unknown
Verified December 2016 by National Cancer Institute, Naples.
Recruitment status was:  Active, not recruiting
First Posted : March 1, 2013
Last Update Posted : December 21, 2016
Mario Negri Institute for Pharmacological Research
Information provided by (Responsible Party):
National Cancer Institute, Naples

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.

Condition or disease Intervention/treatment Phase
Recurrent Ovarian Cancer Drug: Bevacizumab Drug: Paclitaxel Drug: Carboplatin Drug: pegylated liposomal doxorubicin Drug: Gemcitabine Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 406 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : November 2013
Estimated Primary Completion Date : December 2017
Estimated Study Completion Date : July 2018

Arm Intervention/treatment
Active Comparator: chemotherapy

Combination chemotherapy with ONE of the following regimens:

  • PLD-C: Pegylated liposomal doxorubicin 30 mg/m2 + Carboplatin AUC (area under curve) 5 on day 1 every 4 weeks;
  • GEM-C: Gemcitabine 1000 mg/m2 on day 1, 8 every 21 + Carboplatin AUC of 4 on day 1 every 21 days;
  • PAC-C: Paclitaxel 175 mg/m2 on day 1, every 21 + Carboplatin AUC of 5 on day 1 every 21 days.
Drug: Paclitaxel
Drug: Carboplatin
Drug: pegylated liposomal doxorubicin
Other Name: Caelyx

Drug: Gemcitabine
Experimental: Chemotherapy and bevacizumab

Combination chemotherapy AND bevacizumab with ONE of the following regimens:

  • PLD-C: Pegylated liposomal doxorubicin 30 mg/m2 + Carboplatin AUC 5 on day 1 every 4 weeks and Bevacizumab 10 mg/kg i.v. on Day 1 every 2 weeks;
  • GEM-C: Gemcitabine 1000 mg/m2 on day 1, 8 every 21 + Carboplatin AUC of 4 on day 1 every 21 days AND Bevacizumab 15 mg/kg i.v. on Day 1 every 3 weeks;L
  • PAC-C: Paclitaxel 175 mg/m2 on day 1, every 21 + Carboplatin AUC of 5 on day 1 every 21 days AND Bevacizumab 15 mg/kg i.v. on Day 1 every 3 weeks.

Patients whose disease has not progressed after the initial six cycles of combination treatment will continue bevacizumab, at 15 mg/kg every 3 weeks until disease progression,unacceptable toxicity or patient withdrawn.

Drug: Bevacizumab
Other Name: Avastin

Drug: Paclitaxel
Drug: Carboplatin
Drug: pegylated liposomal doxorubicin
Other Name: Caelyx

Drug: Gemcitabine

Primary Outcome Measures :
  1. progression free survival [ Time Frame: 12 months ]
    assessed by local Investigator

Secondary Outcome Measures :
  1. overall survival [ Time Frame: 12 months ]
  2. number of complete or partial responses [ Time Frame: 6 months ]
    according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

  3. worst grade toxicity per patient [ Time Frame: evaluated every 3 weeks up to 12 months ]
    according to Common Toxicity Criteria for Adverse Events v. 4.03

  4. number of patients taking oral antidiabetic therapy [ Time Frame: at baseline ]
  5. number of patients taking antithrombotic therapy [ Time Frame: at baseline ]
  6. progression free survival [ Time Frame: 12 months ]
    as measured by independent central review

Other Outcome Measures:
  1. predictive clinical factors for efficacy of bevacizumab [ Time Frame: 12 months ]
  2. correlation of baseline plasma biomarker expression and clinical outcome [ Time Frame: 12 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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.


  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01802749

  Hide Study Locations
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Centre Hospitalier d'Aix-en-Provence
Aix-en-Provence, France
Hôpital de la Côte Basque
Bayonne, France
Institut Bergoniè
Bordeaux, France
Hôpital Fleyriat
Bourg-en-Bresse, France
Centre François Baclesse
Caen, France
Centre Hospitalier Intercommunal de Créteil
Créteil, France
Centre d'Oncologie et de Radiothérapie
Dijon, France
Centre Georges Francois Leclerc
Dijon, France
Centre Hospitalier du Mans
Le Mans, France
Centre Hospitalier Universitaire Dupuytren
Limoges, France
Centre Léon Bérard
Lyon, France
Clinique de la Sauvegarde
Lyon, France
Hôpital Nord
Marseille, France
Hôpital Saint-Joseph
Marseille, France
Clinique Claude Bernard
Metz, France
Centre Azuréen de Cancérologie
Mougins, France
Centre Hospitalier Général de Pau
Paris, France
Hopital Cochin
Paris, France
Hôpital des Diaconesses
Paris, France
Hôpital Tenon
Paris, France
Centre Hospitalier Général de Pau
Pau, France
Centre Hospitalier de la Région d'Annecy
Pringy, France
Institut Jean Godinot
Reims, France
Hopital Renè Huguenin, Institut Curie
Saint Cloud, France
Hôpital Inter Armées de Begin (HIA Begin),
Saint Mande, France
Senlis, France
Centre de Radiothèrapie - Clinique Sainte-Anne
Strausbourg, France
Clinique des Dentellières,
Valenciennes, France
Institut de Cancérologie Gustave Roussy
Villejuif, France
Anticancer Hospital Agio Savvas
Athens, Greece
General Hospital of Athens Alexandra
Athens, Greece
General Oncology Hospital Agii Anargiri
Athens, Greece
General Hospital of Thessaloniki Papageorgiou
Thessaloniki, Greece
Centro di Riferimento Oncologico
Aviano, Italy
A.O. G. Rummo
Benevento, Italy
Spedali Civili Università di Brescia
Brescia, Italy
Ospedale Senatore Antonio Perrino
Brindisi, Italy
Fondazione del Piemonte per l'Oncologia IRCCS
Candiolo, Italy
Osp. Cannizzaro
Catania, Italy
Ospedale Civile di Faenza
Faenza, Italy
I.R.C.C.S. San Martino IST
Genova, Italy
Ospedale Galliera
Genova, Italy
ASL 5 Spezzino Ospedale Felettino
La Spezia, Italy
A.O. Vito Fazzi
Lecce, Italy
Ospedale Manzoni di Lecco
Lecco, Italy
Istituto Romagnolo per lo Studio e la Cura dei Tumori
Meldola, Italy
Istituto Europeo di Oncologia
Milano, Italy
Istituto Nazionale Tumori
Milano, Italy
U.L.S.S. 13
Mirano, Italy
A.O.U. Federico II
Napoli, Italy
A.O.U. Seconda Università di Napoli
Napoli, Italy
Istituto Nazionale dei Tumori , Oncologia Medica - Dipartimento Uro-Ginecologico
Napoli, Italy
Ist. Sacro Cuore Don Calabria
Negrar, Italy
NO AOU Maggiore della Carità
Novara, Italy
Istituto Oncologico Veneto
Padova, Italy
Casa di Cura La Maddalena
Palermo, Italy
Osp Silvestrini
Perugia, Italy
Ospedale Santa Chiara
Pisa, Italy
A.O. S. Maria degli Angeli
Pordenone, Italy
Prato, Italy
Ospedale S. Maria delle Croci AUSL di Ravenna
Ravenna, Italy
Arcispedale S. Maria Nuova
Reggia Emilia, Italy
Ospedale Civile Rimini
Rimini, Italy
Ospedale S. Giovanni Calibita Fatebenefratelli
Roma, Italy
Policlinico Universitario Gemelli Università Cattolica del Sacro Cuore
Roma, Italy
Policlinico Università Campus Biomedico
Roma, Italy
Ospedale di Sondrio
Sondrio, Italy
A.O. Ordine Mauriziano
Torino, Italy
A.O. di Udine S. Maria della Misericordia
Udine, Italy
Centre Hospitalier Princesse Grace
Monaco, Monaco
Zentrum fùr Onkologie/ Hamat. und Transf
Aarau, Switzerland
Basel, Switzerland
Bellinzona, Switzerland
Klinik Engeried
Bern, Switzerland
Chur, Switzerland
Frauenfeld, Switzerland
HUG Breast Center
Geneva, Switzerland
Luzern, Switzerland
Munsterlingen, Switzerland
Olten, Switzerland
Klinische Forschung Onkologie
St. Gallen, Switzerland
Winterthur, Switzerland
Sponsors and Collaborators
National Cancer Institute, Naples
Mario Negri Institute for Pharmacological Research
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Principal Investigator: Sandro Pignata, M.D., Ph.D. National Cancer Institute, Naples
Principal Investigator: Nicoletta Colombo, M.D. European Institute of Oncology
Principal Investigator: Francesco Perrone, M.D., Ph.D. National Cancer Institute, Naples
Principal Investigator: Gennaro Daniele, M.D., Ph.D. National Cancer Institute, Naples
Principal Investigator: Roldano Fossati, M.D. Mario Negri Institute
Principal Investigator: Ciro Gallo, M.D. University of Campania "Luigi Vanvitelli"
Principal Investigator: Irene Floriani, Ph.D. Mario Negri Institute

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Responsible Party: National Cancer Institute, Naples Identifier: NCT01802749     History of Changes
Other Study ID Numbers: MITO-16 -MANGO-OV2b
2012-004362-17 ( EudraCT Number )
ENGOT-ov 17 ( Other Identifier: ENGOT )
First Posted: March 1, 2013    Key Record Dates
Last Update Posted: December 21, 2016
Last Verified: December 2016

Keywords provided by National Cancer Institute, Naples:
second line
platinum sensitive
first line bevacizumab
biologic factors
clinical factors

Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Immune System Diseases
Albumin-Bound Paclitaxel
Liposomal doxorubicin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action