Bevacizumab Beyond Progression in Platinum Sensitive Ovarian Cancer (MITO16MANGO2b)

• ClinicalTrials.gov Identifier: NCT01802749
• Recruitment Status: Active, not recruiting
• First Posted: March 1, 2013
• Last Update Posted: March 24, 2023
• Sponsor: National Cancer Institute, Naples
• Collaborator: Mario Negri Institute for Pharmacological Research
• Information provided by (Responsible Party): National Cancer Institute, Naples

Tracking Information

• First Submitted Date: February 27, 2013
• First Posted Date: March 1, 2013
• Last Update Posted Date: March 24, 2023
• Study Start Date: November 2013
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 28, 2013)

progression free survival [ Time Frame: 12 months ]

assessed by local Investigator

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 28, 2013)

• overall survival [ Time Frame: 12 months ]
• number of complete or partial responses [ Time Frame: 6 months ]
  according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• 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
• number of patients taking oral antidiabetic therapy [ Time Frame: at baseline ]
• number of patients taking antithrombotic therapy [ Time Frame: at baseline ]
• progression free survival [ Time Frame: 12 months ]
  as measured by independent central review

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: February 28, 2013)

• predictive clinical factors for efficacy of bevacizumab [ Time Frame: 12 months ]
• correlation of baseline plasma biomarker expression and clinical outcome [ Time Frame: 12 months ]

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: 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

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Recurrent Ovarian Cancer

Intervention

• Drug: Bevacizumab
  Other Name: Avastin
• Drug: Paclitaxel
• Drug: Carboplatin
• Drug: pegylated liposomal doxorubicin
  Other Name: Caelyx
• Drug: Gemcitabine

Study Arms

• 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.
  Interventions:

  • Drug: Paclitaxel
  • Drug: Carboplatin
  • Drug: pegylated liposomal doxorubicin
  • 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.

  Interventions:

  • Drug: Bevacizumab
  • Drug: Paclitaxel
  • Drug: Carboplatin
  • Drug: pegylated liposomal doxorubicin
  • Drug: Gemcitabine

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: December 20, 2016): 406
• Original Estimated Enrollment (submitted: February 28, 2013): 400
• Estimated Study Completion Date: December 2023
• Estimated Primary Completion Date: December 2023 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Greece, Italy, Monaco, Switzerland

Administrative Information

• NCT Number: NCT01802749
• Other Study ID Numbers: MITO-16 -MANGO-OV2b; 2012-004362-17 ( EudraCT Number ); ENGOT-ov 17 ( Other Identifier: ENGOT )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Cancer Institute, Naples
• Original Responsible Party: Same as current
• Current Study Sponsor: National Cancer Institute, Naples
• Original Study Sponsor: Same as current
• Collaborators: Mario Negri Institute for Pharmacological Research

Investigators

• 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

• PRS Account: National Cancer Institute, Naples
• Verification Date: March 2023