Bevacizumab and Trabectedin +/- Carboplatin in Advanced Ovarian Cancer

Multicenter, Randomized, Non-comparative, Phase II Trial on the Efficacy and Safety of the Combination of Bevacizumab and Trabectedin With or Without Carboplatin in Adult Women With Platinum Partially Sensitive Recurring Ovarian Cancer.

This study is aimed at assessing the efficacy and the safety of the combination of bevacizumab and trabectedin with or without carboplatin in adult women with epithelial ovarian cancer at first recurrence occurred 6-12 months after the end of the last (first or second) platinum-containing regimen. According to the Bryant and Day design the primary endpoints will be the proportion of progression-free patients at 6 months for the efficacy, and the proportion of patients with severe toxicity for the safety at the same time-point.

Study Overview

• Status: Completed
• Conditions: Ovarian Epithelial Cancer Recurrent
• Intervention / Treatment: Drug: bevacizumab and trabectedin; Drug: bevacizumab, trabectedin and carboplatin

• Study Type: Interventional
• Enrollment (Actual): 71
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Brescia, Italy
    • Azienda Ospedaliera Spedali Civili di Brescia
  • Milan, Italy
    • Istituto Europeo di Oncologia
  • Milano, Italy
    • AO Fatebenefratelli e Oftalmico
  • Monza, Italy
    • Azienda Ospedaliera S. Gerardo
  • Padova, Italy
    • Istituto Oncologico Veneto
  • Roma, Italy
    • Policlinico Universitario Agostino Gemelli di Roma
  • Torino, Italy
    • Mauriziano Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Age≥18years
• Eastern Cooperative Oncology Group (ECOG)- performance status 0-2
• Cytological/histological diagnosis of epithelial ovarian cancer
• Progression free interval between 6-12 months (calculated from the first day of the last cycle of the previous last platinum-based chemotherapy until the date of progression confirmation through radiologic imaging)
• One or two previous platinum-based chemotherapy lines
• Measurable disease according to RECIST version 1.1
• Life expectancy ≥ 12 weeks
• Patients must be able to receive dexamethasone or its equivalent, as a premedication for trabectedin
• Written informed consents given before the enrolment according to International Conference on Harmonization/ Good Clinical Practice (ICH/GCP).

Exclusion Criteria:

• Prior treatment with trabectedin
• Prior progression while on therapy containing bevacizumab or other vascular endothelial growth factor (VEGF) pathway-target therapy
• Pre-existing grade > 1 sensitive/motor neurologic disorder
• Current or recent (within 30 days of first study dosing) treatment with another investigational drug
• Surgery (including open biopsy) within 4 weeks prior to the first planned dose of bevacizumab
• Current or recent (within 10 days prior to the first study drug dose) use of full-dose oral or parenteral anticoagulant or thrombolytic agent 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
• Inadequate bone marrow function: absolute neutrophil count (ANC): <1.5 x 109/l, or platelet count <100 x 109/l 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 >1.5
• Inadequate liver function, defined as: serum (total) bilirubin > ULN for the institution AST/serum glutamic-oxaloacetic transaminase (SGOT) or ALT/ serum glutamic-pyruvic transaminase (SGPT) >2.5 x ULN
• Inadequate renal function: serum creatinine >1.5 mg/dL or >132 micromol/L and urine dipstick for proteinuria > or = 2+ and >1g of protein in their 24-hour urine collection
• History or evidence of brain metastases or spinal cord compression
• Pregnant, breastfeeding women and women of child bearing potential, who do not agree to use a medically acceptable method of contraception through the treatment period and for 6 months after discontinuation of treatment
• History or evidence of thrombotic or hemorrhagic disorders; including cerebrovascular accident, stroke or transient ischemic attack or sub-arachnoid haemorrhage within 6 months prior to the first study treatment
• Uncontrolled hypertension (sustained systolic >150 mmHg and/or diastolic >100 mmHg 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 grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication
• History of bowel obstruction, including subocclusive disease, related to the underlying disease and history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess. Evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction
• Non-healing wound, ulcer or bone fracture
• hepatitis C virus (HCV) positivity
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: bevacizumab and trabectedin; Arm A: bevacizumab (15 mg/kg) given as 1 hour infusion will be followed by trabectedin (1.1 mg/sqm) 3 hour iv infusion; to be repeated every 21 days until progression, unacceptable toxicity, patient or physician decision to discontinue, or death patients	Drug: bevacizumab and trabectedin; Arm A: bevacizumab (15 mg/kg) given as 1 hour infusion will be followed by trabectedin (1.1 mg/sqm) 3 hour iv infusion; to be repeated every 21 days until progression, unacceptable toxicity, patient or physician decision to discontinue, or death patients; Other Names: Avastin; Yondelis
Experimental: bevacizumab, trabectedin and carboplatin; Arm B: cycle 1-6, bevacizumab given as 1 hour infusion will be followed by carboplatin area under curve 4 (AUC 4) and trabectedin 3 hour iv infusion. Cycle 7- end of treatment, bevacizumab given as 1 hour infusion will be followed by trabectedin 3 hour iv infusion. Patient enrolled in arm B will receive (cycle 1-6): trabectedin 0.8 mg/m2 ,carboplatin AUC 4 day 1 every 28 days and bevacizumab 10 mg/kg iv on day 1 and day 15. From cycle 7 to disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death patients will receive bevacizumab 15 mg/kg iv and trabectedin 1.1 mg/m2 day 1 every 21 days	Drug: bevacizumab, trabectedin and carboplatin; Arm B: cycle 1- 6, bevacizumab given as 1 hour infusion will be followed by carboplatin AUC 4 and trabectedin 3 hour iv infusion. Cycle 7- end of treatment, bevacizumab given as 1 hour infusion will be followed by trabectedin 3 hour iv infusion. Patient enrolled in arm B will receive (cycle 1-6): trabectedin 0.8 mg/m2 ,carboplatin AUC 4 day 1 every 28 days and bevacizumab 10 mg/kg iv on day 1 and day 15. From cycle 7 to disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death patients will receive bevacizumab 15 mg/kg iv and trabectedin 1.1 mg/m2 day 1 every 21 days; Other Names: Avastin; Yondelis; Carboplatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival at 6 months (PFS-6)	The PFS-6, defined as the percentage of patients who are alive and progression free at 6 months after the randomization.	from randomization up to 6 months
Proportion of patients with severe toxicity within 6 months from randomization.	The following conditions will be considered as severe toxicity: absolute neutrophil count (ANC) < 0.5x109/L lasting > 7 days and/or with fever; platelets < 25x109/L; any other grade 3-4 (evaluated by the National Cancer Institute-Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 4.0) non-hematological toxicities except for reversible nausea/vomiting, diarrhea, hypersensitivity reactions, and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation reversible to grade 1 by day 28; any toxicity causing a delay of >14 days in the following cycle	from randomization up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	Defined for each patient as the time from the date of randomization to the date of first progression, second primary malignancy or death for any cause, whichever comes first. Subjects not progressed or died at the time of the analysis will be censored at the last disease assessment date.	from randomization up to 30 months
Overall survival at 12 months (OS-12)	Defined as the percentage of patients who are alive at 12 months after the randomization.	one year
Clinical Benefit (CB)	clinical benefit, defined as the percentage of patients who are judged by the Investigators to have a complete response (CR), or partial response (PR) or stable disease (SD) according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria, version 1.1 after 12 weeks from the date of randomization.	from randomization up to 30 months
Incidence of Adverse Events (AEs)	Incidence of AEs, according to NCI-CTCAE, version 4.0	from randomization up to 30 months
Maximum toxicity grade	Maximum toxicity grade experienced by each patient for each specific toxicity	from randomization up to 30 months
Percentage of patients experiencing grade 3-4 toxicity for each specific toxicity	Percentage of patients experiencing grade 3-4 toxicity for each specific toxicity during the study	from randomization up to 30 months
Patients with at least a Serious Adverse Drug Reaction (SADR)	Patients with at least a SADR during the study	from randomization up to 30 months
Patients with at least a Suspect Unexpected Serious Adverse Reaction (SUSAR).	Patients with at least a suspect unexpected serious adverse reaction during the study	from randomization up to 30 months
Percentage of patients with dose and/or time modifications	Percentage of patients with dose and/or time modifications of the study drugs	from randomization up to 30 months
Percentage of premature withdrawals	Percentage of premature withdrawals of the enrolled patients	from randomization up to 30 months
Patients with at least a Serious Adverse Event (SAE)	Patients with at least a SAE during the study	from randomization up to 30 months
Nature of AEs	Nature of AEs, according to NCI-CTCAE, version 4.0	from randomization up to 30 months
Severity of AEs	Severity of AEs, according to NCI-CTCAE, version 4.0	from randomization up to 30 months
Seriousness of AEs	Seriousness of AEs according to NCI-CTCAE, version 4.0	from randomization up to 30 months

Collaborators and Investigators

• Sponsor: Mario Negri Institute for Pharmacological Research
• Collaborators: Hoffmann-La Roche; PharmaMar
• Investigators: Principal Investigator: Nicoletta Colombo, Medical D, IRCCS Istituto Europeo di Oncologia di Milano

Publications and helpful links

General Publications

• Colombo N, Zaccarelli E, Baldoni A, Frezzini S, Scambia G, Palluzzi E, Tognon G, Lissoni AA, Rubino D, Ferrero A, Farina G, Negri E, Pesenti Gritti A, Galli F, Biagioli E, Rulli E, Poli D, Gerardi C, Torri V, Fossati R, D'Incalci M. Multicenter, randomised, open-label, non-comparative phase 2 trial on the efficacy and safety of the combination of bevacizumab and trabectedin with or without carboplatin in women with partially platinum-sensitive recurrent ovarian cancer. Br J Cancer. 2019 Oct;121(9):744-750. doi: 10.1038/s41416-019-0584-5. Epub 2019 Sep 20.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2013
• Primary Completion (Actual): March 18, 2018
• Study Completion (Actual): March 18, 2018

Study Registration Dates

• First Submitted: November 13, 2012
• First Submitted That Met QC Criteria: November 27, 2012
• First Posted (Estimate): November 28, 2012

Study Record Updates

• Last Update Posted (Actual): November 19, 2019
• Last Update Submitted That Met QC Criteria: November 15, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: randomized trial; bevacizumab; carboplatin; ovarian cancer; trabectedin; phase II
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Carboplatin; Bevacizumab; Trabectedin
• Other Study ID Numbers: IRFMN-OVA-6152

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No