Neoadjuvant Therapy in Advanced Ovarian Cancer With Avastin (NOVA)

A Randomized Phase II Multi-centric Open Label Clinical Trial to Determine the Efficacy and Toxicity of Preoperative Chemotherapy With or Without Bevacizumab in Patients With Advanced Ovarian Cancer

Recently results have shown that Bevacizumab is active both in monotherapy and in combination therapy in patients with ovarian cancer. One of our objectives is to evaluate whether the addition of neoadjuvant bevacizumab improves the response and whether this affects the evolution of patients.

Study Overview

• Status: Terminated
• Conditions: Cancer, Ovarian
• Intervention / Treatment: Drug: Carboplatin; Drug: Paclitaxel; Drug: Bevacizumab

Detailed Description

Epithelial ovarian cancer (OC) is the fourth leading cause of cancer death in women, after lung, breast and colon cancer, and it represents the most common cause of death from gynaecological malignancies. The high mortality associated with OC is due to the lack of screening tests that enable an early diagnosis, thus the majority of patients are diagnosed at advanced stages of the disease when the chances of a cure are very limited. In fact, the 5-year overall survival (OS) rate for stage III-IV OC does not exceed 20-30% in many series. The standard treatment for advanced OC is maximal cytoreductive surgery (or debulking) followed by the administration of 6 cycles of adjuvant chemotherapy with carboplatin and paclitaxel.

In recent years, a number of studies have been carried out with antiangiogenic drugs. Specifically, bevacizumab, an anti-VEGF monoclonal antibody, has been shown to be active both in monotherapy and combination therapy in patients with OC that have received multiple previous lines of chemotherapy.

One of the objectives is to evaluate whether the addition of neoadjuvant bevacizumab improves the response and whether this affects the evolution of patients.

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

Contacts and Locations

Study Locations

• Spain
  • Badalona, Spain
    • Hospital Germans Trias i Pujol
  • Barcelona, Spain
    • Hospital Clínic
  • Barcelona, Spain
    • Hospital Sant Pau
  • Cordoba, Spain
    • H. Reina Sofia
  • Girona, Spain
    • ICO Girona
  • Hospitalet del Llobregat, Spain
    • ICO Hospitalet
  • Madrid, Spain
    • Hospital 12 de Octubre
  • Madrid, Spain
    • Hospital Clinico San Carlos
  • Murcia, Spain
    • Hospital Universitario Morales Meseguer
  • Palma Mallorca, Spain
    • Hospital Son Llàtzer
  • Sabadell, Spain
    • Parc Taulí
  • Santander, Spain
    • Hospital Marques de Valdecilla
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46026
      • Hospital La Fe

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:

1. Women over 18 years old
2. Obtained informed consent, in writing and signed
3. Histological confirmation of primary peritoneal carcinoma or fallopian tube carcinoma
4. Planned interval debulking surgery
5. ECOG:0 to 2
6. Life expectancy >12 weeks

Exclusion Criteria:

1. Non-epithelial ovarian cancer, including malignant mixed Müllerian tumors.
2. Borderline ovarian tumors.
3. Administration of intraperitoneal chemotherapy planned.
4. Previous systemic anti-tumor treatment against ovarian cancer.
5. Intestinal obstruction or sub-occlusion, intestinal infiltration shown by CT scan or rectosigmoid infiltration in gynaecological examination.
6. Uncontrolled hypertension.
7. Any previous radiotherapy: abdomen or pelvis.
8. Major traumatic injuries in the 4 weeks prior to the first potential dose of bevacizumab.
9. History or clinical suspicion of brain metastases or spinal cord compression.
10. History or evidence of central nervous system (CNS) disorders, unless properly treated with standard medical treatment.
11. Cerebrovascular accident (CVA), transient ischemic attack (TIA) or subarachnoid haemorrhage (SAH) in the 6 months prior to randomization.
12. Fertile women of childbearing age who are not willing to use effective contraception during the study and at least 6 months after the study.
13. Women that are breastfeeding or pregnant.
14. Prior exposure to mouse CA-125 antibody.
15. Treatment with any other experimental product, or participation in another clinical trial within 30 days prior to inclusion.
16. Malignant tumors other than ovarian cancer within the 5 years prior to randomisation, with the exception of cervical carcinoma in situ treated correctly and/or basal-cell carcinoma.
17. Known hypersensitivity to bevacizumab or any of its excipients (including Cremophor).
18. Non-healing wound, active peptic ulcer or bone fracture. Patients with healing incised granulomas by secondary intention, with no evidence of fascial dehiscence or infection can be included, but they require three weeks of wound control.
19. History or evidence of bleeding or thrombotic diathesis
20. Current or recent continued use of aspirin > 325 mg / day (within 10 days prior to randomization)
21. Current or recent use (within 10 days before the first cycle of treatment) of full doses of anticoagulants or thrombolytics administered orally or parenterally for therapeutic purposes (except for vascular permeability, in which case the INR should be kept below 1.5).

22. Clinically significant cardiovascular disease, including:

    • Myocardial infarction or unstable angina (≤ 6 months before randomization)
    • Congestive heart failure (CHF) class ≥ II of the NYHA (New York Heart Association)
    • Poorly controlled cardiac arrhythmia despite medication (may include patients with atrial fibrillation with controlled frequency)
    • Peripheral vascular disease ≥ grade 3 (i.e. symptomatic and interfering with activities or daily living [ADL] needing repair or review)
23. Pre-existing sensory or motor neuropathy, ≥ grade 2
24. Demonstration of any other neurological or metabolic dysfunction involving a reasonable suspicion of the existence of a disease or condition that contraindicates the use of an experimental drug, or that involves an increased risk to the patient of treatment-related complications
25. No medical or psychiatric illness that may impede the performance of a systemic or surgical treatment
26. Laboratory:

Inadequate bone marrow function:

• ANC: <1.5 x 109/l
• platelet count <100 x 109/l
• Hb <9 g/dl. (Patients may be transfused)

Inadequate coagulation parameters: Activated partial thromboplastin time (APTT) >1.5 x ULN or INR >1.5

Inadequate liver function, defined as:

• Serum (total) bilirubin >1.5 x the upper limit of normal (ULN) for the institution
• AST & ALT > 2.5 x ULN (> 5 x ULN in patients with liver metastases) or alkaline phosphatase > 2.5 x ULN (or > 5 x ULN in case of liver metastases or > 10 x ULN in case of bone metastases).

Inadequate renal function, defined as:

• Serum creatinine >2.0 mg/dl or >177 mol/l
• Urine dipstick for proteinuria >2+
• Patients with 2+ proteinuria on baseline dipstick analysis should undergo a 24-hour urine collection and must demonstrate ≤1g of protein in their 24-hour urine collection

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
Active Comparator: Paclitaxel & Carboplatin; Preoperative treatment Cycle 1 to 4 (4 cycles every 3 weeks of chemotherapy pre-surgery)Carboplatin AUC 6 i.v. first dayPaclitaxel 175 mg/m2 i.v. first day; Surgery; Post-Operative treatment Cycle 5 to 7 (3 cycles every 3 weeks of chemotherapy post-surgery): Carboplatin AUC 6 i.v. first day; Paclitaxel 175 mg/m2 i.v. first day; Bevacizumab 15 mg/Kg i.v. first day1 When the chemotherapy treatment is completed, the patient will continue with maintenance bevacizumab until 15 months length treatment.	Drug: Carboplatin; Other Names: Paraplatin; Drug: Paclitaxel; Other Names: Taxol
Experimental: Paclitaxel & Carboplatin & Bevacizumab; 4 cycles every 3 weeks (at least 3 Bevacizumab neoadjuvant cycles): Carboplatin AUC 6 i.v. first day Paclitaxel 175 mg/m2 i.v. first day Bevacizumab 15 mg/Kg i.v. first day. b) Surgery Ovarian cancer surgery should be performed according to FIGO guidelines. c) Postoperative treatment Both arms: Cycle 5 to 7 (3 cycles every 3 weeks of chemotherapy post-surgery): Carboplatin AUC 6 i.v. first day Paclitaxel 175 mg/m2 i.v. first day Bevacizumab 15 mg/Kg i.v. first day. When the chemotherapy treatment is completed, the patient will continue with maintenance bevacizumab until 15 months length treatment.	Drug: Carboplatin; Other Names: Paraplatin; Drug: Paclitaxel; Other Names: Taxol; Drug: Bevacizumab; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response rate	Complete response rate (microscopic residual tumor included) assessed by the surgeon at laparotomy after neoadjuvant therapy.	average 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: toxicities and surgical complications	Safety and tolerability of the treatment will be assessed by adverse event description: incidence, severity, time of onset, causes, and abnormal laboratory values .	average 24 months
Surgical feasibility	rate of patients in which surgery is feasible, comparing both arms.	average 24 months
Optimal surgery rate	rate of patients in which surgery is optimal (residual disease<1cm), comparing both arms	average 24 months
RECIST 1.1 responses and correlation with serological responses (GCIG criteria)	It will be assesed using descriptive statistics techniques such as frequency tables and contingency tables	average 24 months
Progression-free survival according RECIST 1.1 criteria	tables of survival will be constructed by the Kaplan-Meier method. Mean and median, both with confidence intervals of 95%. Comparisons between groups will be made by log-rank test.	average 24 months
Overall Survival (OS)	tables of survival will be constructed by the Kaplan-Meier method. Mean and median, both with confidence intervals of 95%. Comparisons between groups will be made by log-rank test.	average 24 months
Association between clinical response and the expression of protein biomarkers, in pre-and post-surgical plasma.	It will be assesed using descriptive statistics techniques such as frequency tables and contingency tables	average 24 months
Biomarkers: Epithelial-mesenchymal transition performed at C.S. Parc Taulí	It will be assesed using descriptive statistics techniques such as frequency tables and contingency tables	average 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Histological response: comparison between the obtained response only with chemotherapy or chemotherapy and bevacizumab.	information correlating the clinical laboratory with the response to treatment.	average 24 months
Association of clinical response with other potential biomarkers, including but not limited to, single nucleotide polymorphisms (SNP) and specific tumor markers.	It will be assesed using descriptive statistics techniques such as frequency tables and contingency tables	Average 24 months

Collaborators and Investigators

• Sponsor: Grupo Español de Investigación en Cáncer de Ovario
• Collaborators: Roche Pharma AG
• Investigators: Study Chair: Yolanda García, MD, C.S Parc Taulí

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2013
• Primary Completion (Actual): June 4, 2015
• Study Completion (Actual): May 17, 2019

Study Registration Dates

• First Submitted: April 26, 2013
• First Submitted That Met QC Criteria: May 2, 2013
• First Posted (Estimate): May 7, 2013

Study Record Updates

• Last Update Posted (Actual): April 1, 2020
• Last Update Submitted That Met QC Criteria: March 31, 2020
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: bevacizumab; ovarian cancer; neoadyuvant
• 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; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Carboplatin; Paclitaxel; Bevacizumab
• Other Study ID Numbers: GEICO-1205; 2012-003883-31 (EudraCT Number)