NOVA: Neoadjuvant Therapy in Advanced Ovarian Cancer With Avastin

Sponsor

Grupo Español de Investigación en Cáncer de Ovario (Other)

Overall Status

Terminated

CT.gov ID

NCT01847677

Collaborator

Roche Pharma AG (Industry)

Enrollment

Locations

Arms

72.3

Actual Duration (Months)

5.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Cancer, Ovarian	Drug: Bevacizumab Drug: Paclitaxel Drug: Carboplatin	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

71 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

May 6, 2013

Actual Primary Completion Date :

Jun 4, 2015

Actual Study Completion Date :

May 17, 2019

Arms and Interventions

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 day Paclitaxel 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: Paclitaxel Other Names: Taxol Drug: Carboplatin Other Names: Paraplatin
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: Bevacizumab Other Names: Avastin Drug: Paclitaxel Other Names: Taxol Drug: Carboplatin Other Names: Paraplatin

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 day Paclitaxel 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: Paclitaxel

Other Names:

Taxol

Drug: Carboplatin

Other Names:

Paraplatin

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: Bevacizumab

Other Names:

Avastin

Drug: Paclitaxel

Other Names:

Taxol

Drug: Carboplatin

Other Names:

Paraplatin

Outcome Measures

Primary Outcome Measures

Complete response rate [average 24 months]
Complete response rate (microscopic residual tumor included) assessed by the surgeon at laparotomy after neoadjuvant therapy.

Secondary Outcome Measures

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

Other Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

Non-epithelial ovarian cancer, including malignant mixed Müllerian tumors.
Borderline ovarian tumors.
Administration of intraperitoneal chemotherapy planned.
Previous systemic anti-tumor treatment against ovarian cancer.
Intestinal obstruction or sub-occlusion, intestinal infiltration shown by CT scan or rectosigmoid infiltration in gynaecological examination.
Uncontrolled hypertension.
Any previous radiotherapy: abdomen or pelvis.
Major traumatic injuries in the 4 weeks prior to the first potential dose of bevacizumab.
History or clinical suspicion of brain metastases or spinal cord compression.
History or evidence of central nervous system (CNS) disorders, unless properly treated with standard medical treatment.
Cerebrovascular accident (CVA), transient ischemic attack (TIA) or subarachnoid haemorrhage (SAH) in the 6 months prior to randomization.
Fertile women of childbearing age who are not willing to use effective contraception during the study and at least 6 months after the study.
Women that are breastfeeding or pregnant.
Prior exposure to mouse CA-125 antibody.
Treatment with any other experimental product, or participation in another clinical trial within 30 days prior to inclusion.
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.
Known hypersensitivity to bevacizumab or any of its excipients (including Cremophor).
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.
History or evidence of bleeding or thrombotic diathesis
Current or recent continued use of aspirin > 325 mg / day (within 10 days prior to randomization)
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).
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)

Pre-existing sensory or motor neuropathy, ≥ grade 2
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
No medical or psychiatric illness that may impede the performance of a systemic or surgical treatment
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital La Fe	Valencia	Comunidad Valenciana	Spain	46026
2	Hospital Germans Trias i Pujol	Badalona		Spain
3	Hospital Clínic	Barcelona		Spain
4	Hospital Sant Pau	Barcelona		Spain
5	H. Reina Sofia	Cordoba		Spain
6	ICO Girona	Girona		Spain
7	ICO Hospitalet	Hospitalet del Llobregat		Spain
8	Hospital 12 de Octubre	Madrid		Spain
9	Hospital Clínico San Carlos	Madrid		Spain
10	Hospital Universitario Morales Meseguer	Murcia		Spain
11	Hospital Son Llatzer	Palma Mallorca		Spain
12	Parc Taulí	Sabadell		Spain
13	Hospital Marqués de Valdecilla	Santander		Spain