Clinical trial NCT01847677: Neoadjuvant Therapy in Advanced Ovarian Cancer With Avastin
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Cancer, Ovarian
Keywords: ovarian cancer
neoadyuvant
bevacizumab
Lead sponsor: Grupo Español de Investigación en Cáncer de Ovario
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
First posted: 2013-05-07
Enrollment: 71
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Complete response rate
timeFrame: average 24 months
Secondary outcomes:
measure: Safety: toxicities and surgical complications
timeFrame: average 24 months
measure: Surgical feasibility
timeFrame: average 24 months
measure: Optimal surgery rate
timeFrame: average 24 months
measure: RECIST 1.1 responses and correlation with serological responses (GCIG criteria)
timeFrame: average 24 months
measure: Progression-free survival according RECIST 1.1 criteria
timeFrame: average 24 months
measure: Overall Survival (OS)
timeFrame: average 24 months
measure: Association between clinical response and the expression of protein biomarkers, in pre-and post-surgical plasma.
timeFrame: average 24 months
measure: Biomarkers: Epithelial-mesenchymal transition performed at C.S. Parc Taulí
timeFrame: average 24 months
Other outcomes:
measure: Histological response: comparison between the obtained response only with chemotherapy or chemotherapy and bevacizumab.
timeFrame: average 24 months
measure: Association of clinical response with other potential biomarkers, including but not limited to, single nucleotide polymorphisms (SNP) and specific tumor markers.
timeFrame: Average 24 months
Locations:
city: Valencia
country: Spain
facility: Hospital La Fe
state: Comunidad Valenciana
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Clínic
city: Barcelona
country: Spain
facility: Hospital Sant Pau
city: Cordoba
country: Spain
facility: H. Reina Sofia
city: Girona
country: Spain
facility: ICO Girona
city: Hospitalet del Llobregat
country: Spain
facility: ICO Hospitalet
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Murcia
country: Spain
facility: Hospital Universitario Morales Meseguer
city: Palma Mallorca
country: Spain
facility: Hospital Son Llatzer
city: Sabadell
country: Spain
facility: Parc Taulí
city: Santander
country: Spain
facility: Hospital Marqués de Valdecilla
Study officials:
affiliation: C.S Parc Taulí
name: Yolanda García, MD
role: STUDY_CHAIR
References: