Bevacizumab and Erlotinib Study in Advanced Ovarian Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this project is to determine if a new combination of drugs, erlotinib (Tarceva™) and bevacizumab is safe and effective for treating women diagnosed with ovarian cancer whose cancer has progressed while on prior standard chemotherapy treatment with a taxane (paclitaxel or docetaxel) and a platinum (cisplatin or carboplatin).

Detailed Description
-----------------
Erlotinib and bevacizumab, novel biologics, offer a new regimen for the treatment of ovarian cancer in women who are refractory to standard drug regimens. Because bevacizumab is an anti-angiogenesis drug and erlotinib is an EGFR receptor inhibitor their combination would lead to the inhibition of multiple signal transduction pathways and the reversal of cancer progression in this difficult to treat population. The study seeks to determine the efficacy and safety of the EGFR receptor inhibitor, erlotinib plus the anti-angiogenesis VEGF ligand inhibitor bevacizumab in women with platinum and taxane refractory ovarian cancer. The study design is a non-randomized, open label, single center Phase II trial using a Simon two stage design. Eligible patients are women who have a histologically or pathologically confirmed diagnosis of epithelial carcinoma of the ovary or primary peritoneal carcinoma who have relapsed or are refractory to therapy after primary treatment of their disease. Patients will be treated with erlotinib 150 mg/day orally and bevacizumab 10mg/kg every two weeks plus or minus one day intravenously. Forty patients will be enrolled in the study. Initially 20 eligible patients will be accrued. If one or no confirmed response is observed, the trial will be closed and the agents considered inactive. Otherwise, 20 additional eligible patients will be accrued for a total of 40 patients. Eight or more responses out of 40 will be considered evidence warranting further study of the agents provided other factors, such as progression-free and overall survival, also appear favorable. Previous studies of this combination in non-small cell lung cancer, renal cell carcinoma and metastatic breast cancer have indicated a potential synergistic effect for these two agents. Preliminary data for the use of bevacizumab in advanced ovarian cancer indicates that this agent has single-agent activity. As a result, the researchers are interested in exploring the role of the combination of erlotinib and bevacizumab in advanced ovarian cancer.

Official Title
-----------------
Phase II Open-Label Trial of Erlotinib (Tarceva) and Bevacizumab in Women With Advanced Ovarian Cancer

Conditions
-----------------
Ovarian Neoplasms

Intervention / Treatment
-----------------
* Drug: bevacizumab
* Drug: erlotinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or pathologically confirmed diagnosis of epithelial carcinoma of the ovary or primary peritoneal carcinoma. Relapsed after prior therapy with taxane and platinum-based therapy, within 6 months of completing, or had a best response of stable disease during no more than two prior chemotherapy treatments with a platinum (either cisplatin or carboplatin) and a taxane (paclitaxel or docetaxel). These agents may have been administered concurrently or sequentially. Besides the primary chemotherapy, two additional chemotherapy regimens are allowed. Hormonal therapy is allowed and will not be counted as a chemotherapy regimen. Up to one year of consolidation treatment with intraperitoneal and intravenous administered chemotherapy drugs to consolidate a clinical complete remission is allowed. Patients must have elevated CA-125 or measurable disease. For patients who do not have RECIST measurable disease, an elevated CA-125 (greater than two times the institutional upper limit of normal) will be required for enrollment. Debulking surgery for relapsed disease is allowed but must be completed at least 28 days prior to the first day of study therapy. Patient must have recovered from all side effects of surgery including a completely healed surgical incision. Patient must have a Zubrod performance status of 0-1. Patient must have adequate hepatic function as defined by: a serum bilirubin ≤1.5 x the institutional upper limit of normal (IULN), SGOT or SGPT ≤2.5 x the institutional upper limit of normal obtained within 14 days prior to start of therapy Patient must have an adequate renal function as defined by: a serum creatinine ≤1.5 x the institutional upper limit of normal obtained within 14 days prior to start of therapy and a urine protein:creatinine (UPC) ratio of ≤ 1.0. Patients must be able to take oral medications Patients may not have ongoing problems with bowel obstruction or short bowel syndrome characterized by grade 2 or greater diarrhea or malabsorptive disorders. Patients must have the following hematological criteria: Hemoglobin of >10gm/dL, White blood cell count >2500, Platelets >80,000 Patients must be ≥ 18 years of age. Exclusion Criteria: Subjects with mixed mullerian tumors and borderline ovarian tumors are excluded. Patients with a history of borderline ovarian tumors that have evolved into higher grade tumors will be eligible. The patient must not have received chemotherapy, biologic therapy or any other investigational drug for any reason within 28 days prior to start of therapy and must have recovered from toxicities of prior therapy to grade 1 or less with the exception of alopecia. Patient must not be pregnant or nursing because bevacizumab or erlotinib maybe harmful to the developing fetus and newborn. Women of reproductive potential must have a negative serum pregnancy test within 7 days prior to study consent. Post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug. Patients should not have psychological, familial, sociological, or geographical conditions that do not permit medical follow-up or compliance with the study protocol. Except for cancer-related abnormalities, patients should not have unstable or preexisting major medical conditions. Patients should not have any medical life-threatening complications of their malignancies Patients should not have a known severe and/or uncontrolled concurrent medical disease (e.g., uncontrolled diabetes, uncontrolled chronic renal or liver disease, active uncontrolled infection, or HIV) Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study. Baseline blood pressure of < or equal to 150/100 mmHg. Patients with a blood pressure reading above this level should be initiated on anti-hypertensive therapy and may be considered for protocol treatment when their blood pressure is adequately controlled. New York Heart Association (NYHA) Grade II or greater congestive heart failure History of myocardial infarction, cerebrovascular accident, transient ischemic attack, or unstable angina within 6 months Clinically significant peripheral vascular disease Evidence of bleeding diathesis or coagulopathy Presence of central nervous system or brain metastases Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during the course of the study Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to Day 0 Pregnant (positive pregnancy test) or lactating Urine protein:creatinine ratio > equal to 1.0 at screening History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess Serious, non-healing wound, ulcer, or bone fracture Diagnosis of any other malignancy except non-melanomatous skin cancer in the past 5 years. Inability to comply with study and/or follow-up procedures

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: open label<br> | Drug: bevacizumab<br>* 10mg/kg every two weeks IV-bevacizumab<br>* Other names: Avastin;Drug: erlotinib<br>* 150mg daily by mouth-erlotinib<br>* Other names: Tarceva;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (Complete Partial, Stable and Progression) | Objective response was defined using standard RECIST criteria. CR(complete response)= disappearance of all target lesions PR(partial response)=30% decrease in the sum of the longest diameter of target lesions PD(progressive disease)=20% increase in the sum of the longest diameter of target lesions SD(stable disease)= small changes that do not meet above criteria | 06.16.2005 to 10.05.2009 | 
| Median Response Duration (Weeks) | Response duration=time (in weeks) between date of measurable response and date of progression (progression=20% increase in the sum of longest diameters of target measurable lesions over smallest sum observed or baseline, progression of non-measurable disease in opinion of treating physician, any new lesion/site, death due to disease)if known or the date the subject went off protocol if they were still considered responders (ie do not qualify as progression) or are stable (Does not qualify for CR, PR, progression or Symptomatic Deterioration) | 1 week to 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival(PFS) | PFS was defined as the time from the start of therapy to the time of the first documentation of progression(progression=20% increase in sum of longest diameters of target measurable lesions over smallest sum observed or baseline, progression of non-measurable disease in the opinion of treating physician, appearance of new lesion/site, Death due to disease), symptomatic deterioration (global deterioration of health status requiring discontinuation of treatment without objective evidence of progression), or death due to any cause; | June 2005 to October 5, 2009 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
advanced ovarian cancer, refractory ovarian cancer, primary peritoneal cancer