Evaluation of Weekly Ixabepilone With or Without Biweekly Bevacizumab

Study Overview
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Brief Summary
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This is a randomized, two-arm, open-label Phase II multicenter study designed to examine the effects of adding bevacizumab to ixabepilone for the treatment of patients who have recurrent or persistent platinum-resistant/refractory epithelial (non-mucinous) ovarian, fallopian tube, or primary peritoneal cancer. Its primary objective is to assess whether adding bevacizumab to ixabepilone improves progression-free survival in its target population. Study participants will be stratified by (a) study site and (b) previous receipt of bevacizumab prior to randomization.

Detailed Description
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The primary objective of this study is as follows: To assess the activity of ixabepilone with bevacizumab compared to ixabepilone alone in patients with recurrent or persistent platinum-resistant/refractory epithelial (non-mucinous) ovarian, fallopian tube, or primary peritoneal cancer. We will assess this by comparing the ixabepilone +bevacizumab (experimental) arm to the ixabepilone-alone (control) arm for an improvement in median progression free survival (PFS). The secondary objectives of this study are as follows: To compare the experimental arm to the control arm for increases in objective response rate (ORR) and durable disease control rate (DDCR). To compare the experimental arm to the control arm for an increase in overall survival (OS). To assess the safety profile of ixabepilone in combination with bevacizumab in ovarian, fallopian tube, or primary peritoneal cancer patients. To assess whether prior treatment with bevacizumab impacts future response to bevacizumab in combination with ixabepilone. In addition to the primary and secondary objectives of this study, there are additional exploratory/correlative objectives. The exploratory/correlative objectives of this study are as follows: To characterize number, length and composition (e.g., class III β-tubulin expression) of microtentacles (McTNs) isolated from circulating tumor cells isolated from whole blood of patients undergoing treatment with ixabepilone with or without bevacizumab, and correlate with best response, PFS, and OS. To observe McTNs on circulating tumor cells in blood using a novel polyelectrolyte multi-layer (PEM) tethering technology. To correlate ex vivo response of McTNs to drug treatment with clinical response in order to develop a real-time assay to predict response to therapy. To explore use of circulating tumor (ct) DNA as a biomarker for disease response and compare its performance to CA-125. To examine whether clinical response to ixabepilone with or without bevacizumab differs between high and low expressors of class III β-tubulin.

Official Title
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A Randomized Phase II Evaluation of Weekly Ixabepilone With or Without Biweekly Bevacizumab in Recurrent or Persistent Platinum-resistant/Refractory Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancers

Conditions
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Epithelial Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Cancer

Intervention / Treatment
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* Drug: Ixabepilone
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have platinum-resistant/refractory (i.e., platinum-free interval <6 months) recurrent or persistent histologically confirmed epithelial (non-mucinous) ovarian, fallopian tube, or primary peritoneal cancer. Patients may have serous, endometrioid, clear cell, carcinosarcoma, or transitional cell/malignant Brenner, mixed, or undifferentiated histologies. Patients must have specimen available for immunohistochemistry for class III β-tubulin status; recurrent tumor specimen is preferred, though this may be performed on primary tumor if no recurrent tumor is available. All patients must have measurable disease. Measurable disease is defined as lesions that can be measured by physical examination or by means of medical imaging techniques. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded). Each lesion must be ≥ 20 mm when measured by conventional techniques, including palpation or plain x-ray, or ≥ 10 mm when measured by spiral CT and/or MRI. Ascites and pleural effusions are not to be considered measurable disease. Patients must have at least one target lesion to be used to assess response on this protocol as defined by RECIST v1.1 Tumors within a previously irradiated field will be designated as non-target lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy. At the time of initial surgery, patients may have been optimally (<1 cm diameter residual disease) or sub-optimally (≥1 cm diameter of residual disease) debulked. Patients with measurable recurrent disease of any previous stage (I-IV) are eligible to enrollment. The diagnosis must be histologically confirmed by a gynecologic pathologist. Patients must have adequate bone marrow, kidney, and liver function: Absolute neutrophil count greater than or equal to 1500 cells/mm3 Platelets greater than or equal to 100,000/uL Renal function: creatinine less than or equal to 2.0 mg/dL Hepatic function: Bilirubin ≤ 1.5 X laboratory normal SGOT/SGPT ≤ 3 X laboratory normal. Patients must have an ECOG performance status of 0-2. Patients must have signed an approved informed consent. Patients must have recovered from effects of recent surgery, radiotherapy, or chemotherapy. They should be free of significant infection. Patients must have received prior treatment with taxanes. There is no limit on the number of prior lines of therapy. Patients may have received prior bevacizumab therapy alone or in combination with chemotherapy. A 3-week washout period is required. Patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to the study entry and be practicing an effective form of contraception (section 7.5.3). Patients must be at least 18 years of age. Exclusion Criteria: Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancers, are excluded if there is any evidence of other malignancy present within the last five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol therapy. Patients who have a significant history of cardiac disease, i.e., uncontrolled hypertension, unstable angina, uncontrolled congestive heart failure, or uncontrolled arrhythmias within 6 months of registration (NYHA classification III-IV). Patients with any unstable medical issue (including cardiac issues as above, active treatment for symptomatic pulmonary embolism, CVA, renal or hepatic insufficiency, active infection/sepsis requiring intravenous antibiotics). In patients who have undergone surgery, 28 days should elapse before initiation and the surgical site should be adequately healed. Known brain/leptomeningeal involvement of the disease, active neurological disease such as uncontrolled seizure disorder or moderate to severe dementia. Patients who have received prior therapy with any covalent irreversible anti-angiogenic tyrosine kinase inhibitor (e.g., vandetanib). Patients known to be seropositive for human immunodeficiency virus (HIV) and active hepatitis, even if liver function studies are in the eligible range. Known hemorrhagic diathesis or active bleeding disorder, including platelet count <100,000/uL, or inadequate granulocytes, including an absolute neutrophil count <1500 cells/mm. Any hypersensitivity to Cremophor® EL or polyoxyethylated castor oil. CTCAE grade 2 or higher peripheral neuropathy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ixabepilone<br>Ixabepilone 20 mg/m2 days 1, 8, 15 Q 28 days | Drug: Ixabepilone<br>* Ixabepilone will be administered at 20 mg/m2 intravenously days 1, 8, 15 of a 28-day cycle over one hour. Treatment will continue until progression, death, or prohibitive side effects. If any patient has a complete response, patient may stop treatment after 2 additional consolidation cycles following documented complete response<br>* Other names: Ixempra;|
| Experimental: Ixabepilone + Bevacizumab<br>Ixabepilone 20 mg/m2 days 1, 8, 15 + Bevacizumab 10 mg/kg days 1, 15 Q 28 days | Drug: Ixabepilone<br>* Ixabepilone will be administered at 20 mg/m2 intravenously days 1, 8, 15 of a 28-day cycle over one hour. Treatment will continue until progression, death, or prohibitive side effects. If any patient has a complete response, patient may stop treatment after 2 additional consolidation cycles following documented complete response<br>* Other names: Ixempra;Drug: Bevacizumab<br>* Bevacizumab will be administered at 10 mg/kg intravenously days 1, 15 of a 28-day cycle over one hour. Bevacizumab will be infused after ixabepilone. The first dose of bevacizumab will be administered intravenously over 90 minutes; the second dose may be administered over 60 minutes if no prior reaction to previous infusion; subsequent doses may be administered over 30 minutes if no prior reaction to previous infusion. Treatment will continue until progression, death, or prohibitive side effects. If any patient has a complete response, patient may stop treatment after 2 additional consolidation cycles following documented complete response.<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) differences between Ixabepilone alone and Ixabepilone + Bevacizumab | Progression-free survival (PFS), the primary endpoint, will be defined as the length of time from randomization to disease recurrence, disease progression, or death for any reason. | 5 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) and durable disease control rate (DDCR) differences between Ixabepilone alone and Ixabepilone + Bevacizumab | Treatment response will be based on RECIST v1.1 Guidelines for measurable lesions. Objective response rate (ORR) includes evaluation for partial response (PR) or complete response (CR). Durable Disease Control (DDC) is defined as complete response (CR), partial response (PR), or stable disease (SD) ≥6 months from date of best response. | 5 Years | 
| Overall survival (OS) differences between Ixabepilone alone and Ixabepilone + Bevacizumab | Overall survival (OS) is defined as time from randomization to death from any cause | 5 Years | 
| Safety profile of Ixabepilone in combination with Bevacizumab | Safety profile of Ixabepilone in combination with Bevacizumab as defined by Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | 5 Years | 
| Differences in response to the combination of Ixabepilone and Bevacizumab in relationship to previous treatment with Bevacizumab and taxanes | Assess whether prior treatment with bevacizumab impacts future response to bevacizumab in combination with ixabepilone | 5 Years |