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.
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.
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:
1. Absolute neutrophil count greater than or equal to 1500 cells/mm3
2. Platelets greater than or equal to 100,000/uL
3. Renal function: creatinine less than or equal to 2.0 mg/dL
4. Hepatic function: Bilirubin < 1.5 X laboratory normal
5. 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.
