Epithelial Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Cancer
Conditions
Brief summary
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
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.
Interventions
DRUGIxabepilone
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
DRUGBevacizumab
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.
Sponsors
R-Pharm US LLC.
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 100 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Differences Between Ixabepilone Alone and Ixabepilone + Bevacizumab | Up to 37 months | 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. The timeframe was updated upon results entry. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to 37 months | 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). Time frame was updated upon results entry. |
| Overall Survival (OS) Differences Between Ixabepilone Alone and Ixabepilone + Bevacizumab | Up to 37 months | Overall survival (OS) is defined as time from randomization to death from any cause. Time frame was updated upon results entry. |
| Number of Participants With Treatment Related SAEs | Up to 37 months | Safety profile of Ixabepilone in combination with Bevacizumab as defined by Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Presented are the number of participants that experienced SAE's related to study drug. Full reporting of adverse events is presented in the Adverse Events module. Time frame was updated upon results entry. |
| Differences in Response to the Combination of Ixabepilone and Bevacizumab in Relationship to Previous Treatment With Bevacizumab and Taxanes | Up to 41 months | Assess whether prior treatment with Taxanes impacts future response to Bevacizumab in combination with Ixabepilone. BEST RESPONSE using RECIST Criteria- Complete Response (CR): The disappearance of all target lesions. There should be no evidence of disease, and any pathological lymph nodes must have reduced in size to normal (short axis less than 10 mm). Partial Response (PR): At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started. Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesion |
| Durable Disease Control Rate (DDCR) Differences Between Ixabepilone Alone and Ixabepilone + Bevacizumab | 5 Years | 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. Presented are the counts of those that achieved DDC. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ixabepilone Ixabepilone 20 mg/m2 days 1, 8, 15 Q 28 days
Ixabepilone: 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 | 37 |
| Ixabepilone + Bevacizumab Ixabepilone 20 mg/m2 days 1, 8, 15
\+ Bevacizumab 10 mg/kg days 1, 15 Q 28 days
Ixabepilone: 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
Bevacizumab: 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. | 39 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Not Eligible | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Ixabepilone | Ixabepilone + Bevacizumab | Total |
|---|---|---|---|
| Age, Continuous | 67 years | 67 years | 67 years |
| ECOG Performance Status 0-1 | 31 Participants | 36 Participants | 67 Participants |
| ECOG Performance Status 2 | 6 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 37 Participants | 71 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Histology Carcinosarcoma | 2 Participants | 1 Participants | 3 Participants |
| Histology Other | 6 Participants | 4 Participants | 10 Participants |
| Histology Serous | 29 Participants | 34 Participants | 63 Participants |
| Prior Bevacizumab No | 16 Participants | 18 Participants | 34 Participants |
| Prior Bevacizumab Yes | 21 Participants | 21 Participants | 42 Participants |
| Prior Lines of Chemotherapy Greater than 3 | 19 Participants | 18 Participants | 37 Participants |
| Prior Lines of Chemotherapy Less than or Equal to 3 | 18 Participants | 21 Participants | 39 Participants |
| Race/Ethnicity, Customized Race Black | 8 Participants | 4 Participants | 12 Participants |
| Race/Ethnicity, Customized Race Other | 2 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized Race White | 27 Participants | 31 Participants | 58 Participants |
| Region of Enrollment United States | 37 participants | 39 participants | 76 participants |
| Sex: Female, Male Female | 37 Participants | 39 Participants | 76 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 36 / 37 | 34 / 39 |
| other Total, other adverse events | 36 / 37 | 39 / 39 |
| serious Total, serious adverse events | 24 / 37 | 16 / 39 |
Outcome results
Primary
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. The timeframe was updated upon results entry.
Time frame: Up to 37 months
Population: Those completing treatment post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixabepilone | Progression-free Survival (PFS) Differences Between Ixabepilone Alone and Ixabepilone + Bevacizumab | 2.20 months |
| Ixabepilone + Bevacizumab | Progression-free Survival (PFS) Differences Between Ixabepilone Alone and Ixabepilone + Bevacizumab | 5.46 months |
p-value: <0.00190% CI: [0.2, 0.49]Regression, Cox
Secondary
Differences in Response to the Combination of Ixabepilone and Bevacizumab in Relationship to Previous Treatment With Bevacizumab and Taxanes
Assess whether prior treatment with Taxanes impacts future response to Bevacizumab in combination with Ixabepilone. BEST RESPONSE using RECIST Criteria- Complete Response (CR): The disappearance of all target lesions. There should be no evidence of disease, and any pathological lymph nodes must have reduced in size to normal (short axis less than 10 mm). Partial Response (PR): At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started. Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesion
Time frame: Up to 41 months
Population: Those with prior Taxanes treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ixabepilone | Differences in Response to the Combination of Ixabepilone and Bevacizumab in Relationship to Previous Treatment With Bevacizumab and Taxanes | Partial Response (PR) | 0 Participants |
| Ixabepilone | Differences in Response to the Combination of Ixabepilone and Bevacizumab in Relationship to Previous Treatment With Bevacizumab and Taxanes | Progressive Disease (PD) | 5 Participants |
| Ixabepilone | Differences in Response to the Combination of Ixabepilone and Bevacizumab in Relationship to Previous Treatment With Bevacizumab and Taxanes | Stable Disease (SD) | 7 Participants |
| Ixabepilone | Differences in Response to the Combination of Ixabepilone and Bevacizumab in Relationship to Previous Treatment With Bevacizumab and Taxanes | Not Assessed | 1 Participants |
| Ixabepilone | Differences in Response to the Combination of Ixabepilone and Bevacizumab in Relationship to Previous Treatment With Bevacizumab and Taxanes | Complete Response (CR) | 0 Participants |
| Ixabepilone + Bevacizumab | Differences in Response to the Combination of Ixabepilone and Bevacizumab in Relationship to Previous Treatment With Bevacizumab and Taxanes | Not Assessed | 0 Participants |
| Ixabepilone + Bevacizumab | Differences in Response to the Combination of Ixabepilone and Bevacizumab in Relationship to Previous Treatment With Bevacizumab and Taxanes | Complete Response (CR) | 0 Participants |
| Ixabepilone + Bevacizumab | Differences in Response to the Combination of Ixabepilone and Bevacizumab in Relationship to Previous Treatment With Bevacizumab and Taxanes | Partial Response (PR) | 3 Participants |
| Ixabepilone + Bevacizumab | Differences in Response to the Combination of Ixabepilone and Bevacizumab in Relationship to Previous Treatment With Bevacizumab and Taxanes | Stable Disease (SD) | 6 Participants |
| Ixabepilone + Bevacizumab | Differences in Response to the Combination of Ixabepilone and Bevacizumab in Relationship to Previous Treatment With Bevacizumab and Taxanes | Progressive Disease (PD) | 1 Participants |
Comparison: The RECIST responses were categorized as SD/PD or NA compared to PR or Better as a binary outcome.p-value: 0.068Fisher Exact
Secondary
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. Presented are the counts of those that achieved DDC.
Time frame: 5 Years
Population: Those completing treatment post randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ixabepilone | Durable Disease Control Rate (DDCR) Differences Between Ixabepilone Alone and Ixabepilone + Bevacizumab | 1 Participants |
| Ixabepilone + Bevacizumab | Durable Disease Control Rate (DDCR) Differences Between Ixabepilone Alone and Ixabepilone + Bevacizumab | 14 Participants |
Secondary
Number of Participants With Treatment Related SAEs
Safety profile of Ixabepilone in combination with Bevacizumab as defined by Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Presented are the number of participants that experienced SAE's related to study drug. Full reporting of adverse events is presented in the Adverse Events module. Time frame was updated upon results entry.
Time frame: Up to 37 months
Population: Those completing treatment post randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ixabepilone | Number of Participants With Treatment Related SAEs | 6 Participants |
| Ixabepilone + Bevacizumab | Number of Participants With Treatment Related SAEs | 8 Participants |
p-value: 0.77Fisher Exact
Secondary
Objective Response Rate (ORR)
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). Time frame was updated upon results entry.
Time frame: Up to 37 months
Population: Those completing treatment post randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ixabepilone | Objective Response Rate (ORR) | 3 Participants |
| Ixabepilone + Bevacizumab | Objective Response Rate (ORR) | 15 Participants |
p-value: 0.003Fisher Exact
Secondary
Overall Survival (OS) Differences Between Ixabepilone Alone and Ixabepilone + Bevacizumab
Overall survival (OS) is defined as time from randomization to death from any cause. Time frame was updated upon results entry.
Time frame: Up to 37 months
Population: Those completing treatment post randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ixabepilone | Overall Survival (OS) Differences Between Ixabepilone Alone and Ixabepilone + Bevacizumab | 6.05 months |
| Ixabepilone + Bevacizumab | Overall Survival (OS) Differences Between Ixabepilone Alone and Ixabepilone + Bevacizumab | 10.32 months |
p-value: 0.01890% CI: [0.38, 0.84]Regression, Cox