Clear Cell Mullerian Tumor, Fallopian Tube Cancer, Ovarian Cancer, Papillary Serous Mullerian Tumor, Primary Peritoneal Cancer
Conditions
Brief summary
The purpose of this research study is to evaluate how patients with newly diagnosed advanced ovarian, fallopian tube, primary peritoneal cancer and papillary serous or clear cell mullerian tumors respond to consolidation therapy with Avastin and erlotinib or Avastin alone over 1 year. These drugs have been used in the treatment of other types of cancers and information from those studies suggests that these agents may help to treat the cancers studied here.
Detailed description
Objectives: Primary To examine the progression free survival (PFS) of Avastin and Erlotinib (AE) or Avastin (A) as consolidation therapy. Secondary To examine the toxicity between the two consolidative regimens AE vs. A. To assess the response rate of CTA. STATISTICAL DESIGN This study uses a randomized selection design. Both consolidation treatment arms are deemed experimental and are compared against a historical control \[McGuire WP et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. NEJM 1996: 334:1-6. PMID:7494563\]. With 30 patients in a given arm and 6 months of follow-up, there was 80% power to detect a 61.5% increase in median PFS from 13 months to 21 months assuming 1-sided 10% significance.
Interventions
DRUGbevacizumab
DRUGerlotinib
DRUGpaclitaxel
DRUGcarboplatin
Sponsors
Genentech, Inc.
Beth Israel Deaconess Medical Center
Brigham and Women's Hospital
Massachusetts General Hospital
Dana-Farber Cancer Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 18 years of age and older * Histological diagnosis of epithelial ovarian carcinoma, fallopian tube cancer, primary peritoneal carcinoma, or papillary serous mullerian carcinoma * Previous attempted surgical debulking * Stage III or IV * Willing and able to undergo second look laparoscopy * Performance status 0-1 by ECOG scale * Peripheral neuropathy \< grade 2 * Life expectancy of 6 months or greater
Exclusion criteria
* Patients with clinically significant cardiovascular disease as outlined in the protocol * Neutrophil count \< 1,500/mm3; platelet count \<100,000/m3 * Alkaline phosphatase or bilirubin \> 1.5 x ULN, SGOT \> 5 x ULN * Calculated creatinine clearance \< 50ml/min * Prior chemotherapy or radiotherapy for other malignancy except for the treatment for localized breast cancer greater than five years prior to diagnosis * No more than one cycle of first line chemotherapy with carboplatin and paclitaxel * Inadequate surgical cytoreduction such that interval cytoreductive surgery could materially improve prognosis * Concurrent invasive malignancy * Evidence of bleeding diathesis or coagulopathy * Evidence of tumor involving major blood vessels on any prior CT scans * Surgical wound that has failed to close * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, or anticipation of need for major surgical procedure during the course of this study * Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to day 0 * Serious non-healing wound, ulcer, or bone fracture * Prior treatment with an anti-angiogenic agent * Any active bleeding * Active psychiatric disease or neurologic symptoms requiring treatment * Presence of central nervous system brain metastases * Proteinuria at screening as demonstrated by criteria in protocol * Dementia or significantly altered mental status that would prohibit the understanding and/or giving of informed consent * Known hypersensitivity to Cremophor EL or any component of Avastin * Active bacterial, viral, or fungal infections * Receiving any other investigational agent * History of gastrointestinal perforation * Prior therapies targeting the epidermal growth factor receptor * Symptoms of bowel obstruction * Dependence on TPN or IV hydration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Consolidation Progression-Free Survival | Assessments occurred every cycle (serologic) and every 3 cycles (radiologic) on consolidation treatment. Pts were allowed on consolidation therapy for up to 1 year and upon treatment discontinuation were followed for another year. | Consolidation PFS based on the Kaplan-Meier method was defined as the time from the first day of consolidation therapy to documented disease progression (PD) or disease-specific death. Based on RECIST 1.1, radiographic PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum since beginning consolidation, the appearence of one or more new lesions and/or unequivocal progression of existing non-target lesions. Based on Rustin criteria, serlogic PD was a rise in CA125 since beginning of consolidation or previously normal CA125 that rises to \>/= 2xULN with either event documented on 2 occasions. Patients who were event-free were censored at the date of their last disease evaluation. |
| Consolidation Treatment-related Toxicity Rate | Assessed every cycle during consolidation treatment and up to 30 days post-treatment. Per protocol, consolidation treatment was a fixed duration of 1 year. | Consolidation treatment-related toxicity rates based on CTCAEv3 were defined as rates of maximum grade 3 or higher toxicity events with attribution possible, probable or definite occurring during consolidation treatment and up to 30 days post-treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Consolidation Objective Response Rate | Assessments occurred every cycle (serologic) and every 3 cycles (radiologic) on consolidation treatment. Pts were allowed on consolidation therapy for up to 1 year. | Consolidation objective response (OR) was based on RECIST 1.0 criteria with OR defined as achieving partial response (PR) or complete response (CR). Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. For CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed no fewer than 4 weeks after the response criteria are first met. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. If CA125 disease then OR based on Rustin criteria is a 50% decrease in serum CA125 level from two initially elevated samples confirmed by a 4th sample. |
Countries
United States
Participant flow
Recruitment details
Sixty patients were enrolled between Aug 3, 2007 and Jan 6, 2010.
Pre-assignment details
Patients with disease progression based on radiographic evaluation after induction could not advance to the randomized consolidation phase.
Participants by arm
| Arm | Count |
|---|---|
| Carboplatin/Paclitaxel/Bevacizumab Then Bevacizumab Induction (CTA): Patients received carboplatin IV AUC 5, paclitaxel IV 175 mg/m2 and bevacizumab IV 15 mg/kg on day 1 (+/- 3d) of a 21 day cycle for 6 cycles. Bevacizumab started with cycle 2.
Patients with disease progression based on radiographic evaluation after induction could not advance to the randomized consolidation phase.
Consolidation (A): Patients received bevacizumab IV 15 mg/kg on day 1 (+/- 3d) of a 21 day cycle for 1 year.
bevacizumab
paclitaxel
carboplatin | 23 |
| Carboplatin/Paclitaxel/Bevacizumab Then Bevacizumab/Erlotinib Induction (CTA): Patients received carboplatin IV AUC 5, paclitaxel IV 175 mg/m2 and bevacizumab IV 15 mg/kg on day 1 (+/- 3d) of a 21 day cycle for 6 cycles. Bevacizumab started with cycle 2.
Patients with disease progression based on radiographic evaluation after induction could not advance to the randomized consolidation phase.
Consolidation (AE): Patients received bevacizumab IV 15 mg/kg on day 1 (+/- 3d) of a 21 day cycle and oral erlotinib 150mg daily for 1 year.
bevacizumab
erlotinib
paclitaxel
carboplatin | 25 |
| Carboplatin/Paclitaxel/Bevacizumab Induction (CTA): Patients received carboplatin IV AUC 5, paclitaxel IV 175 mg/m2 and bevacizumab IV 15 mg/kg on day 1 (+/- 3d) of a 21 day cycle for 6 cycles. Bevacizumab started with cycle 2.
Patients with disease progression based on radiographic evaluation after induction could not advance to the randomized consolidation phase.
Consolidation: None
bevacizumab
paclitaxel
carboplatin | 11 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 10 | 7 |
| Overall Study | Clinical Progression | 3 | 1 | 0 |
| Overall Study | Death | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 3 |
| Overall Study | Progressive Disease | 7 | 3 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Carboplatin/Paclitaxel/Bevacizumab Then Bevacizumab | Carboplatin/Paclitaxel/Bevacizumab Then Bevacizumab/Erlotinib | Carboplatin/Paclitaxel/Bevacizumab | Total |
|---|---|---|---|---|
| Age, Continuous | 58 years | 56 years | 54 years | 57 years |
| Cancer Type Epithelial ovarian | 10 participants | 17 participants | 8 participants | 35 participants |
| Cancer Type Fallopian tube | 5 participants | 4 participants | 1 participants | 10 participants |
| Cancer Type Other (mixed, carcinosarcoma) | 2 participants | 2 participants | 0 participants | 4 participants |
| Cancer Type Primary peritoneal | 4 participants | 1 participants | 1 participants | 6 participants |
| Cancer Type Uterine papillary serous | 2 participants | 1 participants | 1 participants | 4 participants |
| Region of Enrollment United States | 23 participants | 25 participants | 11 participants | 59 participants |
| Sex: Female, Male Female | 23 Participants | 25 Participants | 11 Participants | 59 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 23 / 23 | 25 / 25 |
| serious Total, serious adverse events | 7 / 23 | 18 / 25 |
Outcome results
Primary
Consolidation Progression-Free Survival
Consolidation PFS based on the Kaplan-Meier method was defined as the time from the first day of consolidation therapy to documented disease progression (PD) or disease-specific death. Based on RECIST 1.1, radiographic PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum since beginning consolidation, the appearence of one or more new lesions and/or unequivocal progression of existing non-target lesions. Based on Rustin criteria, serlogic PD was a rise in CA125 since beginning of consolidation or previously normal CA125 that rises to \>/= 2xULN with either event documented on 2 occasions. Patients who were event-free were censored at the date of their last disease evaluation.
Time frame: Assessments occurred every cycle (serologic) and every 3 cycles (radiologic) on consolidation treatment. Pts were allowed on consolidation therapy for up to 1 year and upon treatment discontinuation were followed for another year.
Population: The analysis dataset is comprised of patients randomized to consolidation treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carboplatin/Paclitaxel/Bevacizumab Then Bevacizumab | Consolidation Progression-Free Survival | 13.3 months |
| Carboplatin/Paclitaxel/Bevacizumab Then Bevacizumab/Erlotinib | Consolidation Progression-Free Survival | 18.9 months |
Primary
Consolidation Treatment-related Toxicity Rate
Consolidation treatment-related toxicity rates based on CTCAEv3 were defined as rates of maximum grade 3 or higher toxicity events with attribution possible, probable or definite occurring during consolidation treatment and up to 30 days post-treatment.
Time frame: Assessed every cycle during consolidation treatment and up to 30 days post-treatment. Per protocol, consolidation treatment was a fixed duration of 1 year.
Population: The analysis dataset is comprised of patients who were randomized to consolidation treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carboplatin/Paclitaxel/Bevacizumab Then Bevacizumab | Consolidation Treatment-related Toxicity Rate | 30.4 percentage of participants |
| Carboplatin/Paclitaxel/Bevacizumab Then Bevacizumab/Erlotinib | Consolidation Treatment-related Toxicity Rate | 72.0 percentage of participants |
Secondary
Consolidation Objective Response Rate
Consolidation objective response (OR) was based on RECIST 1.0 criteria with OR defined as achieving partial response (PR) or complete response (CR). Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. For CR or PR, changes in tumor measurements must be confirmed by repeat assessments performed no fewer than 4 weeks after the response criteria are first met. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. If CA125 disease then OR based on Rustin criteria is a 50% decrease in serum CA125 level from two initially elevated samples confirmed by a 4th sample.
Time frame: Assessments occurred every cycle (serologic) and every 3 cycles (radiologic) on consolidation treatment. Pts were allowed on consolidation therapy for up to 1 year.
Population: The analysis dataset is comprised of all patient who started consolidation treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carboplatin/Paclitaxel/Bevacizumab Then Bevacizumab | Consolidation Objective Response Rate | 0.65 proportion of patients |
| Carboplatin/Paclitaxel/Bevacizumab Then Bevacizumab/Erlotinib | Consolidation Objective Response Rate | .60 proportion of patients |