Avastin +/- Erlotinib Consolidation Chemotherapy After Carboplatin, Paclitaxel, and Avastin (CTA) Induction Therapy for Advanced Ovarian, Fallopian Tube, Primary Peritoneal Cancer & Papillary Serous or Clear Cell Mullerian Tumors

Phase 2

Completed

Conditions: Ovarian Cancer
Fallopian Tube Cancer
Primary Peritoneal Cancer
Papillary Serous Mullerian Tumor
Clear Cell Mullerian Tumor

Interventions: Drug: bevacizumab
Drug: paclitaxel
Drug: erlotinib
Drug: carboplatin

Registration Number: NCT00520013

Lead Sponsor: Dana-Farber Cancer Institute

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 60

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
carboplatin/paclitaxel/bevacizumab then bevacizumab	paclitaxel	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.
carboplatin/paclitaxel/bevacizumab then bevacizumab	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.
carboplatin/paclitaxel/bevacizumab then bevacizumab	carboplatin	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.
carboplatin/paclitaxel/bevacizumab then bevacizumab/erlotinib	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.
carboplatin/paclitaxel/bevacizumab then bevacizumab/erlotinib	paclitaxel	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.
carboplatin/paclitaxel/bevacizumab then bevacizumab/erlotinib	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 (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.
carboplatin/paclitaxel/bevacizumab then bevacizumab/erlotinib	carboplatin	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.
carboplatin/paclitaxel/bevacizumab	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
carboplatin/paclitaxel/bevacizumab	carboplatin	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
carboplatin/paclitaxel/bevacizumab	paclitaxel	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

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (3): Massachusetts General Hospital
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Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
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Boston, Massachusetts, United States
Dana-Farber Cancer Institute
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Boston, Massachusetts, United States