Trial of Paclitaxel, Bevacizumab, and Enzastaurin Versus Paclitaxel, Bevacizumab and Placebo for Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine efficacy and safety of paclitaxel, bevacizumab and enzastaurin versus paclitaxel, bevacizumab, and placebo in participants who are diagnosed with locally recurrent or metastatic breast cancer.

Official Title
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A Randomized, Double-Blind, Phase 2 Trial of Paclitaxel Plus Bevacizumab and Enzastaurin Versus Paclitaxel Plus Bevacizumab and Placebo for Locally Recurrent or Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Enzastaurin
* Drug: Bevacizumab
* Drug: Paclitaxel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have signed an inform consent document Have histologic or cytologic diagnosis of breast cancer with evidence of unresectable locally recurrent or metastatic disease Have not received any prior chemotherapy for locally recurrent or metastatic disease Have not had adjuvant or neoadjuvant taxane therapy within 12 months prior to assignment to study treatment Age 18 years or older at time of informed consent Exclusion Criteria: Have any clinical evidence of central nervous system (CNS) metastases Have a history of seizure Have had a major surgical procedure within 4 weeks prior to assignment to study treatment Have had a minor surgical procedure, placement of an access device, or fine needle aspiration within 7 days prior to assignment to study treatment Have symptomatic peripheral vascular disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzastaurin + Bevacizumab + Paclitaxel<br>Participants randomized to this arm (Arm A) will receive enzastaurin, paclitaxel and bevacizumab until disease progression. Prior to randomization, a safety lead-in will be conducted in 6 participants who will be treated according to Arm A for 2 cycles (1 cycle = 28 days). Only after an acceptable safety analysis of the safety lead-in, will other participants be randomized to Phase 2 (either Arm A or Arm B). In Phase 2, participants from the safety lead-in will continue treatment according to Enzastaurin + Bevacizumab + Paclitaxel (Arm A). | Drug: Enzastaurin<br>* 1125 milligrams (mg) loading dose on Day 1 of Cycle 1 only then 500 mg oral once daily, until disease progression<br>* Other names: LY317615;Drug: Bevacizumab<br>* 10 milligrams per kilogram (mg/kg) intravenously, Days 1 and 15 every 28 days, until disease progression<br>Drug: Paclitaxel<br>* 90 milligrams per square meter (mg/m^2), intravenously, Days 1 ,8, and 15 every 28 days until disease progression<br>|
| Placebo Comparator: Bevacizumab + Paclitaxel + Placebo<br>Participants randomized to this arm (Arm B) will receive bevacizumab, paclitaxel and placebo until disease progression. | Drug: Bevacizumab<br>* 10 milligrams per kilogram (mg/kg) intravenously, Days 1 and 15 every 28 days, until disease progression<br>Drug: Paclitaxel<br>* 90 milligrams per square meter (mg/m^2), intravenously, Days 1 ,8, and 15 every 28 days until disease progression<br>Drug: Placebo<br>* Oral, daily, until disease progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS was defined as the time from the date of study enrollment to the first date of objectively determined progressive disease (PD) or death from any cause. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST version 1.0). PD is ≥20% increase in the sum of the longest diameter (LD) of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. For participants not known to have died and who did not have PD, PFS was censored at the date of the last progression-free assessment. For participants who received subsequent systemic anticancer therapy (after discontinuation from the study treatment) prior to disease progression or death, PFS was censored at the date of last progression-free assessment prior to the initiation of post-discontinuation systemic anticancer therapy. No participant completed a full cycle of therapy and thus no formal analysis was performed. | Baseline to measured PD (up to 15 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR was defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR), assessed according to the Response Evaluation Criteria In Solid Tumors (RECIST version 1.0). CR was defined as the disappearance of all tumor lesions; PR was defined as either ≥30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LDs or complete disappearance of target lesions, with persistence (but not worsening) of 1 or more non-target lesions. In either case of PR, no new lesions should have appeared. The percentage of participants with ORR was calculated as a total number of participants with CR or PR from the start of study treatment until disease progression or recurrence divided by the total number of participants treated, then multiplied by 100. No participant completed a full cycle of therapy and thus no formal analysis was performed. | Baseline to measured Progressive disease (up to 15 days) | 
| Number of Participants With Adverse Events (AEs) or Any Serious AEs (SAEs) | A summary of SAEs and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Event module. | Baseline to study completion (Day 15) plus 30-day safety follow-up |