Brief Summary
This phase I/II trial is studying the side effects and best dose of vorinostat when given together with paclitaxel and bevacizumab and to see how well they work in treating patients with metastatic breast cancer and/or breast cancer that has recurred in the chest wall and cannot be removed by surgery. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving vorinostat together with paclitaxel and bevacizumab may kill more tumor cells.
Brief Title
Phase I-II Study of Vorinostat, Paclitaxel, and Bevacizumab in Metastatic Breast Cancer
Detailed Description
PRiMARY OBJECTIVES:
I. To determine the recommended phase II dose of oral suberoylanilide hydroxamic acid (vorinostat) in combination with weekly paclitaxel and bevacizumab in patients with chest wall recurrent or metastatic breast cancer. (Phase I) II. To determine the efficacy (response rate, response duration, time to disease progression, time to treatment failure, and overall survival) and toxicity of oral suberoylanilide hydroxamic acid (vorinostat) in combination with weekly paclitaxel and bevacizumab in patients with chest wall recurrent or metastatic breast cancer. (Phase II)
SECONDARY OBJECTIVES:
I. To determine whether in vivo treatment with vorinostat induces a) acetylation of proteins including histone H3 and H4, b) ubiquitylation of proteins, and c) the levels of p21 and p27 levels in the peripheral blood mononuclear cells (pre treatment vs. cycle 1 day 2 after 3 VORINOSTAT doses but prior to paclitaxel.
II. To determine whether in vivo treatment with vorinostat induces a) acetylation of proteins including histone H3 and H4, ubiquitylation of proteins, and c) the levels of Bim, Bak, tBID, p21 and p27 levels, as well as down regulate Bcl-2, Bcl-xL and survivin in chest wall recurrent or metastatic breast cancer cells (pre treatment vs. cycle 1 day 2 after 3 vorinostat doses but prior to paclitaxel).
III. To determine whether in the primary breast cancer (and metastatic cancer if available) pretreatment levels of Her-2, Estrogen Receptor (ER)-alpha, Progesterone Receptor (PR), p21, p27, p-AKT, p-ERK1/2, HDAC1, 2, 3, 4, 6, 10 and SIRT2 levels predict for the response to treatment with VORINOSTAT plus paclitaxel.
OUTLINE: This is a phase I, multicenter, dose-escalation study of vorinostat (SAHA) followed by a phase II, open-label study.
Phase I: Patients receive oral SAHA twice daily on days 1-3, 8-10, and 15-17, paclitaxel IV over 1 hour on days 2, 9, and 16, and bevacizumab IV over 30-90 minutes on days 2 and 16. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. The recommended phase II dose is defined as one dose level below the MTD.
Phase II: Patients receive SAHA at the recommended phase II dose and paclitaxel and bevacizumab as in phase I.
I. To determine the recommended phase II dose of oral suberoylanilide hydroxamic acid (vorinostat) in combination with weekly paclitaxel and bevacizumab in patients with chest wall recurrent or metastatic breast cancer. (Phase I) II. To determine the efficacy (response rate, response duration, time to disease progression, time to treatment failure, and overall survival) and toxicity of oral suberoylanilide hydroxamic acid (vorinostat) in combination with weekly paclitaxel and bevacizumab in patients with chest wall recurrent or metastatic breast cancer. (Phase II)
SECONDARY OBJECTIVES:
I. To determine whether in vivo treatment with vorinostat induces a) acetylation of proteins including histone H3 and H4, b) ubiquitylation of proteins, and c) the levels of p21 and p27 levels in the peripheral blood mononuclear cells (pre treatment vs. cycle 1 day 2 after 3 VORINOSTAT doses but prior to paclitaxel.
II. To determine whether in vivo treatment with vorinostat induces a) acetylation of proteins including histone H3 and H4, ubiquitylation of proteins, and c) the levels of Bim, Bak, tBID, p21 and p27 levels, as well as down regulate Bcl-2, Bcl-xL and survivin in chest wall recurrent or metastatic breast cancer cells (pre treatment vs. cycle 1 day 2 after 3 vorinostat doses but prior to paclitaxel).
III. To determine whether in the primary breast cancer (and metastatic cancer if available) pretreatment levels of Her-2, Estrogen Receptor (ER)-alpha, Progesterone Receptor (PR), p21, p27, p-AKT, p-ERK1/2, HDAC1, 2, 3, 4, 6, 10 and SIRT2 levels predict for the response to treatment with VORINOSTAT plus paclitaxel.
OUTLINE: This is a phase I, multicenter, dose-escalation study of vorinostat (SAHA) followed by a phase II, open-label study.
Phase I: Patients receive oral SAHA twice daily on days 1-3, 8-10, and 15-17, paclitaxel IV over 1 hour on days 2, 9, and 16, and bevacizumab IV over 30-90 minutes on days 2 and 16. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. The recommended phase II dose is defined as one dose level below the MTD.
Phase II: Patients receive SAHA at the recommended phase II dose and paclitaxel and bevacizumab as in phase I.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Male Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Eligibility Criteria
Inclusion Criteria:
* histologically or cytologically confirmed adenocarcinoma of the breast; effective with version 2.2 (1/26/09), only patients with disease that is accessible to biopsy and consent to serial biopsy are eligible
* stage IV disease, locally recurrent inoperable chest wall disease; at least one bidimensional and/or unidimensional, measurable indicator lesion must be present (patients with only non-measurable disease are eligible for the phase I trial only); all sites of disease should be noted and followed
* ECOG performance status =\< 1 (Karnofsky \>= 70%)
* Absolute neutrophil count \>= 1,500/ul
* Platelets \>= 100,000/ul
* Total bilirubin within normal institutional limits
* AST(SGOT)/ALT(SGPT) =\< 2.5 x institutional upper limit of normal
* PTT and either INR or PT \< 1.5 x normal
* Creatinine within normal institutional limits OR creatinine clearance \>= mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
* Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC) ratio; for UPC ratio \> 0.5, 24-hour urine protein should be obtained and the level should be \< 1000 mg for patient enrollment;
* LVEF must be at or above the lower institutional limit of the normal range (on MUGA or Echo obtained within 12 weeks of registration, or within 4 weeks of prior Herceptin)
* Not pregnant/lactating
Exclusion criteria:
* chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
* may not be receiving any other investigational agents.
* history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat or other agents used in the study (e.g., paclitaxel, bevacizumab, quinolones)
* uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* histologically or cytologically confirmed adenocarcinoma of the breast; effective with version 2.2 (1/26/09), only patients with disease that is accessible to biopsy and consent to serial biopsy are eligible
* stage IV disease, locally recurrent inoperable chest wall disease; at least one bidimensional and/or unidimensional, measurable indicator lesion must be present (patients with only non-measurable disease are eligible for the phase I trial only); all sites of disease should be noted and followed
* ECOG performance status =\< 1 (Karnofsky \>= 70%)
* Absolute neutrophil count \>= 1,500/ul
* Platelets \>= 100,000/ul
* Total bilirubin within normal institutional limits
* AST(SGOT)/ALT(SGPT) =\< 2.5 x institutional upper limit of normal
* PTT and either INR or PT \< 1.5 x normal
* Creatinine within normal institutional limits OR creatinine clearance \>= mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
* Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC) ratio; for UPC ratio \> 0.5, 24-hour urine protein should be obtained and the level should be \< 1000 mg for patient enrollment;
* LVEF must be at or above the lower institutional limit of the normal range (on MUGA or Echo obtained within 12 weeks of registration, or within 4 weeks of prior Herceptin)
* Not pregnant/lactating
Exclusion criteria:
* chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
* may not be receiving any other investigational agents.
* history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat or other agents used in the study (e.g., paclitaxel, bevacizumab, quinolones)
* uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Inclusion Criteria
Inclusion Criteria:
* histologically or cytologically confirmed adenocarcinoma of the breast; effective with version 2.2 (1/26/09), only patients with disease that is accessible to biopsy and consent to serial biopsy are eligible
* stage IV disease, locally recurrent inoperable chest wall disease; at least one bidimensional and/or unidimensional, measurable indicator lesion must be present (patients with only non-measurable disease are eligible for the phase I trial only); all sites of disease should be noted and followed
* ECOG performance status =\< 1 (Karnofsky \>= 70%)
* Absolute neutrophil count \>= 1,500/ul
* Platelets \>= 100,000/ul
* Total bilirubin within normal institutional limits
* AST(SGOT)/ALT(SGPT) =\< 2.5 x institutional upper limit of normal
* PTT and either INR or PT \< 1.5 x normal
* Creatinine within normal institutional limits OR creatinine clearance \>= mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
* Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC) ratio; for UPC ratio \> 0.5, 24-hour urine protein should be obtained and the level should be \< 1000 mg for patient enrollment;
* LVEF must be at or above the lower institutional limit of the normal range (on MUGA or Echo obtained within 12 weeks of registration, or within 4 weeks of prior Herceptin)
* Not pregnant/lactating
* histologically or cytologically confirmed adenocarcinoma of the breast; effective with version 2.2 (1/26/09), only patients with disease that is accessible to biopsy and consent to serial biopsy are eligible
* stage IV disease, locally recurrent inoperable chest wall disease; at least one bidimensional and/or unidimensional, measurable indicator lesion must be present (patients with only non-measurable disease are eligible for the phase I trial only); all sites of disease should be noted and followed
* ECOG performance status =\< 1 (Karnofsky \>= 70%)
* Absolute neutrophil count \>= 1,500/ul
* Platelets \>= 100,000/ul
* Total bilirubin within normal institutional limits
* AST(SGOT)/ALT(SGPT) =\< 2.5 x institutional upper limit of normal
* PTT and either INR or PT \< 1.5 x normal
* Creatinine within normal institutional limits OR creatinine clearance \>= mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
* Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC) ratio; for UPC ratio \> 0.5, 24-hour urine protein should be obtained and the level should be \< 1000 mg for patient enrollment;
* LVEF must be at or above the lower institutional limit of the normal range (on MUGA or Echo obtained within 12 weeks of registration, or within 4 weeks of prior Herceptin)
* Not pregnant/lactating
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Estimated
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT00368875
Org Class
Nih
Org Full Name
National Cancer Institute (NCI)
Org Study Id
NCI-2012-03012
Overall Status
Completed
Phases
Phase 1
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Phase I/II Study of a Combination of Suberoylanilide Hydroxamic Acid (Vorinostat) Plus Paclitaxel and Bevacizumab in Patients With Advanced Metastatic and/or Local Chest Wall Recurrent Breast Cancer
Primary Outcomes
Outcome Description
Dose-limiting toxcities (DLT) were defined as grade 3-4 febrile neutropenia, thrombocytopenia and non-hemtological toxicity attributed to therapy (nausea, vomiting and diarrhea would be considered dose limiting only if not adequately controlled with therapy). Any toxicity occurring during cycle 1 that resulted in dose reduction of vorinostat or paclitaxel or failure to complete all protocol specificed doses in the first cycle was also considered a DLT
Outcome Measure
Recommended Phase II Dose as Assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Phase I)
Outcome Time Frame
28 days
Outcome Description
Estimated and a 95% confidence interval will be estimated via binomial proportions. Per Response Evaluation Criteria in Solid Tumors (RECIST) for target lesions and assessed by CT scan: Complete response (CR): Disappearance of all target lesions; Partial Response (PR): \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR+PR.
Outcome Measure
Objective Response Rate (CR + PR)
Outcome Time Frame
Up to 12 months
Secondary Ids
Secondary Id
NCI-2012-03012
Secondary Id
06-05-291
Secondary Id
7703
Secondary Id
N01CM62204
Secondary Id
N01CM62207
Secondary Id
N01CM62205
Secondary Id
N01CM62209
Secondary Outcomes
Outcome Description
Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
Outcome Time Frame
From first treatment day until objective or symptomatic progression, assessed up to 12 months
Outcome Measure
Progression-free Survival (PFS),
Outcome Description
Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae. Time to treatment failure was not reported for this study.
Outcome Time Frame
Time from the first treatment day until disease progression or discontinuation of treatment due to toxicity, assessed up to 12 months
Outcome Measure
Time to Treatment Failure (TTF)
Outcome Description
Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
Outcome Time Frame
Time from first treatment day until death, assessed up to 12 months
Outcome Measure
Overall Survival(OS)
Start Date
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Christine Pellegrino
Investigator Email
CPELLEGR@montefiore.org
Investigator Phone