Breast Cancer
Conditions
Keywords
Vorinostat, Neoadjuvant Chemotherapy
Brief summary
Vorinostat is a histone deacetylase (HDAC) inhibitor which is approved by the U.S. Food and Drug Administration for the treatment of a rare type of cancer involving the skin (cutaneous T cell lymphoma), but not for breast cancer. HDAC inhibitors work by unsilencing tumor suppressor genes and other genes in the cancer cells that are repressed; when the genes are turned back on by the drug, it leads to death of the cancer cells. HDAC inhibitors such as vorinostat have been shown to enhance the effects of chemotherapy and trastuzumab in experimental systems. The purpose of this trial is to determine the optimal dose of vorinostat to use in combination with standard chemotherapy alone (or in combination with plus trastuzumab for HER2-positive disease), and to determine whether vorinostat enhances the effectiveness of standard chemotherapy (+/- trastuzumab) in patients with locally advanced breast cancer.
Detailed description
This is a phase I-II trial in which patients with stage IIB-IIIC breast cancer will receive: 1. Neoadjuvant weekly paclitaxel (80 mg/m2 IV weekly x 12 weeks) plus vorinostat (200 or 300 mg PO BID on days 1-3 each paclitaxel dose) and trastuzumab (4 mg/kg loading dose, 2 mg/kg IV weekly x 12 total doses if HER2 positive, followed by: 2. Doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) every 2 weeks x 4 cycles (plus G-CSF), followed by: 3. Surgery (lumpectomy or mastectomy)
Interventions
DRUGVorinostat
Vorinostat 200 or 300 mg PO BID on days 1-3 of each weekly paclitaxel dose
DRUGPaclitaxel
Paclitaxel 80 mg/m2 weekly for 12 weeks
DRUGTrastuzumab
Trastuzumab (if HER2-positive) 4 mg/kg, then 2 mg/kg weekly for 12 weeks including loading dose
DRUGDoxorubicin
Doxorubicin 60 mg/m2 every 2 weeks for 8 weeks
DRUGCyclophosphamide
Cyclophosphamide 600 mg/m2 every 2 weeks for 8 weeks
PROCEDURESurgery
Surgical excision of tumor from breast
Sponsors
Merck Sharp & Dohme LLC
Albert Einstein College of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed adenocarcinoma of the breast associated with the following stages: IIB, IIIA, IIIB or IIIC. * Tumor must be Her2/neu positive * No prior chemotherapy, radiation or definitive therapeutic surgery
Exclusion criteria
* May not be receiving any other investigational agents * Uncontrolled intercurrent illness
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase II Dose of Vorinostat in Combination With Weekly Paclitaxel/Trastuzumab | 3 weeks | Dose limiting toxicity in cycle 1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (CR) Rate in Patients With Her2/Neu Positive Locally Advanced Breast Cancer. | 6 months | Pathological Complete Response (CR) defined as absence of invasive cancer at surgery |
Countries
United States
Participant flow
Recruitment details
Dates of recruitment: April 2008 - September 2013
Pre-assignment details
Patients with HER2 positive disease also received trastuzumab.
Participants by arm
| Arm | Count |
|---|---|
| Stratum A (HER2-positive): Dose Level 1 Vorinostat (PO days 1-3) plus weekly paclitaxel x 12 weeks and trastuzumab, followed by doxorubicin-cyclophosphamide every 2 weeks x 4 cycles, followed by surgery
Vorinostat: Vorinostat 200 mg PO BID on days 1-3 of each weekly paclitaxel dose
Paclitaxel: Paclitaxel 80 mg/m2 weekly for 12 weeks
Trastuzumab: Trastuzumab (if HER2-positive) 4 mg/kg, then 2 mg/kg weekly for 12 weeks including loading dose
Doxorubicin: Doxorubicin 60 mg/m2 every 2 weeks for 8 weeks
Cyclophosphamide: Cyclophosphamide 600 mg/m2 every 2 weeks for 8 weeks
Surgery: Surgical excision of tumor from breast | 3 |
| Stratum A (HER2-positive): Dose Level 2 Vorinostat (PO days 1-3) plus weekly paclitaxel x 12 weeks and trastuzumab, followed by doxorubicin-cyclophosphamide every 2 weeks x 4 cycles, followed by surgery
Vorinostat: Vorinostat 300 mg PO BID on days 1-3 of each weekly paclitaxel dose
Paclitaxel: Paclitaxel 80 mg/m2 weekly for 12 weeks
Trastuzumab: Trastuzumab (if HER2-positive) 4 mg/kg, then 2 mg/kg weekly for 12 weeks including loading dose
Doxorubicin: Doxorubicin 60 mg/m2 every 2 weeks for 8 weeks
Cyclophosphamide: Cyclophosphamide 600 mg/m2 every 2 weeks for 8 weeks
Surgery: Surgical excision of tumor from breast | 23 |
| Stratum B: Triple Negative Vorinostat (PO days 1-3) plus weekly paclitaxel x 12 weeks and trastuzumab, followed by doxorubicin-cyclophosphamide every 2 weeks x 4 cycles, followed by surgery
Vorinostat: Vorinostat 300 mg PO BID on days 1-3 of each weekly paclitaxel dose
Paclitaxel: Paclitaxel 80 mg/m2 weekly for 12 weeks
Trastuzumab: Trastuzumab (if HER2-positive) 4 mg/kg, then 2 mg/kg weekly for 12 weeks including loading dose
Doxorubicin: Doxorubicin 60 mg/m2 every 2 weeks for 8 weeks
Cyclophosphamide: Cyclophosphamide 600 mg/m2 every 2 weeks for 8 weeks
Surgery: Surgical excision of tumor from breast | 16 |
| Stratum C: ER-Positive, HER2-Negative Vorinostat (PO days 1-3) plus weekly paclitaxel x 12 weeks and trastuzumab, followed by doxorubicin-cyclophosphamide every 2 weeks x 4 cycles, followed by surgery
Vorinostat: Vorinostat 300 mg PO BID on days 1-3 of each weekly paclitaxel dose
Paclitaxel: Paclitaxel 80 mg/m2 weekly for 12 weeks
Trastuzumab: Trastuzumab (if HER2-positive) 4 mg/kg, then 2 mg/kg weekly for 12 weeks including loading dose
Doxorubicin: Doxorubicin 60 mg/m2 every 2 weeks for 8 weeks
Cyclophosphamide: Cyclophosphamide 600 mg/m2 every 2 weeks for 8 weeks
Surgery: Surgical excision of tumor from breast | 13 |
| Total | 55 |
Baseline characteristics
| Characteristic | Stratum A (HER2-positive): Dose Level 1 | Stratum A (HER2-positive): Dose Level 2 | Stratum B: Triple Negative | Stratum C: ER-Positive, HER2-Negative | Total |
|---|---|---|---|---|---|
| Age, Continuous | 54 years | 54 years | 48 years | 46 years | 52 years |
| Sex: Female, Male Female | 3 Participants | 23 Participants | 16 Participants | 13 Participants | 55 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 23 | 1 / 16 | 0 / 13 |
| other Total, other adverse events | 0 / 3 | 0 / 23 | 0 / 16 | 0 / 13 |
| serious Total, serious adverse events | 0 / 3 | 2 / 23 | 1 / 16 | 0 / 13 |
Outcome results
Primary
Recommended Phase II Dose of Vorinostat in Combination With Weekly Paclitaxel/Trastuzumab
Dose limiting toxicity in cycle 1
Time frame: 3 weeks
Population: The recommended Phase II Dose of vorinostat was determined in Stratum A and B participants only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stratum A: VR-Paclitaxel-Trastuzumab | Recommended Phase II Dose of Vorinostat in Combination With Weekly Paclitaxel/Trastuzumab | 300 mg |
| Stratum B: VR-Paclitaxel-Trastuzumab | Recommended Phase II Dose of Vorinostat in Combination With Weekly Paclitaxel/Trastuzumab | 300 mg |
Secondary
Pathological Complete Response (CR) Rate in Patients With Her2/Neu Positive Locally Advanced Breast Cancer.
Pathological Complete Response (CR) defined as absence of invasive cancer at surgery
Time frame: 6 months
Population: Stratum A (HER2-positive): Dose Level 1 and Stratum A (HER2-positive): Dose Level 2 are combined. Data was collected for outcome measures per stratum not per dose level. 2 pts in Stratum A were not evaluable (1 lost to f/u; 1 death); 1 pt was not evaluable in Stratum B (1 death) and 1 pt was not evaluable in C (1 declined surgery)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stratum A: VR-Paclitaxel-Trastuzumab | Pathological Complete Response (CR) Rate in Patients With Her2/Neu Positive Locally Advanced Breast Cancer. | 13 Participants |
| Stratum B: VR-Paclitaxel-Trastuzumab | Pathological Complete Response (CR) Rate in Patients With Her2/Neu Positive Locally Advanced Breast Cancer. | 4 Participants |
| Stratum C: ER-Positive, HER2-negative | Pathological Complete Response (CR) Rate in Patients With Her2/Neu Positive Locally Advanced Breast Cancer. | 0 Participants |
p-value: <0.120% CI: [34, 74]Simon's Mimimax 2-stage design