Breast Cancer, Triple Negative Breast Cancer
Conditions
Brief summary
This is a phase II single-arm, open-label, prospective study to evaluate the efficacy of the low dose weekly Carboplatin/Paclitaxel followed by dose-dense Doxorubicin/Cyclophosphamide in subjects with triple-negative breast cancer in neoadjuvant settings.
Interventions
DRUGCarboplatin
Carboplatin is a platinum compound alkylating agent which covalently binds to DNA; interferes with the function of DNA by producing interstrand DNA cross-links.
DRUGPaclitaxel
Paclitaxel promotes microtubule assembly by enhancing the action of tubulin dimers, stabilizing existing microtubules, and inhibiting their disassembly, interfering with the late G2 mitotic phase, and inhibiting cell replication. In addition, the drug can distort mitotic spindles, resulting in the breakage of chromosomes. Paclitaxel may also suppress cell proliferation and modulate immune response.
DRUGDoxorubicin
Inhibition of DNA and RNA synthesis by intercalation between DNA base pairs by inhibition of topoisomerase II and by steric obstruction. Doxorubicin intercalates at points of local uncoiling of the double helix. Although the exact mechanism is unclear, it appears that direct binding to DNA (intercalation) and inhibition of DNA repair (topoisomerase II inhibition) result in blockade of DNA and RNA synthesis and fragmentation of DNA. Doxorubicin is also a powerful iron chelator; the iron-doxorubicin complex can bind DNA and cell membranes and produce free radicals that immediately cleave the DNA and cell membranes.
DRUGCyclophosphamide
Cyclophosphamide is an alkylating agent that prevents cell division by cross-linking DNA strands and decreasing DNA synthesis. It is a cell cycle phase nonspecific agent. Cyclophosphamide also possesses potent immunosuppressive activity. Cyclophosphamide is a prodrug that must be metabolized to active metabolites in the liver.
DRUGPegfilgrastim
Pegfilgrastim provides growth factor support in a single dose. It stimulates bone marrow to create neutrophils for patients undergoing chemotherapy.
DRUGFilgrastim
Filgrastim provides growth factor support in multiple doses. It stimulates bone marrow to create neutrophils for patients undergoing chemotherapy.
Sponsors
University of Wisconsin, Madison
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects must have histologically or cytologically confirmed invasive breast cancer which meets the following criteria: 1. Estrogen Receptor (ER) and Progesterone Receptor (PR)-negative as defined by local standard clinical immunohistochemistry (IHC) \< 1%. 2. HER2-negative using local standard testing. Negative is defined as IHC 0 or 1+ (if 2+, must reflex to ISH method). If ISH method is used, ratio \< 2 is considered negative. 3. Clinical tumor size of at least 2.1 cm (T2) by palpation or imaging, regardless of the ipsilateral regional lymph node status, or any tumor size but with ipsilateral regional lymph nodes involved by the tumor (any T if ipsilateral regional node positive). Subjects with inflammatory breast cancer are eligible. If bilateral breast cancer is present, the subject is eligible if the contralateral tumor is DCIS only (without any invasive disease on biopsy) or another invasive breast cancer of any size that is also ER, PR and HER2 negative. 4. Any radiographic abnormal ipsilateral regional lymph nodes or any clinically concerning ipsilateral regional lymph nodes with the exception of internal mammary nodes should be sampled with percutaneous biopsy, but no sentinel axillary lymph node mapping/biopsy is allowed before chemotherapy. If clinically node negative (cNO), pre-chemotherapy ipsilateral sentinel axillary lymph node mapping/biopsy is not allowed. 2. Candidate for neoadjuvant chemotherapy. 3. Age \> 18 years and \< 75 years 4. ECOG Performance Status \< 1. 5. Left ventricular ejection fraction (LVEF) ≥ LLN (per institutional normal) determined by 6. Adequate organ and marrow function as determined by study protocol 7. Non Pregnant. Women of childbearing potential must have a negative pregnancy test (HCG serum or urine) within 30 days prior to study registration and to be repeated if not done within 7 days of starting chemotherapy. 1. Female subjects must meet one of the following: * Natural postmenopausal before the screening visit defined as no menses at any time in the preceding 12 consecutive months, or * Prior bilateral oophorectomy or bilateral tubal ligation, or * If they are of childbearing potential, agree to practice two effective methods of contraception per discussion with the treating physicians from 2. Male subjects, even if surgically sterilized (i.e., status post vasectomy) must agree to one of the following: * Practice effective barrier contraception during the entire study treatment period and through 90 days after the last study drug dose, or * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.) 8. Ability to understand a written informed consent document, and the willingness to sign it.
Exclusion criteria
1. Prior chemotherapy or radiation therapy for invasive breast cancer within 6 months before registration. 2. Prior investigational drugs or interventions for invasive breast cancer within 6 months before registration are not allowed. Prior participation in window-of-opportunity trials without therapeutic intent is allowed if intervention is no more than 3 weeks duration. 3. Stage IV metastatic breast cancer 4. History of allergic reactions attributed to compounds of similar chemical composition to chemotherapy to be used in this study. 5. Breastfeeding women. Cytotoxic chemotherapy is drug with the potential for teratogenic or abortifacient effects. Due to unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cytotoxic chemotherapy, breastfeeding should be discontinued. 6. Baseline peripheral neuropathy of severity \> grade 1 7. Other invasive cancer diagnosis within the past 5 years other than non-melanoma skin cancer. 8. Prior axillary lymph node dissection that preclude patient from surgical evaluation of axillary lymph node status.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number and Percentage of Participants With Pathologic Complete Response (pCR) Rate | Up to 2 years | pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy. pCR will be assessed according to RECIST 1.1 criteria. The point estimate of the primary efficacy endpoint pCR and its exact 95% confidence intervals (CI) will be calculated. In evaluating pCR, subjects with missing data will be considered non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Cycles of Chemotherapy Administered | Week 12 to week 18 to account for possible delays | To evaluate the number of cycles low dose weekly Carboplatin/Paclitaxel regimen administered. Simple descriptive statistics will be used to describe the number of cycles of chemotherapy administered. |
| Total Dose of Chemotherapy Administered | Week 12 to week 18 to account for possible delays | To evaluate the total dose of weekly Carboplatin/Paclitaxel regimen administered. Simple descriptive statistics will be used to describe the dose amount of chemotherapy administered. |
| Delays of Administered Chemotherapy | Week 12 to week 18 to account for possible delays | To evaluate the delays of low dose weekly Carboplatin/Paclitaxel regimen administered. Simple descriptive statistics will be used to describe the delays of chemotherapy administered. |
| Number of Treatment-related Toxicities Experienced by Participants | Up to week 12 | Count of any treatment-related toxicities from the low dose weekly Carboplatin/Paclitaxel regimen. Will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 |
| Recurrence-free Survival (RFS) | Up to 2 years | To evaluate two-year RFS after treatment with this neoadjuvant regimen. Count of participants without evidence for local-regional or distant relapse, second primary, or death will be reported. |
| Overall Survival (OS) | Up to 2 years | To evaluate the two-year overall survival after treatment with this neoadjuvant regimen. Count of participants who achieved 2 year OS is reported. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORKari Wisinski, MD
University of Wisconsin, Madison
Participant flow
Pre-assignment details
29 participants were assigned, but only 28 participants started treatment
Participants by arm
| Arm | Count |
|---|---|
| Neoadjuvant Chemotherapy Paclitaxel (cycles 1-4):
Doxorubicin, Cyclophosphamide, and Pegfilgrastim (cycles 5-8):
Surgical intervention for management of breast cancer diagnosis; procedure and timing as determined by surgical team. | 29 |
| Total | 29 |
Baseline characteristics
| Characteristic | Neoadjuvant Chemotherapy |
|---|---|
| Age, Customized 30-39 | 5 Participants |
| Age, Customized 40-49 | 7 Participants |
| Age, Customized 50-59 | 12 Participants |
| Age, Customized 60-69 | 3 Participants |
| Age, Customized 70-79 | 1 Participants |
| Age, Customized 80-89 | 1 Participants |
| Age, Customized Unknown | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Region of Enrollment United States | 29 participants |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 28 |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 17 / 28 |
Outcome results
Primary
Number and Percentage of Participants With Pathologic Complete Response (pCR) Rate
pCR is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy. pCR will be assessed according to RECIST 1.1 criteria. The point estimate of the primary efficacy endpoint pCR and its exact 95% confidence intervals (CI) will be calculated. In evaluating pCR, subjects with missing data will be considered non-responders.
Time frame: Up to 2 years
Population: 4 participants did not reach the timepoint at which pCR was measured, therefore are not counted in the analysis
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neoadjuvant Chemotherapy | Number and Percentage of Participants With Pathologic Complete Response (pCR) Rate | 8 Participants |
Secondary
Delays of Administered Chemotherapy
To evaluate the delays of low dose weekly Carboplatin/Paclitaxel regimen administered. Simple descriptive statistics will be used to describe the delays of chemotherapy administered.
Time frame: Week 12 to week 18 to account for possible delays
Population: 2 participants were withdrawn from study prior to completing carbo-paclitaxel; thus, have not been included in this measure
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neoadjuvant Chemotherapy | Delays of Administered Chemotherapy | Participants with no delays | 12 Participants |
| Neoadjuvant Chemotherapy | Delays of Administered Chemotherapy | Participants with single 1 week delay | 7 Participants |
| Neoadjuvant Chemotherapy | Delays of Administered Chemotherapy | Participants with single 2 week delay | 3 Participants |
| Neoadjuvant Chemotherapy | Delays of Administered Chemotherapy | Participants with more than 1 delay | 4 Participants |
Secondary
Number of Cycles of Chemotherapy Administered
To evaluate the number of cycles low dose weekly Carboplatin/Paclitaxel regimen administered. Simple descriptive statistics will be used to describe the number of cycles of chemotherapy administered.
Time frame: Week 12 to week 18 to account for possible delays
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neoadjuvant Chemotherapy | Number of Cycles of Chemotherapy Administered | 4 complete cycles | 25 Participants |
| Neoadjuvant Chemotherapy | Number of Cycles of Chemotherapy Administered | Less than 1 cycle | 3 Participants |
Secondary
Number of Treatment-related Toxicities Experienced by Participants
Count of any treatment-related toxicities from the low dose weekly Carboplatin/Paclitaxel regimen. Will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time frame: Up to week 12
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Neoadjuvant Chemotherapy | Number of Treatment-related Toxicities Experienced by Participants | Neutrophil count decreased | 26 treatment related toxicities |
| Neoadjuvant Chemotherapy | Number of Treatment-related Toxicities Experienced by Participants | Anemia | 27 treatment related toxicities |
| Neoadjuvant Chemotherapy | Number of Treatment-related Toxicities Experienced by Participants | Platelet count decreased | 22 treatment related toxicities |
| Neoadjuvant Chemotherapy | Number of Treatment-related Toxicities Experienced by Participants | White blood cells decreased | 25 treatment related toxicities |
| Neoadjuvant Chemotherapy | Number of Treatment-related Toxicities Experienced by Participants | ALT increased | 9 treatment related toxicities |
| Neoadjuvant Chemotherapy | Number of Treatment-related Toxicities Experienced by Participants | AST increased | 8 treatment related toxicities |
| Neoadjuvant Chemotherapy | Number of Treatment-related Toxicities Experienced by Participants | Creatinine increased | 2 treatment related toxicities |
| Neoadjuvant Chemotherapy | Number of Treatment-related Toxicities Experienced by Participants | Bilirubin increased | 1 treatment related toxicities |
Secondary
Overall Survival (OS)
To evaluate the two-year overall survival after treatment with this neoadjuvant regimen. Count of participants who achieved 2 year OS is reported.
Time frame: Up to 2 years
Population: 3 participants did not reach the timepoint at which OS was measured, therefore are not counted in the analysis
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neoadjuvant Chemotherapy | Overall Survival (OS) | 2 year survival | 22 Participants |
| Neoadjuvant Chemotherapy | Overall Survival (OS) | Deceased | 3 Participants |
Secondary
Recurrence-free Survival (RFS)
To evaluate two-year RFS after treatment with this neoadjuvant regimen. Count of participants without evidence for local-regional or distant relapse, second primary, or death will be reported.
Time frame: Up to 2 years
Population: 4 participants did not reach the timepoint at which RFS was measured, therefore are not counted in the analysis
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neoadjuvant Chemotherapy | Recurrence-free Survival (RFS) | No evidence of disease | 18 Participants |
| Neoadjuvant Chemotherapy | Recurrence-free Survival (RFS) | Alive, recurrent disease | 2 Participants |
| Neoadjuvant Chemotherapy | Recurrence-free Survival (RFS) | Deceased, recurrent disease | 2 Participants |
| Neoadjuvant Chemotherapy | Recurrence-free Survival (RFS) | Alive, unknown disease status | 2 Participants |
Secondary
Total Dose of Chemotherapy Administered
To evaluate the total dose of weekly Carboplatin/Paclitaxel regimen administered. Simple descriptive statistics will be used to describe the dose amount of chemotherapy administered.
Time frame: Week 12 to week 18 to account for possible delays
Population: 2 participants were withdrawn from study prior to completing carbo-paclitaxel; thus, have not been included in this measure
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Neoadjuvant Chemotherapy | Total Dose of Chemotherapy Administered | paclitaxel dose: 80 mg/m2 - full dose | 279 doses administered |
| Neoadjuvant Chemotherapy | Total Dose of Chemotherapy Administered | Carboplatin reduced dose AUC 1.6 | 15 doses administered |
| Neoadjuvant Chemotherapy | Total Dose of Chemotherapy Administered | Carboplatin dose AUC of 2.0 - full dose | 285 doses administered |
| Neoadjuvant Chemotherapy | Total Dose of Chemotherapy Administered | Carboplatin reduced dose AUC 1.5 | 2 doses administered |
| Neoadjuvant Chemotherapy | Total Dose of Chemotherapy Administered | Paclitaxel - reduced dose | 23 doses administered |