Triple-negative Breast Cancer
Conditions
Keywords
TNBC, breast cancer, neoadjuvant, carboplatin, docetaxel, paclitaxel, doxorubicin, cyclophosphamide
Brief summary
Evaluate if the two carboplatin containing chemotherapy regimens will reduce the growth of breast cancer cells in women with Stage I, II, or III triple negative breast cancer.
Detailed description
Sporadic and germline BRCA mutation associated triple-negative breast cancer share several pathological and molecular similarities which have led to the exploration of DNA damaging agents like platinum compounds in patients with triple-negative breast cancer. Recent studies demonstrate that addition of neoadjuvant carboplatin to doxorubicin/cyclophosphamide/taxane-based chemotherapy improves pathological complete response in patients with stage I-III triple-negative breast cancer but also increase toxicity. A recent study reported encouraging pathological complete response rates with a non-anthracycline carboplatin plus docetaxel neoadjuvant chemotherapy regimen in a cohort of 49 triple negative breast cancer patients. This chemotherapy regimen of carboplatin plus docetaxel yielded an overall pathological complete response rate of 65% in unselected triple-negative breast cancer with pathological complete response rates of 61% in sporadic and 77% in germline BRCA-associated triple-negative breast cancer. The chemotherapy regimen of carboplatin/docetaxel is well tolerated and should be studied further and compared with regimens that add carboplatin to the standard anthracycline/taxane containing regimens. This is the basis for the proposed randomized neoadjuvant phase II study to further estimate and compare pathological complete response rates of carboplatin plus docetaxel x 6 cycles to carboplatin plus paclitaxel x 4 cycles followed by doxorubicin plus cyclophosphamide x 4 cycles in stage I-III triple negative-breast cancer.
Interventions
DRUGPaclitaxel
DRUGCarboplatin
DRUGDoxorubicin
DRUGCyclophosphamide
DRUGDocetaxel
Sponsors
Priyanka Sharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Patients with newly diagnosed stage I (T\>1cm), II or III triple negative breast cancer who have not had definitive breast surgery or received systemic chemotherapy * The invasive tumor must be hormone receptor-poor, defined as both estrogen receptor and progesterone receptor staining present in ≤ 10% of invasive cancer cells by Immunohistochemistry. * HER- 2 negativity will be based on the current ASCO-CAP guidelines for HER testing * No prior chemotherapy, endocrine therapy or radiation therapy with therapeutic intent for this cancer * Female subjects age 18 - 70 years * ECOG Performance Status of 0-1 * Adequate organ and marrow function as defined below: * Leukocytes ≥ 3,000/uL * Absolute neutrophil count ≥ 1500/uL * Platelets ≥ 100,000/uL * Total bilirubin ≤ 1.5mg/dL * AST(SGOT)/ALT(SPGT) ≤ 2 x institutional upper limit of normal * Creatinine ≤ 1.5mg/dl and/or Creatinine Clearance ≥ 60mL/min * Serum albumin ≥ 3.0 g/dL * Women of child-bearing potential must agree to use adequate contraception * Pretreatment lab values must be performed within 14 days of treatment initiation, and other baseline studies performed within 30 days prior to registration * Subjects should have LVEF ≥ 50% by echocardiogram or MUGA scan performed within 4 weeks prior to treatment initiation * Subjects should have breast and axillary imaging with breast MRI or breast and axillary ultrasound within 4 weeks prior to treatment initiation * Subjects with clinically/radiologically abnormal axillary lymph nodes should have pathological confirmation of disease with image guided biopsy/fine needle aspiration. * Subjects must be already enrolled in P.R.O.G.E.C.T observational registry * Staging to rule out metastatic disease is recommended for subjects with clinical stage III disease * Subjects with bilateral disease are eligible if they meet other eligibility criteria. * Neuropathy: No baseline neuropathy grade \> 2
Exclusion criteria
* Current or anticipated use of other investigational agents * Subject has received chemotherapy, radiotherapy or surgery for the treatment of breast cancer * Subject with metastatic disease * History of allergic reactions to compounds of similar chemical or biologic composition to carboplatin, docetaxel, doxorubicin, cyclophosphamide, paclitaxel, or other agents used in the study * Subjects with inflammatory breast cancer * Uncontrolled intercurrent illness including, but not limited to ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements * Subject is pregnant or nursing * Subjects with concomitant or previous malignancies within the last 5 years. Exceptions include: adequately treated basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, and ductal carcinoma in situ (DCIS). * Ejection Fraction \<50% on ECHO or MUGA * Cardiac function: Subjects with congestive heart failure, myocardial infarction, unstable angina pectoris, an arterial thrombotic event, stroke or transient ischemia attack within the past 12 months, uncontrolled hypertension (Systolic BP\>160 or Diastolic BP\>90), uncontrolled or symptomatic arrhythmia, or grade ≥ 2 peripheral vascular disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Pathological Complete Response | 20 weeks | To evaluate the pathological complete response rates with neoadjuvant chemotherapy regimens of carboplatin plus paclitaxel x 4 cycles followed by doxorubicin plus cyclophosphamide X 4 cycles and carboplatin plus docetaxel X 6 cycles in subjects with stage I-III triple-negative breast cancer. Pathological complete response is defined as no evidence of disease in the breast and axilla at the time of pathology review except for DCIS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Minimal Residual Disease | 20 weeks | To evaluate minimal residual disease rates (residual cancer burden 0+1) with two neoadjuvant chemotherapy regimens in subjects with stage I-III triple-negative breast cancer. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Carboplatin + Paclitaxel Then Doxorubicin + Cyclophosphamide Paclitaxel (80mg/m2) given IV every week x12 weeks and Carboplatin (AUC 6) given IV every 21 days x 4 cycles, followed by Doxorubicin (60mg/m2) given IV and Cyclophosphamide (600mg/m2) given IV every 14 days X 4 cycles | 48 |
| Carboplatin + Docetaxel Carboplatin (AUC 6) given IV and Docetaxel (75mg/m2) given IV every 21 days x 6 cycles | 52 |
| Total | 100 |
Baseline characteristics
| Characteristic | Carboplatin + Docetaxel | Carboplatin + Paclitaxel Then Doxorubicin + Cyclophosphamide | Total |
|---|---|---|---|
| Age, Continuous | 54 years | 51 years | 51 years |
| Lymph node status Negative | 36 Participants | 34 Participants | 70 Participants |
| Lymph node status Positive | 16 Participants | 14 Participants | 30 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 10 Participants | 9 Participants | 19 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Non-Hispanic | 51 Participants | 47 Participants | 98 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 36 Participants | 35 Participants | 71 Participants |
| Region of Enrollment United States | 52 participants | 48 participants | 100 participants |
| Sex: Female, Male Female | 52 Participants | 48 Participants | 100 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| T stage T1 | 8 Participants | 11 Participants | 19 Participants |
| T stage T2 | 39 Participants | 31 Participants | 70 Participants |
| T stage T3-4 | 5 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 52 |
| other Total, other adverse events | 41 / 48 | 13 / 52 |
| serious Total, serious adverse events | 0 / 48 | 0 / 52 |
Outcome results
Primary
Number of Participants With Pathological Complete Response
To evaluate the pathological complete response rates with neoadjuvant chemotherapy regimens of carboplatin plus paclitaxel x 4 cycles followed by doxorubicin plus cyclophosphamide X 4 cycles and carboplatin plus docetaxel X 6 cycles in subjects with stage I-III triple-negative breast cancer. Pathological complete response is defined as no evidence of disease in the breast and axilla at the time of pathology review except for DCIS.
Time frame: 20 weeks
Population: Intention-to-treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carboplatin + Paclitaxel Then Doxorubicin + Cyclophosphamide | Number of Participants With Pathological Complete Response | 26 Participants |
| Carboplatin + Docetaxel | Number of Participants With Pathological Complete Response | 28 Participants |
Secondary
Number of Participants With Minimal Residual Disease
To evaluate minimal residual disease rates (residual cancer burden 0+1) with two neoadjuvant chemotherapy regimens in subjects with stage I-III triple-negative breast cancer.
Time frame: 20 weeks
Population: Patients with residual cancer burden index available
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carboplatin + Paclitaxel Then Doxorubicin + Cyclophosphamide | Number of Participants With Minimal Residual Disease | 31 Participants |
| Carboplatin + Docetaxel | Number of Participants With Minimal Residual Disease | 35 Participants |