Breast Cancer
Conditions
Keywords
neoadjuvant breast cancer, stage I-III breast cancer, HER 2 positive breast cancer
Brief summary
Neoadjuvant therapy is given to breast cancer patients whose cancers are relatively large or have spread to lymph nodes or both. The primary goal of this treatment is to prevent the cancer from coming back (recurring) elsewhere in the body, but if it makes the cancer in the breast and lymph nodes shrink it might be easier to remove. This could allow a patient to have a lumpectomy instead of a mastectomy and reduce the number of lymph nodes that the surgeon has to remove. In some cases, the neoadjuvant therapy works so well that it kills all of the cancer in the breast and lymph nodes. This is referred to as a pathologic complete response (pCR). Patients who achieve a pCR have a much lower risk of the cancer recurring elsewhere in their bodies. Investigators aren't sure which chemotherapy drugs work best with the HER2-targeted drugs, and what combination of these drugs causes the fewest side effects.Thus, this study has two main goals: 1. To find out if treatment with wPCbTP, weekly paclitaxel and carboplatin given with trastuzumab and pertuzumab every 3 weeks, leads to as many pCRs as TCHP in patients with HER2-positive breast cancer, but has fewer side effects. 2. To find out if HER2-positive patients whose cancers are not responding well after 12 weeks of wPCbTP get a better response when they are switched to a doxorubicin-containing regimen called AC for 4 cycles (8-12 weeks).
Detailed description
See summary above
Interventions
DRUGpaclitaxel
80 mg/m2 (or nab-paclitaxel 80-100 mg/m2) weekly
DRUGTrastuzumab
Either every 3 weeks (8 mg/kg cycle 1 then 6 mg/kg cycles 2-4) or weekly (4 mg/kg week 1 then 2 mg/kg weeks 2-12)
DRUGPertuzumab
every 3 weeks (840 mg cycle 1 then 420 mg cycles 2-4) or weeks 1 and 2 cycle 1 (420 mg each dose) during the first 3-6 weeks of treatment, then 420 mg day 1 of cycles 2-4.
DRUGcarboplatin
AUC 2 administered weekly with no planned treatment breaks
PROCEDUREBreast surgery
breast conserving or mastectomy
DRUGAC
doxorubicin and cyclophosphamide (AC) every 2 or 3 weeks for 4 cycles Dose-dense AC: Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 IV day 1 every 2 weeks x 4 cycles Standard AC: Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 IV day 1 r every 3 weeks x 4 cycles
Sponsors
Women and Infants Hospital of Rhode Island
Rhode Island Hospital
The Miriam Hospital
Brown University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1 Histologically confirmed adenocarcinoma of the breast, with sufficient tissue available from needle or incisional biopsy (excisional biopsy not permitted) for ER, PR and HER2 testing. 2\. Resectable - clinical stage I (only with T=2.0 cm), IIA-IIIA - T2 N0-T3N0 or T1-3 N1-N2a - or unresectable - clinical stage IIIB-C - T4 or N2b-3 - disease. No evidence of M1 disease. Pretreatment clinical stage will be recorded by the treating physician. 3\. Breast tumor measuring at least 1 cm in greatest dimension by ultrasound or MRI; patients without measurable disease in the breast (TX) by imaging studies are eligible if they have measurable disease (a node measuring at least 1 cm along its short axis, and histologically confirmed to contain metastatic disease) in the axilla. 4\. HER2+, defined by either IHC 3+ or amplification of the HER2 gene by FISH analysis (ratio \>2.0 or \>6 HER2 targets per cell; patients with equivocal HER2 testing, 2+ by IHC with a FISH ratio of \<2.0 and 4-6 HER2 signals per nucleus, are not eligible). 5\. Patients with multiple foci of invasive cancer in the same breast are eligible if any single lesion meets the above size criteria and all sampled lesions \> 1 cm in maximum dimension are histologically similar and HER2+. Patients are also eligible , or if there is a focus of HER2- invasive cancer that is \<1 cm in maximum dimension and in a different quadrant of the breast from the HER2+ cancer, such that its presence will not interfere with clinical or pathologic assessment of response of the HER2+ cancer. The presence of DCIS or LCIS in either breast will not render a patient ineligible. Patients with a small focus of invasive cancer detected in the contralateral breast (clinical T1a/bN0) are eligible, whether the contralateral tumor is HER2+ or HER2-, while patients with a more advanced invasive cancer in the contralateral breast are not eligible; in patients with a small focus of invasive cancer in the contralateral breast or a small focus of HER2- cancer in the same breast only the histologic response in the HER2+ target lesion will be considered in determining the patient's pathologic response. 6 It is recommended that patients have a pretreatment echocardiogram or MUGA scan with an LVEF above the institutional lower limit of normal. 7\. Female, age \>18, Zubrod PS 0-1. 8. It is recommended that patients have adequate bone marrow, renal and hepatic function. Examples of this include: ANC \> 1000/ul, platelet count \>100,000/ul, HGB\> 9.0 g/dl, serum creatinine \<1.5 mg/dl or measured creatinine clearance of \>30 ml/min and AST \<5 x ULN. 9\. Signed informed consent.
Exclusion criteria
1. Prior chemotherapy, hormonal therapy, or radiation therapy for this cancer 2. Patients with congestive heart failure, unstable angina pectoris, absolute exclusion for BP \>180 (systolic) or \>100 (diastolic); for BP 160-180/90-100, assurance from the treating MD that this is being addressed and that the MD is comfortable initiating study treatment despite the elevated value(s)uncontrolled clinically significant arrhythmia or grade II or greater peripheral vascular disease are not eligible. Patients with BP \>180 (systolic) or \>100 (diastolic) are excluded; patients with BP 160-180/90-100 are eligible with assurance from the treating MD that this is being addressed and that the MD is comfortable initiating study treatment despite the elevated value(s). 3. Patients with myocardial infarction, stroke or arterial thrombotic event within the past 12 months are not eligible. 4. Pregnant and lactating women are not eligible. All patients of reproductive potential should have a negative pregnancy test at baseline and be advised to use an effective barrier method of contraception if sexually active during treatment on the study and for 2 months post the last treatment. Sites will be asked to confirm the patient's menopausal status at study entry and that premenopausal women had a negative pregnancy test performed within 7 days of starting treatment, but will not be required to submit test results. 5. Active (defined as symptomatic, currently requiring treatment or likely to require treatment within the 6 months following study enrollment, or likely to affect the efficacy or tolerability of the study treatment) non-breast malignancy. 6. Baseline grade \>2 peripheral neuropathy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Patients Who Achieve a pCR | at surgery post approximately 18 weeks of treatment | pCR is pathologic complete response defined as ypT0/isN0 on pathology report |
| Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | From start of neo-adjuvant treatment through approximately 18 weeks. | Defined based on CTCAE version 4: 1. Neutropenia (grade\>2) 2. Thrombocytopenia (grade \>2) 3. Anemia (grade \>2) 4. Diarrhea (any grade, grade \>3) 5. Neuropathy (any grade, grade 2, grade \>3) 6. Vomiting (any grade, grade \>3) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Optimal- 18 Weeks 18 weeks (6 cycles) of paclitaxel, carboplatin, trastuzumab and pertuzumab. Post treatment, patients will undergo surgery. | 27 |
| Experimental: Sub-optimal With AC 12 weeks (4 cycles) of paclitaxel, carboplatin, trastuzumab and pertuzumab. Post 12 weeks, initiation of doxorubicin and cyclophosphamide for 4 cycles (6 weeks), followed by surgery. | 3 |
| Experimental: Optimal With AC Less than 18 weeks (6 cycles) of paclitaxel, carboplatin, trastuzumab and pertuzumab, followed by initiation of doxorubicin and cyclophosphamide. Post treatment, patients will undergo surgery. | 0 |
| Experimental: Sub-optimal no AC 18 weeks (6 cycles) of paclitaxel, carboplatin, trastuzumab and pertuzumab. Post treatment, patients will undergo surgery. | 2 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Experimental: Sub-optimal With AC | Experimental: Optimal With AC | Experimental: Optimal- 18 Weeks | Experimental: Sub-optimal no AC | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 5 Participants | 0 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 0 Participants | 22 Participants | 2 Participants | 27 Participants |
| Age, Continuous | 48 years | — | 51 years | 45 years | 50 years |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Region of Enrollment United States | 3 participants | — | 27 participants | 2 participants | 32 participants |
| Sex: Female, Male Female | 3 Participants | 0 Participants | 27 Participants | 2 Participants | 32 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 |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 25 | 0 / 3 | 0 / 2 |
| other Total, other adverse events | 25 / 25 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 5 / 25 | 2 / 3 | 1 / 2 |
Outcome results
Primary
Number of of Patients Who Develop Major Toxicities as Defined in Protocol.
Defined based on CTCAE version 4: 1. Neutropenia (grade\>2) 2. Thrombocytopenia (grade \>2) 3. Anemia (grade \>2) 4. Diarrhea (any grade, grade \>3) 5. Neuropathy (any grade, grade 2, grade \>3) 6. Vomiting (any grade, grade \>3)
Time frame: From start of neo-adjuvant treatment through approximately 18 weeks.
Population: No participants received less than 18 weeks (6 cycles) of paclitaxel, carboplatin, trastuzumab and pertuzumab, followed by initiation of doxorubicin and cyclophosphamide.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental: Optimal- 18 Weeks | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Neuropathy | 5 Participants |
| Experimental: Optimal- 18 Weeks | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Anemia | 20 Participants |
| Experimental: Optimal- 18 Weeks | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Vomiting | 5 Participants |
| Experimental: Optimal- 18 Weeks | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | ANC | 19 Participants |
| Experimental: Optimal- 18 Weeks | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Diarrhea | 23 Participants |
| Experimental: Optimal- 18 Weeks | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Thrombocytopenia | 2 Participants |
| Experimental: Sub-optimal With AC | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Diarrhea | 3 Participants |
| Experimental: Sub-optimal With AC | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Thrombocytopenia | 2 Participants |
| Experimental: Sub-optimal With AC | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Vomiting | 1 Participants |
| Experimental: Sub-optimal With AC | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Neuropathy | 0 Participants |
| Experimental: Sub-optimal With AC | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | ANC | 3 Participants |
| Experimental: Sub-optimal With AC | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Anemia | 3 Participants |
| Experimental: Sub-optimal no AC | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Vomiting | 0 Participants |
| Experimental: Sub-optimal no AC | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | ANC | 2 Participants |
| Experimental: Sub-optimal no AC | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Thrombocytopenia | 0 Participants |
| Experimental: Sub-optimal no AC | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Anemia | 2 Participants |
| Experimental: Sub-optimal no AC | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Diarrhea | 2 Participants |
| Experimental: Sub-optimal no AC | Number of of Patients Who Develop Major Toxicities as Defined in Protocol. | Neuropathy | 0 Participants |
Primary
Percent of Patients Who Achieve a pCR
pCR is pathologic complete response defined as ypT0/isN0 on pathology report
Time frame: at surgery post approximately 18 weeks of treatment
Population: No participants received less than 18 weeks (6 cycles) of paclitaxel, carboplatin, trastuzumab and pertuzumab, followed by initiation of doxorubicin and cyclophosphamide.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Optimal- 18 Weeks | Percent of Patients Who Achieve a pCR | 19 Participants |
| Experimental: Sub-optimal With AC | Percent of Patients Who Achieve a pCR | 2 Participants |
| Experimental: Optimal With AC | Percent of Patients Who Achieve a pCR | 0 Participants |
| Experimental: Sub-optimal no AC | Percent of Patients Who Achieve a pCR | 0 Participants |