Cisplatin vs. Doxorubicin/Cyclophosphamide in BrCa

Study Overview
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Brief Summary
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This research study is a Phase II clinical trial. Phase II clinical trials test the effectiveness of an investigational drug, which is cisplatin in this trial, to learn how well it works in treating a specific cancer. Investigational means that cisplatin is still being studied for use in this setting and that research doctors are trying to find out more about it-in this case, how effective cisplatin is for treating breast cancer in BRCA mutation carriers. It also means that the FDA has not yet approved cisplatin for your type of cancer. Cisplatin has been approved by the FDA for treatment of other cancers. The purpose of this study is to evaluate cisplatin, a chemotherapy drug that has been shown to be active in the treatment of women with breast cancer and a BRCA mutation. In this study, we are comparing cisplatin to the standard chemotherapy, doxorubicin and cyclophosphamide (AC) that you might receive if you did not participate in this study.

Detailed Description
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If screening tests show that you are eligible to participate in the research study you will begin study treatment. You may undergo an optional research biopsy so the study team can obtain tissue samples. This will be used for biomarker research and will help your doctors to better understand your disease, how the drug is working in your body, and may help to identify which people may benefit most from platinum or from adriamycin/cytoxan in the future. Because no one knows which of the study options is best, you will be randomized to receive either cisplatin or doxorubicin and cyclophosphamide (AC) chemotherapy prior to removal of your breast cancer. Chemotherapy administered before the removal of the cancer is known as neoadjuvant chemotherapy. Randomization means that you are put into a group by chance. It is like flipping a coin. Neither you nor the research doctor will choose what group you will be in. You will have an equal chance of being placed in either group. If you are randomized to receive cisplatin you will receive cisplatin once every three weeks for a total of four doses. You will be given cisplatin by vein (IV) on the first day of each treatment cycle. The cisplatin infusion can take between 1 to 2 hours. Before and after receiving cisplatin, you will receive fluid hydration by vein, and you will also be given medicine to help prevent side effects such as nausea. The total time of the infusion of cisplatin and the additional fluid and medications will take about 6 hours. After you receive cisplatin, you will be asked to drink about 12 eight ounce glasses of fluid per day, especially 2 or 3 days after therapy. The study treatment will stop if you have serious side effects or if the tumor grows despite receiving cisplatin chemotherapy. If you are randomized to AC chemotherapy you will receive both doxorubicin and cyclophosphamide once every 2 or 3 weeks for a total of four doses by vein on the first day of each treatment cycle. The interval between chemotherapy will be decided by your research doctor. If you receive the chemotherapy every two weeks, you will also receive a subcutaneous injection the day after chemotherapy. This injection contains a medicine that contains a growth factor that will boost your immune system in order to allow your body to be ready for chemotherapy in two weeks. The study treatment will be stopped if you have serious side effects or if the tumor grows despite the doxorubicin and cyclophosphamide chemotherapy. At the beginning of each treatment cycle you will have a physical exam (including weight and vital signs) and you will be asked general questions about your health and any medications you may be taking, as well as specific questions about any side effects you may be experiencing while receiving study treatment. Prior to each cycle of chemotherapy, you will have standard blood tests to check your blood counts. If you are receiving cisplatin your kidney function and body salts will also be checked prior to each chemotherapy cycle. In addition, 7-10 days after chemotherapy your blood will be drawn to look at your blood cell count to determine your risk of infection; if you have received cisplatin, your kidney function and blood electrolytes will also be evaluated. The blood draw performed 7-10 days after chemotherapy can be done in the hospital where you received your chemotherapy or closer to home. About 1 tablespoon of blood will be drawn for these tests. Surgery to remove your tumor will occur within six weeks after the last dose of chemotherapy. Your surgery will be performed by your surgeon, as part of the standard care for your disease. Your treating physician or nurse practitioner will examine you to assess your tumor each time you receive chemotherapy. A measurement of your tumor will be performed on the first day of each treatment cycle as part of your physical exam. After the slides of your initial breast cancer biopsy have been reviewed at your hospital, these slides and your tumor block will be sent to the study pathologist at DF/HCC. Likewise, after chemotherapy, your breast cancer will be removed by lumpectomy or mastectomy. After these slides are reviewed at your hospital, they will also be sent with the tumor block to the study pathologist so that the response of your tumor to the study treatment can be assessed. After these slides are reviewed, they will be returned to the hospital at which the biopsy and surgery were performed. Decisions about whether you will receive more chemotherapy after your surgery is up to your treating physicians. If you receive chemotherapy, the choice of chemotherapy is also up to your doctors. Decisions about post-operative chemotherapy are not part of this study.

Official Title
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A Randomized Phase II Trial of Neoadjuvant Cisplatin vs. Doxorubicin/Cyclophosphamide (AC) in Women With Newly Diagnosed Breast Cancer and Germline BrCa Mutations

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Cisplatin
* Drug: Cyclophosphamide
* Drug: Doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologic confirmation of invasive breast cancer Stage: Clinical T1 >/= 1.0 cm, T2 or T3, N0-3, M0 HER2 negative ER and PgR status by immunohistochemistry must be known. ER positive patients are allowed if physicain has determined neoadjuvant chemo is appropriate. Life expectancy greater than six months Use of an effective means of contraception is required Exclusion Criteria: Pregnant or breastfeeding Prior anthracycline or platinum based therapy Prior treatment for the current breast cancer, including chemotherapy, hormonal therapy, radiation or experimental therapy Ipsilateral breast recurrence, unless prior treatment consisted of excision alone for DCIS or breast-conserving treatment and hormonal therapy for DCIS or invasive cancer Peripheral neuropathy of any etiology that exceeds grade 1 Significant hearing loss Renal dysfunction Use of other investigational or study agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to study drugs Uncontrolled intercurrent illness Any condition that would prohibit administration of corticosteroids Uncontrolled diabetes Pre-existing medical condition that would represent toxicity in excess of grade 1 as measured by CTCAE (unless not considered medically significant by the physician) Known HIV positive individuals on combination antiretroviral therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Doxorubicin-Cyclophosphamide<br>Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4 | Drug: Cyclophosphamide<br>* administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses<br>* Other names: Cytoxan;Drug: Doxorubicin<br>* administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses<br>* Other names: Adriamycin;|
| Active Comparator: Cisplatin<br>Cisplatin q 3 wk x 4 | Drug: Cisplatin<br>* administered intravenously every 3 weeks for 4 doses<br>* Other names: cisplatinum, or cis-diamminedichloroplatinum(II) (CDDP);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Pathologic Complete Response (pCR) | Pathologic complete response (pCR) rate (determined by the Miller-Payne method) in doxorubicin-cyclophosphamide vs cisplatin arms. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Residual Cancer Burden (RCB) 0/1 | Residual Cancer Burden (RCB) rate of RCB 0 or 1 in participants receiving Doxorubicin-Cyclophosphamide vs participants receiving Cisplatin. | 2 years | 
| Clinical Response Rate | Clinical response rate, defined as the number of partial and complete responses, after preoperative therapy with either cisplatin or AC in participants with germline BRCA mutation and breast cancer. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or ultrasound: Complete Response (CR) = Disappearance of all target lesions; Partial Response (PR) is >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | 3 years | 
| Number of Grade 3 and Grade 4 Adverse Events | Comparison of toxicities for cisplatin and AC preoperative chemotherapy in BRCA mutation carriers with newly diagnosed breast cancer, reported as number of all Grade 3 and 4 adverse events and number of non-hematologic Grade 3 and 4 adverse events. | 2 years | 
| Analysis of Pre-chemotherapy Biopsies | Biopsies collected for future analyses of biomarkers that predict for response to cisplatin or AC chemotherapy in BRCA mutation carriers. Pretreatment tumor biopsies will be analyzed using genome wide SNP profiling to determine number of regions of telomeric allelic imbalance (NtAI) and chromosome 15q26 copy number, and chromosome 8q22 copy number. Tumor sections will be examined for gene amplifications, losses and NtAI in tumors. Gene expression profiling will be performed to determine intrinsic subtype (basal-like, claudin-low, etc.) and to measure biomarker genes including BLM and FANCI associated with cisplatin sensitivity or LAPTM4B and YWHAZ associated with anthracycline resistance. Exploratory analysis will be performed to seek new measures of therapy response using the data from DNA copy number and gene expression profiles. In addition, we will plan to perform whole exome and possibly whole genome sequencing of tumors to identify potential modifiers of response to therapy. | 5 years | 
| Rate of Miller Payne 4 and 5 | Rates of Miller Payne 4 (near pCR) and 5 (near pCR) combined between those subjects who received neoadjuvant cisplatin and those who received neoadjuvant AC. Definitions: Miller Payne 4: a marked disappearance of tumor cells (more than 90%) such that only small clusters or widely dispersed individual cells remain (almost pCR); Miller Payne 5: no malignant cells identifiable in sections from the site of the tumor (pCR) | 3 years | 
| Rate of Recurrence Free Survival (RFS) After Cisplatin or AC | Rate of 3-year recurrence free survival in doxorubicin-cyclophosphamide and cisplatin arms for germline BRCA mutation (gBRCAm) carriers with newly diagnosed HER2-negative breast cancer | 5 years | 
| Rate of Recurrence Free Survival (RFS) With Pathologic Complete Response (pCR) vs. With no pCR | Rate of 3-year recurrence free survival for gBRCAm carriers who achieved pCR with those who did not. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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germline mutation, BRCA1 mutation, BRCA2 mutation