Clinical trial NCT01670500: Cisplatin vs. Doxorubicin/Cyclophosphamide in BrCa
Official title: A Randomized Phase II Trial of Neoadjuvant Cisplatin vs. Doxorubicin/Cyclophosphamide (AC) in Women With Newly Diagnosed Breast Cancer and Germline BrCa Mutations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: germline mutation
BRCA1 mutation
BRCA2 mutation
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: Dana-Farber Cancer Institute
First posted: 2012-08-22
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Rate of Pathologic Complete Response (pCR)
timeFrame: 3 years
Secondary outcomes:
measure: Rate of Residual Cancer Burden (RCB) 0/1
timeFrame: 2 years
measure: Clinical Response Rate
timeFrame: 3 years
measure: Number of Grade 3 and Grade 4 Adverse Events
timeFrame: 2 years
measure: Analysis of Pre-chemotherapy Biopsies
timeFrame: 5 years
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Derby
country: United States
facility: Smilow Cancer Hospital Care Center at Derby
state: Connecticut
city: Guilford
country: United States
facility: Smilow Cancer Hospital Care Center at Guilford
state: Connecticut
city: Hartford
country: United States
facility: St. Francis Hospital and Medical Center
state: Connecticut
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Washington
country: United States
facility: Sibley Memorial Hospital
state: District of Columbia
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Providence
country: United States
facility: Women and Infants Hospital
state: Rhode Island
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Nadine Tung, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Takamizawa S, Ishiki H, Shimoi T, Shimizu M, Satomi E. Neoadjuvant Cisplatin in BRCA Carriers With HER2-Negative Breast Cancer. J Clin Oncol. 2020 Aug 10;38(23):2699-2700. doi: 10.1200/JCO.20.00789. Epub 2020 Jun 9. No abstract available.
citation: Tung N, Hacker MR, Garber JE. Reply to S. Takamizawa et al. J Clin Oncol. 2020 Aug 10;38(23):2700-2701. doi: 10.1200/JCO.20.01190. Epub 2020 Jun 9. No abstract available.
citation: Tung N, Arun B, Hacker MR, Hofstatter E, Toppmeyer DL, Isakoff SJ, Borges V, Legare RD, Isaacs C, Wolff AC, Marcom PK, Mayer EL, Lange PB, Goss AJ, Jenkins C, Krop IE, Winer EP, Schnitt SJ, Garber JE. TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial). J Clin Oncol. 2020 May 10;38(14):1539-1548. doi: 10.1200/JCO.19.03292. Epub 2020 Feb 25.