Cisplatin vs. Doxorubicin/Cyclophosphamide in BrCa

• ClinicalTrials.gov Identifier: NCT01670500
• Recruitment Status: Active, not recruiting
• First Posted: August 22, 2012
• Results First Posted: August 3, 2020
• Last Update Posted: September 1, 2020
• Sponsor: Beth Israel Deaconess Medical Center
• Information provided by (Responsible Party): Nadine Tung, MD, Dana-Farber Cancer Institute

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer
• Interventions: Drug: Cisplatin; Drug: Cyclophosphamide; Drug: Doxorubicin
• Enrollment: 118

Participant Flow

Recruitment Details	The trial was conducted at 13 academic centers and participants were recruited from these locations. Accrual occurred between January 2012 and January 2019.
Pre-assignment Details

Arm/Group Title	Doxorubicin-Cyclophosphamide	Cisplatin
Arm/Group Description	Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4 Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses	Cisplatin q 3 wk x 4 Cisplatin: administered intravenously every 3 weeks for 4 doses
Period Title: Overall Study
Started	58	60
Completed [1]	57 [2]	60 [3]
Not Completed	1	0
Reason Not Completed
Withdrawal by Subject	1	0
[1] Participants received allocated intervention; [2] 1 patient withdrew after 3 cycles; 5 patients received additional non-protocol chemo before surgery; [3] 4 pts received <4 cycles of assigned chemo; 2 pts received add'l non-protocol chemo before surgery

Baseline Characteristics

Arm/Group Title		Doxorubicin-Cyclophosphamide	Cisplatin	Total
Arm/Group Description		Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4 Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses	Cisplatin q 3 wk x 4 Cisplatin: administered intravenously every 3 weeks for 4 doses	Total of all reporting groups
Overall Number of Baseline Participants		58	60	118
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	58 participants	60 participants	118 participants
		44 (10)	40 (9)	42 (10)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	60 participants	118 participants
	Female	58 100.0%	59 98.3%	117 99.2%
	Male	0 0.0%	1 1.7%	1 0.8%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	60 participants	118 participants
	Hispanic or Latino	7 12.1%	8 13.3%	15 12.7%
	Not Hispanic or Latino	49 84.5%	48 80.0%	97 82.2%
	Unknown or Not Reported	2 3.4%	4 6.7%	6 5.1%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	60 participants	118 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	2 3.4%	2 3.3%	4 3.4%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	5 8.6%	7 11.7%	12 10.2%
	White	44 75.9%	43 71.7%	87 73.7%
	More than one race	2 3.4%	3 5.0%	5 4.2%
	Unknown or Not Reported	5 8.6%	5 8.3%	10 8.5%
BRCA status [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	60 participants	118 participants
	BRCA 1	37 63.8%	44 73.3%	81 68.6%
	BRCA 2	20 34.5%	15 25.0%	35 29.7%
	BRCA 1 and BRCA 2	1 1.7%	1 1.7%	2 1.7%
		[1] Measure Description: Eligible patients had a germline pathogenic or likely pathogenic variant (i.e. mutation) in BRCA1 or BRCA2; genetic testing was not performed as part of the trial, but known genetic status was required for eligibility
Tumor size by imaging; Median (Inter-Quartile Range); Unit of measure: Centimeters
	Number Analyzed	58 participants	60 participants	118 participants
		2; (2 to 4)	3; (2 to 4)	2; (2 to 4)
T Stage (Tumor Size) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	60 participants	118 participants
	T1	17 29.3%	12 20.0%	29 24.6%
	T2	31 53.4%	35 58.3%	66 55.9%
	T3	10 17.2%	12 20.0%	22 18.6%
	unknown	0 0.0%	1 1.7%	1 0.8%
		[1] Measure Description: Per National Cancer Institute (NCI) definition, T describes the size of the tumor and any spread of cancer into nearby tissue. The higher the T number, the larger the tumor and/or the more it has grown into nearby tissues. T1: The tumor in the breast is 20 millimeters (mm) or smaller in size at its widest area. T2: The tumor is larger than 20 mm but not larger than 50 mm. T3: The tumor is larger than 50 mm.
N stage [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	60 participants	118 participants
	N0	34 58.6%	31 51.7%	65 55.1%
	N1	19 32.8%	24 40.0%	43 36.4%
	N2	2 3.4%	2 3.3%	4 3.4%
	N3	3 5.2%	3 5.0%	6 5.1%
		[1] Measure Description: Per the National Cancer Institute Definition: N stage refers to the number of nearby lymph nodes that have cancer. N0: There is no cancer in nearby lymph nodes. N1, N2, N3: Refers to the number and location of lymph nodes that contain cancer. The higher the number after the N, the more lymph nodes that contain cancer.
Node status: biopsy before chemotherapy; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	60 participants	118 participants
	positive	24 41.4%	29 48.3%	53 44.9%
	negative	34 58.6%	31 51.7%	65 55.1%
Stage [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	60 participants	118 participants
	I	15 25.9%	8 13.3%	23 19.5%
	II	34 58.6%	40 66.7%	74 62.7%
	III	9 15.5%	12 20.0%	21 17.8%
		[1] Measure Description: Per the National Cancer Institute Definitions: Stage of Cancer. For Stage I, II, III, cancer is present. The higher the number, the larger the cancer tumor and the more it has spread into nearby tissues.
Estrogen Receptor (ER); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	60 participants	118 participants
	Positive (>/= 1%)	20 34.5%	20 33.3%	40 33.9%
	Negative (< 1%)	38 65.5%	40 66.7%	78 66.1%
Hormone receptor 1% cutoff [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	60 participants	118 participants
	Triple Negative Breast Cancer (ER & PR < 1%)	36 62.1%	40 66.7%	76 64.4%
	ER+ or PR+	22 37.9%	20 33.3%	42 35.6%
		[1] Measure Description: ER= estrogen receptor; PR= progesterone receptor
Histology; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	60 participants	118 participants
	Invasive ductal	52 89.7%	57 95.0%	109 92.4%
	Invasive lobular	2 3.4%	2 3.3%	4 3.4%
	Mixed	3 5.2%	1 1.7%	4 3.4%
	Other	1 1.7%	0 0.0%	1 0.8%
Pre-chemotherapy tumor grade [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	60 participants	118 participants
	1	1 1.7%	2 3.3%	3 2.5%
	2	12 20.7%	11 18.3%	23 19.5%
	3	45 77.6%	46 76.7%	91 77.1%
	unknown	0 0.0%	1 1.7%	1 0.8%
		[1] Measure Description: Per the National Cancer Institute Definition: Tumor grade is description of tumor based on how abnormal the tumor cells and tumor tissue look under a microscope. In general, tumors are graded as 1, 2, 3, or 4, depending on the amount of abnormality. In Grade 1 tumors, the tumor cells and organization of the tumor tissue appear close to normal. These tumors tend to grow and spread slowly. In contrast, the cells and tissue of Grade 3 and Grade 4 tumors do not look like normal cells and tissue. Grade 3 and Grade 4 tumors tend to grow rapidly and spread faster than tumors with a lower grade.
Lymphovascular invasion; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	60 participants	118 participants
	Present	11 19.0%	12 20.0%	23 19.5%
	Absent	47 81.0%	48 80.0%	95 80.5%
lymphocytic infiltrate; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	60 participants	118 participants
	moderate/marked	22 37.9%	21 35.0%	43 36.4%
	absent/scant	33 56.9%	36 60.0%	69 58.5%
	unknown	3 5.2%	3 5.0%	6 5.1%
Stromal TILs [1] [2]; Median (Inter-Quartile Range); Unit of measure: Percentage of stromal TILs
	Number Analyzed	53 participants	56 participants	109 participants
		10; (1 to 20)	10; (3 to 30)	10; (1 to 20)
		[1] Measure Description: TILs= tumor infiltrating lymphocytes The pre-chemotherapy clinical biopsy was assessed for tumor infiltrating lymphocytes.; [2] Measure Analysis Population Description: Stromal TILS missing for 5 in Doxorubicin-Cyclophosphamide arm and 4 in the Cisplatin arm

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doxorubicin-Cyclophosphamide	Cisplatin
Arm/Group Description:	Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4 Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses	Cisplatin q 3 wk x 4 Cisplatin: administered intravenously every 3 weeks for 4 doses
Overall Number of Participants Analyzed	57	60
Measure Type: Number; Unit of Measure: percentage of participants
	26	18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Doxorubicin-Cyclophosphamide, Cisplatin
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	.70
	Confidence Interval	(2-Sided) 90%; 0.39 to 1.2
	Estimation Comments	The risk ratio is comparing cisplatin to doxorubicin-cyclophosphamide (AC)

2. Secondary Outcome

Title	Rate of Residual Cancer Burden (RCB) 0/1
Description	Residual Cancer Burden (RCB) rate of RCB 0 or 1 in participants receiving Doxorubicin-Cyclophosphamide vs participants receiving Cisplatin.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doxorubicin-Cyclophosphamide	Cisplatin
Arm/Group Description:	Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4 Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses	Cisplatin q 3 wk x 4 Cisplatin: administered intravenously every 3 weeks for 4 doses
Overall Number of Participants Analyzed	57	60
Measure Type: Number; Unit of Measure: percentage of participants
	46	33

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Doxorubicin-Cyclophosphamide, Cisplatin
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	.73
	Confidence Interval	(2-Sided) 90%; .5 to 1.1
	Estimation Comments	The risk ratio is comparing cisplatin to doxorubicin-cyclophosphamide (AC)

3. Secondary Outcome

Title	Clinical Response Rate
Description	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.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doxorubicin-Cyclophosphamide	Cisplatin
Arm/Group Description:	Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4 Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses	Cisplatin q 3 wk x 4 Cisplatin: administered intravenously every 3 weeks for 4 doses
Overall Number of Participants Analyzed	58	60
Measure Type: Count of Participants; Unit of Measure: Participants
	43 74.1%	45 75.0%

4. Secondary Outcome

Title	Number of Grade 3 and Grade 4 Adverse Events
Description	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.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doxorubicin-Cyclophosphamide	Cisplatin
Arm/Group Description:	Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4 Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses	Cisplatin q 3 wk x 4 Cisplatin: administered intravenously every 3 weeks for 4 doses
Overall Number of Participants Analyzed	57	60
Measure Type: Number; Unit of Measure: Adverse Events
All Grade 3 & 4 Adverse Events	15	16
Non-hematologic Grade 3 & 4 Adverse Events	4	11

5. Secondary Outcome

Title	Analysis of Pre-chemotherapy Biopsies
Description	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.
Time Frame	5 years

Outcome Measure Data Not Reported

6. Secondary Outcome

Title	Rate of Miller Payne 4 and 5
Description	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)
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doxorubicin-Cyclophosphamide	Cisplatin
Arm/Group Description:	Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4 Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses	Cisplatin q 3 wk x 4 Cisplatin: administered intravenously every 3 weeks for 4 doses
Overall Number of Participants Analyzed	58	60
Measure Type: Count of Participants; Unit of Measure: Participants
	30 51.7%	22 36.7%

7. Secondary Outcome

Title	Rate of Recurrence Free Survival (RFS) After Cisplatin or AC
Description	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
Time Frame	5 years

Outcome Measure Data Not Reported

8. Secondary Outcome

Title	Rate of Recurrence Free Survival (RFS) With Pathologic Complete Response (pCR) vs. With no pCR
Description	Rate of 3-year recurrence free survival for gBRCAm carriers who achieved pCR with those who did not.
Time Frame	5 years

Outcome Measure Data Not Reported

Adverse Events

Time Frame	Adverse event information was collected from time of treatment start, during treatment, and until 30 days after the last dose of treatment, about 3 months on average per participant.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Doxorubicin-Cyclophosphamide	Cisplatin
Arm/Group Description	Doxorubicin q 2-3 wk x 4 Cyclophosphamide q 2-3 wk x 4 Cyclophosphamide: administered with doxorubicin intravenously every 2 or 3 weeks for 4 doses Doxorubicin: administered with Cyclophosphamide intravenously every 2 or 3 weeks for 4 doses	Cisplatin q 3 wk x 4 Cisplatin: administered intravenously every 3 weeks for 4 doses
All-Cause Mortality
	Doxorubicin-Cyclophosphamide	Cisplatin
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/57 (0.00%)	0/60 (0.00%)
Serious Adverse Events
	Doxorubicin-Cyclophosphamide	Cisplatin
	Affected / at Risk (%)	Affected / at Risk (%)
Total	6/57 (10.53%)	5/60 (8.33%)
Blood and lymphatic system disorders
Febrile Neutropenia † 1	1/57 (1.75%)	0/60 (0.00%)
General disorders
Non-Cardiac Chest Pain † 1	0/57 (0.00%)	1/60 (1.67%)
Immune system disorders
Allergic Reaction † 1	1/57 (1.75%)	0/60 (0.00%)
Infections and infestations
Breast Infection † 1	0/57 (0.00%)	1/60 (1.67%)
Investigations
Neutrophil Count Decreased † 1	4/57 (7.02%)	0/60 (0.00%)
Increased Creatinine † 1	0/57 (0.00%)	2/60 (3.33%)
Metabolism and nutrition disorders
Dehydration † 1	0/57 (0.00%)	1/60 (1.67%)
Vascular disorders
Thromboembolic event † 1	0/57 (0.00%)	2/60 (3.33%)
1 Term from vocabulary, CTCAE v 4; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Doxorubicin-Cyclophosphamide	Cisplatin
	Affected / at Risk (%)	Affected / at Risk (%)
Total	55/57 (96.49%)	60/60 (100.00%)
Blood and lymphatic system disorders
Anemia † 1	13/57 (22.81%)	15/60 (25.00%)
Ear and labyrinth disorders
Tinnitus † 1	0/57 (0.00%)	32/60 (53.33%)
Gastrointestinal disorders
Nausea † 1	40/57 (70.18%)	52/60 (86.67%)
Vomiting † 1	9/57 (15.79%)	13/60 (21.67%)
Diarrhea † 1	10/57 (17.54%)	7/60 (11.67%)
Constipation † 1	20/57 (35.09%)	13/60 (21.67%)
Oral Mucositis † 1	15/57 (26.32%)	7/60 (11.67%)
General disorders
Fatigue † 1	45/57 (78.95%)	48/60 (80.00%)
Investigations
Decreased Neutrophil Count † 1	5/57 (8.77%)	8/60 (13.33%)
Decreased White Blood Cell Count † 1	5/57 (8.77%)	4/60 (6.67%)
Decreased lymphocyte count † 1	3/57 (5.26%)	1/60 (1.67%)
Metabolism and nutrition disorders
Hyperglycemia † 1	2/57 (3.51%)	3/60 (5.00%)
Nervous system disorders
Headache † 1	7/57 (12.28%)	4/60 (6.67%)
Dysgeusia † 1	14/57 (24.56%)	6/60 (10.00%)
Skin and subcutaneous tissue disorders
Alopecia † 1 [1]	31/57 (54.39%)	4/60 (6.67%)
1 Term from vocabulary, CTCAE v 4; † Indicates events were collected by systematic assessment; [1] Note: Hair loss could not be accurately assessed for patients receiving AC, since hair loss was anticipated in this study before initiation of scalp cooling techniques and many patients shaved their hair in anticipation.

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Project Manager
• Organization: DFCI
• Phone: 617-632-2257
• EMail: CTOPM@dfci.harvard.edu

• Responsible Party: Nadine Tung, MD, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT01670500
• Other Study ID Numbers: 12-258
• First Submitted: August 16, 2012
• First Posted: August 22, 2012
• Results First Submitted: June 12, 2020
• Results First Posted: August 3, 2020
• Last Update Posted: September 1, 2020