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Cisplatin vs. Doxorubicin/Cyclophosphamide in BrCa

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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:
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
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
Hide 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
Arm/Group Title Doxorubicin-Cyclophosphamide Cisplatin Total
Hide 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
Hide 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
1.Primary Outcome
Title Rate of Pathologic Complete Response (pCR)
Hide Description Pathologic complete response (pCR) rate (determined by the Miller-Payne method) in doxorubicin-cyclophosphamide vs cisplatin arms.
Time Frame 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Doxorubicin-Cyclophosphamide Cisplatin
Hide 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
Hide 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
Hide Description Residual Cancer Burden (RCB) rate of RCB 0 or 1 in participants receiving Doxorubicin-Cyclophosphamide vs participants receiving Cisplatin.
Time Frame 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Doxorubicin-Cyclophosphamide Cisplatin
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Doxorubicin-Cyclophosphamide Cisplatin
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Doxorubicin-Cyclophosphamide Cisplatin
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Doxorubicin-Cyclophosphamide Cisplatin
Hide 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
Hide 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
Hide 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
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
Hide 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%) 
Hide 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
Hide 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.
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
Layout table for Results Point of Contact information
Name/Title: Project Manager
Organization: DFCI
Phone: 617-632-2257
EMail: CTOPM@dfci.harvard.edu
Layout table for additonal information
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