Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Docetaxel as Neoadjuvant Treatment of Breast Cancer Patients

• Sponsor: Spanish Breast Cancer Research Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00129376
• Collaborator: Sanofi (Industry)
• Enrollment: 63
• Locations: 6
• Arm: 1
• Actual Duration (Months): 84
• Patients Per Site: 10.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Treatment consists of 4 AC cycles followed by 2 weekly docetaxel cycles (12 infusions).

The pathological complete response rate obtained in previous studies is around 12%. The expected pathological complete response rate in this study is 25%. With an alpha error of 0.05 and a beta error of 0.2, and following Simon´s 2 phase test, 19 patients are needed initially. With 2 pathological complete responses, patient recruitment will continue until approximately 61 patients are recruited. Twelve pathological complete responses are needed to confirm the study hypothesis.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Docetaxel	Phase 2

Detailed Description

Patients received doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), both in a short intravenous infusion, every three weeks for four cycles (days 1, 22, 43 and 64). Three weeks later, docetaxel (36 mg/m2) was administered as a 30-min intravenous infusion, weekly for six weeks (days 85, 92, 99, 106, 113 and 120) followed by a 2-week resting period (8-week cycle). After that, patients received a second docetaxel cycle (infusions on days 141, 148, 155, 162, 169 and 176). Adjuvant chemotherapy and radiotherapy were delivered according to the protocol of each participating center. Hormonal treatment was started after the last chemotherapy infusion in all patients with positive estrogen and/or progesterone receptor tumors and was continued for five years.

Semiquantitative determination of three molecular markers was carried out by immunocytochemical methods. Tissue samples were taken prior to initiation of chemotherapy from the core of the primary tumors. Specimens were sent to a central laboratory for analysis of Topo II, survivin and p27.

Study Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multicenter Phase II Trial of Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Docetaxel (T) as Neoadjuvant Treatment for Operable Stage II and IIIA Breast Cancer Patients
• Actual Study Start Date: Feb 1, 2003
• Actual Primary Completion Date: Jul 1, 2005
• Actual Study Completion Date: Feb 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Doxorubicin+cyclophosphamide - Docetaxel Patients received doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), both in a short intravenous infusion, every three weeks for four cycles. Later, docetaxel (36 mg/m2) was administered an intravenous infusion, weekly for six weeks followed by a 2-week resting period (8-week cycle).	Drug: Doxorubicin; Other Names: adriamycin ; Drug: Cyclophosphamide; Other Names: Cytoxan ; Drug: Docetaxel; Other Names: Taxotere

Outcome Measures

Primary Outcome Measures

1. Pathological Complete Response (pCR) Rate [Up to 29 weeks]

   Pathological complete response was defined by the Miller & Payne criteria. pCR was defined as no invasive cells identifiable in breast sections at surgery. Response was measured by physical exam and breast imaging before surgery and was evaluated according to the World Health Organization (WHO) criteria. Pathological response after surgery, was based on the proportion of remaining tumor and postchemotherapy changes, evaluating separately the response in the breast and in the axilla lymph nodes.

Secondary Outcome Measures

1. Clinical Response Rate (CRR) [Up to 29 weeks]

   CRR measured according to the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions, where: Complete Response (CR): disappearance of all target lesions Partial Response (PR): >=30% decrease in the sum of the longest diameter of target lesions Progresive Disease (PD): >=20% increase from smallest sum of longest diameter recorded since treatment started (best response). Stable Disease (SD): Neither PD nor PR

2. Number of Participants With Over-expression of Topo II (>10% Cells With Nuclear Staining) [Up to 29 weeks]

   Paraffin-embedded tumors were processed with standard immunocytochemical techniques. Over-expression of Topo II was defined as >10% cells with nuclear staining.

3. Number of Participants With Over-expression of Survivin (>1% Cells With Nuclear Staining) [Up to 29 weeks]

   Paraffin-embedded tumors were processed with standard immunocytochemical techniques. Tumors with more than 1% of cells with nuclear staining were considered to be over-expressing this protein.

4. Number of Participants With Over-expression of p27 (>75% Cells With Nuclear Staining) [Up to 29 weeks]

   Paraffin-embedded tumors were processed with standard immunocytochemical techniques. Sections were rated according to the percentage of tumor cells nuclei with positive staining (1 = < 25%; 2 = between 25-75% and 3 = > 75%).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent.

• Patients with breast cancer stages II and IIIA, with histological diagnoses as per true-cut or open biopsy.

• Negative extension study, including bilateral mammography, thoracic x-ray, computed tomography (CT)-scan or abdominal echography and bone scintigraphy.

• Analysis of hormone receptor status in primary tumour. It is highly recommended to obtain a tumour tissue sample before start of treatment, and after definitive surgery. These samples will be analysed centrally by Spanish Breast Cancer Research Group (GEICAM).

• Age >= 18 and <= 70 years old.

• Performance status as per Karnofsky index >= 80.

• Minimum life expectancy of 6 months.

• Electrocardiogram (EKG) 12 weeks before registration to the study. If abnormalities are suspected, cardiac function must be assessed by left ventricular ejection fraction (LVEF).

• Haematology: neutrophils >= 2.0 x10^{9/l; platelets >= 100 x10}9/l; hemoglobin >=10 g/dl.

• Hepatic function: total bilirubin <= 1 x upper normal limit (UNL); Aspartate aminotransferase (AST) (SGOT) and and Alanine aminotransferase (ALT) (SGPT) <= 2.5 x UNL; alkaline phosphatase <= 5 x UNL.

• Renal function: creatinine <= 1.5 x UNL; creatinine clearance >= 60 ml/min.

• Patients able to comply with study requirements.

• Negative pregnancy test.

• Adequate contraceptive method during the study and up to 3 months after definitive surgery.

Exclusion Criteria:

• Previous systemic therapy for breast cancer treatment.

• Previous treatments with anthracyclines or taxanes for any malignancy.

• Previous radiotherapy for breast cancer.

• Bilateral invasive breast cancer.

• Pregnant or lactating women.

• Previous motor or sensorial neurotoxicity grade >=2.

• Other serious pathologies: congestive heart failure or angina pectoris; history of myocardial infarction in the previous year; uncontrolled hypertension (HT) or high risk arrhythmias.

• History of neurological or psychiatric impairment, precluding patients from providing free informed consent.

• Active infection.

• Active peptic ulcer; unstable diabetes mellitus.

• History of previous or current malignancies other than breast cancer, except for basal skin carcinoma, cervical in situ carcinoma, other tumour diagnosed and treated more than 10 years before, ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS).

• Chronic treatment with corticoids unless the treatment started > 6 months before registration to the study, and low doses are administered.

• Substitutive hormonal therapy. This treatment must be interrupted before inclusion in the study.

• Concomitant treatment with other investigational products or administration in the 30 previous days.

• Males.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital Universitario Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
2	Corporació Sanitaria Parc Taulí	Sabadell	Barcelona	Spain	08208
3	Hospital de la Ribera	Alcira	Valencia	Spain	46600
4	Complejo Hospitalario Universitario A Coruña	A Coruña		Spain	15006
5	Hospital General Universitario de Alicante	Alicante		Spain	03010
6	Fundación Jiménez Díaz	Madrid		Spain	28040

Sponsors and Collaborators

• Spanish Breast Cancer Research Group
• Sanofi

Investigators

• Study Director: Study Director, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz
• Study Director: Study Director, Hospital Universitario Marqués de Valdecilla

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for more information about this study: GEICAM 2002-03

Publications

None provided.

• Responsible Party: Spanish Breast Cancer Research Group
• ClinicalTrials.gov Identifier: NCT00129376
• Other Study ID Numbers: GEICAM 2002-03
• First Posted: Aug 11, 2005
• Last Update Posted: Jul 5, 2019
• Last Verified: Apr 1, 2019

• Keywords provided by Spanish Breast Cancer Research Group: Stage II and IIIA breast Cancer.; Neoadjuvant chemotherapy.; Weekly docetaxel.
• Additional relevant MeSH terms: Breast Neoplasms; Cyclophosphamide; Docetaxel; Doxorubicin

Study Results

Participant Flow

Arm/Group Title	Doxorubicin + Cyclophosphamide Followed Docetaxel
Arm/Group Description	Patients received doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), both in a short intravenous infusion, every three weeks for four cycles (days 1, 22, 43 and 64). Three weeks later, docetaxel (36 mg/m2) was administered as a 30-min intravenous infusion, weekly for six weeks (days 85, 92, 99, 106, 113 and 120) followed by a 2-week resting period (8-week cycle). After that, patients received a second docetaxel cycle (infusions on days 141, 148, 155, 162, 169 and 176).
Period Title: Overall Study
STARTED	63
COMPLETED	61
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Doxorubicin + Cyclophosphamide Followed Docetaxel
Arm/Group Description	Patients received doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), both in a short intravenous infusion, every three weeks for four cycles (days 1, 22, 43 and 64). Three weeks later, docetaxel (36 mg/m2) was administered as a 30-min intravenous infusion, weekly for six weeks (days 85, 92, 99, 106, 113 and 120) followed by a 2-week resting period (8-week cycle). After that, patients received a second docetaxel cycle (infusions on days 141, 148, 155, 162, 169 and 176).
Overall Participants	63
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	48.43
Sex: Female, Male (Count of Participants)
Female	63 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	63 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
Spain	63 100%
Menopausal status (Count of Participants)
Premenopausal	35 55.6%
Postmenopausal	28 44.4%
Median Tumor size, cm (cm) [Median (Full Range) ]
Median (Full Range) [cm]	4.8
Disease stage (I, IIA, IIB y IIIA) (Count of Participants)
I	1 1.6%
IIA	23 36.5%
IIB	35 55.6%
IIIA	4 6.3%
Hormonal receptors (Estrogen Receptor [ER]+/ Progesterone Receptor [PR]+, ER+/PR-, ER-/PR+, ER-/PR-) (Count of Participants)
ER+/PR+	32 50.8%
ER+/PR-	18 28.6%
ER-/PR+	3 4.8%
ER-/PR-	10 15.9%

Outcome Measures

1. Primary Outcome

Title	Pathological Complete Response (pCR) Rate
Description	Pathological complete response was defined by the Miller & Payne criteria. pCR was defined as no invasive cells identifiable in breast sections at surgery. Response was measured by physical exam and breast imaging before surgery and was evaluated according to the World Health Organization (WHO) criteria. Pathological response after surgery, was based on the proportion of remaining tumor and postchemotherapy changes, evaluating separately the response in the breast and in the axilla lymph nodes.
Time Frame	Up to 29 weeks

Outcome Measure Data

Analysis Population Description

2 patients did not received surgery, 1 because of disease progression, and 1 due to inacceptable toxicity.

Arm/Group Title	Doxorubicin + Cyclophosphamide Followed Docetaxel
Arm/Group Description	Patients received doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), both in a short intravenous infusion, every three weeks for four cycles (days 1, 22, 43 and 64). Three weeks later, docetaxel (36 mg/m2) was administered as a 30-min intravenous infusion, weekly for six weeks (days 85, 92, 99, 106, 113 and 120) followed by a 2-week resting period (8-week cycle). After that, patients received a second docetaxel cycle (infusions on days 141, 148, 155, 162, 169 and 176).
Measure Participants	61
Count of Participants [Participants]	11 17.5%

2. Secondary Outcome

Title	Clinical Response Rate (CRR)
Description	CRR measured according to the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions, where: Complete Response (CR): disappearance of all target lesions Partial Response (PR): >=30% decrease in the sum of the longest diameter of target lesions Progresive Disease (PD): >=20% increase from smallest sum of longest diameter recorded since treatment started (best response). Stable Disease (SD): Neither PD nor PR
Time Frame	Up to 29 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Doxorubicin + Cyclophosphamide Followed Docetaxel
Arm/Group Description	Patients received doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), both in a short intravenous infusion, every three weeks for four cycles (days 1, 22, 43 and 64). Three weeks later, docetaxel (36 mg/m2) was administered as a 30-min intravenous infusion, weekly for six weeks (days 85, 92, 99, 106, 113 and 120) followed by a 2-week resting period (8-week cycle). After that, patients received a second docetaxel cycle (infusions on days 141, 148, 155, 162, 169 and 176).
Measure Participants	63
Complete response	29 46%
Partial response	28 44.4%
Stable Disease	5 7.9%
Unknown	1 1.6%

3. Secondary Outcome

Title	Number of Participants With Over-expression of Topo II (>10% Cells With Nuclear Staining)
Description	Paraffin-embedded tumors were processed with standard immunocytochemical techniques. Over-expression of Topo II was defined as >10% cells with nuclear staining.
Time Frame	Up to 29 weeks

Outcome Measure Data

Analysis Population Description

20 patient tumor sample could not be evaluated

Arm/Group Title	Doxorubicin + Cyclophosphamide Followed Docetaxel
Arm/Group Description	Patients received doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), both in a short intravenous infusion, every three weeks for four cycles (days 1, 22, 43 and 64). Three weeks later, docetaxel (36 mg/m2) was administered as a 30-min intravenous infusion, weekly for six weeks (days 85, 92, 99, 106, 113 and 120) followed by a 2-week resting period (8-week cycle). After that, patients received a second docetaxel cycle (infusions on days 141, 148, 155, 162, 169 and 176).
Measure Participants	41
> 10%	20 31.7%
< 10%	21 33.3%

4. Secondary Outcome

Title	Number of Participants With Over-expression of Survivin (>1% Cells With Nuclear Staining)
Description	Paraffin-embedded tumors were processed with standard immunocytochemical techniques. Tumors with more than 1% of cells with nuclear staining were considered to be over-expressing this protein.
Time Frame	Up to 29 weeks

Outcome Measure Data

Analysis Population Description

17 patient tumor sample could not be evaluated

Arm/Group Title	Doxorubicin + Cyclophosphamide Followed Docetaxel
Arm/Group Description	Patients received doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), both in a short intravenous infusion, every three weeks for four cycles (days 1, 22, 43 and 64). Three weeks later, docetaxel (36 mg/m2) was administered as a 30-min intravenous infusion, weekly for six weeks (days 85, 92, 99, 106, 113 and 120) followed by a 2-week resting period (8-week cycle). After that, patients received a second docetaxel cycle (infusions on days 141, 148, 155, 162, 169 and 176).
Measure Participants	44
> 1 %	18 28.6%
< 1%	26 41.3%

5. Secondary Outcome

Title	Number of Participants With Over-expression of p27 (>75% Cells With Nuclear Staining)
Description	Paraffin-embedded tumors were processed with standard immunocytochemical techniques. Sections were rated according to the percentage of tumor cells nuclei with positive staining (1 = < 25%; 2 = between 25-75% and 3 = > 75%).
Time Frame	Up to 29 weeks

Outcome Measure Data

Analysis Population Description

20 patient tumor sample could not be evaluated

Arm/Group Title	Doxorubicin + Cyclophosphamide Followed Docetaxel
Arm/Group Description	Patients received doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), both in a short intravenous infusion, every three weeks for four cycles (days 1, 22, 43 and 64). Three weeks later, docetaxel (36 mg/m2) was administered as a 30-min intravenous infusion, weekly for six weeks (days 85, 92, 99, 106, 113 and 120) followed by a 2-week resting period (8-week cycle). After that, patients received a second docetaxel cycle (infusions on days 141, 148, 155, 162, 169 and 176).
Measure Participants	41
< 75%	24 38.1%
> 75%	17 27%

Adverse Events

Time Frame	Through study treatment up to surgery, an average of 26 weeks
Arm/Group Title	Doxorubicin + Cyclophosphamide Followed Docetaxel
Arm/Group Description	Patients received doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2), both in a short intravenous infusion, every three weeks for four cycles (days 1, 22, 43 and 64). Three weeks later, docetaxel (36 mg/m2) was administered as a 30-min intravenous infusion, weekly for six weeks (days 85, 92, 99, 106, 113 and 120) followed by a 2-week resting period (8-week cycle). After that, patients received a second docetaxel cycle (infusions on days 141, 148, 155, 162, 169 and 176).
All Cause Mortality
	Doxorubicin + Cyclophosphamide Followed Docetaxel
	Affected / at Risk (%)	# Events
Total	0/63 (0%)
Serious Adverse Events
	Doxorubicin + Cyclophosphamide Followed Docetaxel
	Affected / at Risk (%)	# Events
Total	12/63 (19%)
Blood and lymphatic system disorders
Febrile neutropenia	4/63 (6.3%)	4
Cardiac disorders
Congestive heart failure	1/63 (1.6%)	1
Cardiac-ischemia/infarction	1/63 (1.6%)	1
Gastrointestinal disorders
Vomiting	1/63 (1.6%)	1
Infections and infestations
Acute Pharyngitis	1/63 (1.6%)	1
Infection	3/63 (4.8%)	3
Investigations
Neutrophil count decreased	1/63 (1.6%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis/pulmonary infiltrates	1/63 (1.6%)	1
Other (Not Including Serious) Adverse Events
	Doxorubicin + Cyclophosphamide Followed Docetaxel
	Affected / at Risk (%)	# Events
Total	63/63 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	3/63 (4.8%)
Leukopenia	5/63 (7.9%)
Lymphopenia	26/63 (41.3%)
Neutropenia	10/63 (15.9%)
Cardiac disorders
Congestive heart failure	1/63 (1.6%)
Edema	1/63 (1.6%)
Gastrointestinal disorders
Diarrhoea	1/63 (1.6%)
Nausea	2/63 (3.2%)
Vomiting	5/63 (7.9%)
General disorders
Asthenia	5/63 (7.9%)
Weight loss	1/63 (1.6%)
Hepatobiliary disorders
Hepatic dysfunction	2/63 (3.2%)
Infections and infestations
Infection without neutropenia	1/63 (1.6%)
Nervous system disorders
Anxiety	1/63 (1.6%)
Syncope	1/63 (1.6%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/63 (3.2%)
Skin and subcutaneous tissue disorders
Dry skin	1/63 (1.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.