Bevacizumab and Combination Chemotherapy in Patients With Lymph Node Positive Breast Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00119262
• Collaborator: (none)
• Enrollment: 226
• Location: 1
• Arms: 2
• Duration (Months): 47
• Patients Per Site Per Month: 4.8

Study Details

Study Description

Brief Summary

This phase II trial is studying how well giving bevacizumab together with combination chemotherapy works in treating patients who have undergone surgery for breast cancer that has spread to the lymph nodes. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with more than one chemotherapy drug (combination chemotherapy), may be a better way to block tumor growth.

Condition or Disease	Intervention/Treatment	Phase
Male Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer	Drug: doxorubicin hydrochloride; Drug: cyclophosphamide; Biological: bevacizumab; Drug: paclitaxel; Biological: filgrastim; Biological: pegfilgrastim; Radiation: radiation therapy; Drug: tamoxifen citrate; Drug: aromatase inhibition therapy	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the incidence of clinically apparent cardiac dysfunction in patients with lymph node positive breast cancer treated with bevacizumab and dose dense doxorubicin/cyclophosphamide followed by paclitaxel (ddAC > T).

SECONDARY OBJECTIVES:

1. To evaluate changes in LVEF during treatment. II. To evaluate non-cardiac toxicity.

OUTLINE: This is a non-randomized, multicenter study. Patients are sequentially assigned to 1 of 2 treatment arms.

Arm A: Patients receive doxorubicin IV, cyclophosphamide IV over 20-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Patients also receive filgrastim (G-CSF) subcutaneously (SQ) on days 2-11 or pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients then receive paclitaxel IV over 3 hours and bevacizumab IV over 30-90 minutes on day 1. Patients also receive G-CSF or pegfilgrastim as above. Treatment with paclitaxel, bevacizumab, and G-CSF or pegfilgrastim repeats every 14 days for 4 courses. Patients then receive bevacizumab alone every 14 days for up to 18 courses.

Arm B: Patients receive doxorubicin, cyclophosphamide, and G-CSF or pegfilgrastim as in group

1. Patients then receive paclitaxel, bevacizumab, and G-CSF or pegfilgrastim as in group I. Patients then receive bevacizumab alone every 14 days for up to 22 courses.

Treatment in both groups continues in the absence of disease recurrence or unacceptable toxicity.

Patients who require radiotherapy (post-lumpectomy) or who plan radiotherapy at the discretion of the investigator (post-mastectomy) undergo radiotherapy beginning within 6 weeks after the completion of chemotherapy.

Premenopausal patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive disease receive oral tamoxifen once daily for 5 years beginning at the time of radiotherapy or within 6 weeks after the completion of chemotherapy. Postmenopausal patients with ER and/or PR positive disease receive an aromatase inhibitor (e.g., anastrozole, letrozole, or exemestane) or tamoxifen followed by an aromatase inhibitor once daily for up to 10 years.

After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for up to 3 years from study entry.

ACCRUAL: A total of 226 patients (104 on arm A and 122 on arm B) were accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 226 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Feasibility Trial Incorporating Bevacizumab Into Dose Dense Doxorubicin and Cyclophosphamide Followed by Paclitaxel in Patients With Lymph Node Positive Breast Cancer
• Study Start Date: Oct 1, 2005
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Sep 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (combination chemotherapy, 18 courses of bevacizumab) See detailed description.	Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Drug: cyclophosphamide; Given IV; Other Names: CPM CTX Cytoxan Endoxan Endoxana ; Biological: bevacizumab; Given IV; Other Names: anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody Avastin rhuMAb VEGF ; Drug: paclitaxel; Given IV; Other Names: Anzatax Asotax TAX Taxol ; Biological: filgrastim; Given SC; Other Names: G-CSF Neupogen ; Biological: pegfilgrastim; Given SC; Other Names: Filgrastim SD-01 GCSF-SD01 Neulasta SD-01 sustained duration G-CSF ; Radiation: radiation therapy; Undergo radiation therapy; Other Names: irradiation radiotherapy therapy, radiation ; Drug: tamoxifen citrate; Given orally; Other Names: Nolvadex TAM tamoxifen TMX ; Drug: aromatase inhibition therapy; Receive aromatase inhibition therapy; Other Names: inhibition therapy, aromatase
Active Comparator: Arm II (combination chemotherapy, 22 courses of bevacizumab) See detailed description.	Drug: doxorubicin hydrochloride; Given IV; Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF ; Drug: cyclophosphamide; Given IV; Other Names: CPM CTX Cytoxan Endoxan Endoxana ; Biological: bevacizumab; Given IV; Other Names: anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody Avastin rhuMAb VEGF ; Drug: paclitaxel; Given IV; Other Names: Anzatax Asotax TAX Taxol ; Biological: filgrastim; Given SC; Other Names: G-CSF Neupogen ; Biological: pegfilgrastim; Given SC; Other Names: Filgrastim SD-01 GCSF-SD01 Neulasta SD-01 sustained duration G-CSF ; Radiation: radiation therapy; Undergo radiation therapy; Other Names: irradiation radiotherapy therapy, radiation ; Drug: tamoxifen citrate; Given orally; Other Names: Nolvadex TAM tamoxifen TMX ; Drug: aromatase inhibition therapy; Receive aromatase inhibition therapy; Other Names: inhibition therapy, aromatase

Outcome Measures

Primary Outcome Measures

1. Congestive Heart Failure Rate [assessed on day 1 of cycles 5, 9, 17 and 25, and at end of treatment, then every 3 months for <2 years and every 6 months for 2-3 years from study entry]

   Clinical congestive heart failure includes patients with symptomatic decline in LVEF to at or below the lower limit of normal (LLN), or symptomatic diastolic dysfunction. 223 treated patients were included in the analysis.

Secondary Outcome Measures

1. Proportion of Patients With Absolute Decrease in Left Ventricular Ejection Fraction (LVEF) Levels Post Doxorubicin and Cyclophosphamide(AC) [assessed on day 1 of cycles 5, 9, 17, 25, and at end of treatment]

   The endpoint was measured by absolute decrease from baseline in LVEF of >15% or >10% decline from baseline to below the LLN post doxorubicin and cyclophosphamide (AC) Day 1 Cycle 5 (DIC5). 207 patients who were treated and had baseline and DIC5 LVEF values were included in the analysis.

2. Proportion of Patients With Absolute Decrease in LVEF Levels Post Bevacizumab [assessed on day 1 of cycles 5, 9, 17, 25, and at end of treatment]

   The endpoint was measured by absolute decrease from baseline in LVEF of >15% or >10% decline from baseline to below the LLN post bevacizumab (the end of treatment). 158 patients who were treated and had baseline and end of treatment LVEF values were included in the analysis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the breast with involvement of at least one axillary or internal mammary lymph node on routine histologic examination with hematoxylin and eosin staining; NOTE: patients with axillary or internal mammary node involvement only demonstrated by immunohistochemistry are not eligible

• Patients must have completed definitive breast surgery including total mastectomy and axillary dissection (modified radical mastectomy), total mastectomy and sentinel node biopsy, lumpectomy and axillary dissection, or lumpectomy and sentinel node biopsy; NOTE: axillary dissection is strongly encouraged in patients with lymph node involvement identified on sentinel node biopsy

• Margins of lumpectomy or mastectomy must be histologically free of invasive breast cancer and ductal carcinoma in situ (DCIS); patients with resection margins positive for lobular carcinoma in situ (LCIS) are eligible

• (ARM A ONLY) Interval between last surgery for breast cancer (lumpectomy, mastectomy, sentinel node biopsy, axillary dissection or re-excision of lumpectomy margins) and D1 must be > 28 days and =< 84 days

• ECOG performance status of 0-2

• Absolute neutrophil count >= 1000/mm^3

• Platelet count >= 100,000/mm^3

• Total bilirubin =< 1.5 mg/dL

• AST =< 2 upper limit of normal

• Serum creatinine =< 1.5 mg/dL

• Urine protein: creatinine ratio < 1.0

• PT INR =< 1.5

• PTT =< 1.5 x normal

• LVEF >= institutional limits of normal by MUGA or ECHO

• Prior to registration the investigator must specify if radiation is planned; patients who have undergone a lumpectomy must receive radiation; post-mastectomy radiation is at the investigator's discretion

• Patients with HER2+ (3+ by IHC or FISH+) breast cancer are not eligible and should be treated with a trastuzumab-based adjuvant therapy

• Patients with synchronous bilateral breast cancer (diagnosed within one month) are eligible if the higher TMN stage tumor meets the eligibility criteria for this trial

• Patients must not have clinical evidence of inflammatory disease or fixed axillary nodes (N2) at diagnosis

• Patients must not have received prior cytotoxic chemotherapy, hormonal therapy or radiation for this breast cancer; prior treatment with an anthracycline, anthracenedione or taxane for any condition is not allowed; NOTE: prior use of tamoxifen for chemoprevention is allowed but must be discontinued at study entry; similarly prior raloxifene use is allowed but must be discontinued at study entry

• Patients must not have had a major surgical procedure within 4 weeks of entry; NOTE: non-operative biopsy or placement of a vascular access device is not considered a major surgery

• Patients must not have clinically significant cardiovascular disease including:

• New York Heart Association (NYHA) grade II or greater congestive heart failure

• Grade II or greater peripheral vascular disease

• Uncontrolled hypertension defined as SBP > 160 or DBP > 90

• Any prior history of cerebrovascular disease including TIA or stroke

• Patients must not require therapeutic anticoagulation; patients with a history of deep venous thrombosis or pulmonary embolism are not eligible; NOTE: prophylactic use of anticoagulants to maintain patency of a vascular assess device is permitted

• Patients may not require regular use of aspirin (daily for >= 10 days at doses of > 325 mg/day) or regular therapeutic doses of other nonsteroidal anti-inflammatory agents known to inhibit platelet function; additionally, patients using any of the following drugs known to inhibit platelet function are not eligible: dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and cilostazol (Pletal); NOTE: regular use of Cox-2 inhibitors is permitted; NOTE: low-dose aspirin is permitted

• Patients must not have a non-healing wound or fracture; patients with an abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months are excluded

• Patients must not have hypersensitivity to paclitaxel or drugs using the vehicle Cremophor, Chinese hamster ovary cell products or other recombinant human antibodies

• Patients who have experienced myocardial infarction or unstable angina within 12 months are excluded

• Patients who have had experienced an arterial thrombotic event within 12 months are excluded

• Patients must not have uncontrolled or clinical significant arrhythmia

• Women must not be pregnant or breast-feeding due to the potential harmful effects of bevacizumab on the developing fetus; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy

• Women of childbearing potential and sexually active males are required to use an accepted and effective method of contraception while on study and for at least 3-4 months after the last dose of bevacizumab

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Eastern Cooperative Oncology Group	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Kathy Miller, Eastern Cooperative Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00119262
• Other Study ID Numbers: NCI-2012-02977; NCI-2012-02977; U10CA021115; E2104; E2104
• First Posted: Jul 13, 2005
• Last Update Posted: May 15, 2014
• Last Verified: Dec 1, 2012

• Additional relevant MeSH terms: Breast Neoplasms; Breast Neoplasms, Male; Tamoxifen; Cyclophosphamide; Bevacizumab; Doxorubicin; Liposomal doxorubicin; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Lenograstim; Aromatase Inhibitors

Study Results

Participant Flow

Recruitment Details	E2104 was opened on October 6,2005, and closed on November 6, 2006 with the final accrual of 226 patients.Study participants included Eastern Cooperative Oncology Group (ECOG) entire group, North Central Cancer Treatment Group (NCCTG) entire group and Cancer and Leukemia Group B (CALGB) entire group.

Arm/Group Title	Arm A (ddBAC > BT > B)	Arm B (ddAC > BT > B)
Arm/Group Description	Dose dense bevacizumab, cyclophosphamide and doxorubicin, followed by paclitaxel and bevacizumab, followed by bevacizumab	Dose dense doxorubicin and cyclophosphamide, followed by paclitaxel and bevacizumab, followed by bevacizumab
Period Title: Overall Study
STARTED	104	122
Eligible	103	120
Treated	103	120
Eligible and Treated	102	119
COMPLETED	58	64
NOT COMPLETED	46	58

Baseline Characteristics

Arm/Group Title	Arm A (ddBAC > BT > B)	Arm B (ddAC > BT > B)	Total
Arm/Group Description	Dose dense bevacizumab, cyclophosphamide and doxorubicin, followed by paclitaxel and bevacizumab, followed by bevacizumab	Dose dense doxorubicin and cyclophosphamide, followed by paclitaxel and bevacizumab, followed by bevacizumab	Total of all reporting groups
Overall Participants	103	120	223
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	50	50	50
Sex: Female, Male (Count of Participants)
Female	103 100%	119 99.2%	222 99.6%
Male	0 0%	1 0.8%	1 0.4%
Region of Enrollment (participants) [Number]
United States	103 100%	120 100%	223 100%

Outcome Measures

1. Primary Outcome

Title	Congestive Heart Failure Rate
Description	Clinical congestive heart failure includes patients with symptomatic decline in LVEF to at or below the lower limit of normal (LLN), or symptomatic diastolic dysfunction. 223 treated patients were included in the analysis.
Time Frame	assessed on day 1 of cycles 5, 9, 17 and 25, and at end of treatment, then every 3 months for <2 years and every 6 months for 2-3 years from study entry

Outcome Measure Data

Analysis Population Description

223 treated patients

Arm/Group Title	Arm A (ddBAC > BT > B)	Arm B (ddAC > BT > B)
Arm/Group Description	Dose dense bevacizumab, cyclophosphamide and doxorubicin, followed by paclitaxel and bevacizumab, followed by bevacizumab	Dose dense doxorubicin and cyclophosphamide, followed by paclitaxel and bevacizumab, followed by bevacizumab
Measure Participants	103	120
Number (95% Confidence Interval) [percentage of participants]	2.9 2.8%	2.5 2.1%

2. Secondary Outcome

Title	Proportion of Patients With Absolute Decrease in Left Ventricular Ejection Fraction (LVEF) Levels Post Doxorubicin and Cyclophosphamide(AC)
Description	The endpoint was measured by absolute decrease from baseline in LVEF of >15% or >10% decline from baseline to below the LLN post doxorubicin and cyclophosphamide (AC) Day 1 Cycle 5 (DIC5). 207 patients who were treated and had baseline and DIC5 LVEF values were included in the analysis.
Time Frame	assessed on day 1 of cycles 5, 9, 17, 25, and at end of treatment

Outcome Measure Data

Analysis Population Description

Patients who were treated and had baseline and DIC5 LVEF values

Arm/Group Title	Arm A (ddBAC > BT > B)	Arm B (ddAC > BT > B)
Arm/Group Description	Dose dense bevacizumab, cyclophosphamide and doxorubicin, followed by paclitaxel and bevacizumab, followed by bevacizumab	Dose dense doxorubicin and cyclophosphamide, followed by paclitaxel and bevacizumab, followed by bevacizumab
Measure Participants	94	113
Number (95% Confidence Interval) [percentage of participants]	7.4 7.2%	3.5 2.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (ddBAC > BT > B), Arm B (ddAC > BT > B)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.12
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Proportion of Patients With Absolute Decrease in LVEF Levels Post Bevacizumab
Description	The endpoint was measured by absolute decrease from baseline in LVEF of >15% or >10% decline from baseline to below the LLN post bevacizumab (the end of treatment). 158 patients who were treated and had baseline and end of treatment LVEF values were included in the analysis.
Time Frame	assessed on day 1 of cycles 5, 9, 17, 25, and at end of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A (ddBAC > BT > B)	Arm B (ddAC > BT > B)
Arm/Group Description	Dose dense bevacizumab, cyclophosphamide and doxorubicin, followed by paclitaxel and bevacizumab, followed by bevacizumab	Dose dense doxorubicin and cyclophosphamide, followed by paclitaxel and bevacizumab, followed by bevacizumab
Measure Participants	72	86
Number (95% Confidence Interval) [percentage of participants]	15.3 14.9%	11.6 9.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (ddBAC > BT > B), Arm B (ddAC > BT > B)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.32
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	assessed at the end of each cycle while on treatment and for 30 days after the end of treatment, and assessed every 3 months if patient is <2 years and every 6 months if patient is 2-3 years from study entry
Arm/Group Title	Arm A (ddBAC > BT > B)		Arm B (ddAC > BT > B)
Arm/Group Description	Dose dense bevacizumab, cyclophosphamide and doxorubicin, followed by paclitaxel and bevacizumab, followed by bevacizumab		Dose dense doxorubicin and cyclophosphamide, followed by paclitaxel and bevacizumab, followed by bevacizumab
All Cause Mortality
	Arm A (ddBAC > BT > B)		Arm B (ddAC > BT > B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A (ddBAC > BT > B)		Arm B (ddAC > BT > B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	71/103 (68.9%)		65/120 (54.2%)
Blood and lymphatic system disorders
Anemia	1/103 (1%)		4/120 (3.3%)
Hemolysis	1/103 (1%)		0/120 (0%)
Febrile neutropenia	4/103 (3.9%)		5/120 (4.2%)
Cardiac disorders
Cardiac-Ischemia	1/103 (1%)		0/120 (0%)
Left ventricular diastolic dysfunction	1/103 (1%)		2/120 (1.7%)
Left ventricular systolic dysfunction	4/103 (3.9%)		4/120 (3.3%)
Gastrointestinal disorders
Diarrhea w/o prior colostomy	2/103 (1.9%)		0/120 (0%)
Muco/stomatitis (symptom), oral cavity	3/103 (2.9%)		3/120 (2.5%)
Muco/stomatitis (symptom), pharynx	1/103 (1%)		0/120 (0%)
Nausea	3/103 (2.9%)		0/120 (0%)
Vomiting	1/103 (1%)		0/120 (0%)
Rectum, hemorrhage	1/103 (1%)		0/120 (0%)
General disorders
Fatigue	11/103 (10.7%)		7/120 (5.8%)
Fever w/o neutropenia	2/103 (1.9%)		0/120 (0%)
Nonneuropathic generalized weakness	1/103 (1%)		0/120 (0%)
Hepatobiliary disorders
ALT increased	2/103 (1.9%)		1/120 (0.8%)
AST increased	1/103 (1%)		1/120 (0.8%)
Gallbladder, pain	1/103 (1%)		0/120 (0%)
Immune system disorders
Allergic reaction	4/103 (3.9%)		0/120 (0%)
Infections and infestations
Infection w/gr3-4 neut,lung	1/103 (1%)		0/120 (0%)
Infection w/gr3-4 neut, mucosa	0/103 (0%)		1/120 (0.8%)
Infection w/gr3-4 neut, urinary tract	1/103 (1%)		0/120 (0%)
Infection w/gr0-2 neut, bronchus	1/103 (1%)		0/120 (0%)
Infection w/gr0-2 neut, catheter	1/103 (1%)		0/120 (0%)
Infection w/gr 0-2 neut, lung	1/103 (1%)		0/120 (0%)
Infection w/gr 0-2 neut, pharynx	0/103 (0%)		1/120 (0.8%)
Infection w/gr 0-2 neut, skin	1/103 (1%)		2/120 (1.7%)
Infection w/gr 0-2 neut, urinary tract	1/103 (1%)		0/120 (0%)
Infection w/ unknown ANC, mucosa	0/103 (0%)		1/120 (0.8%)
Infection w/ unknown ANC, oral activity/gums	0/103 (0%)		1/120 (0.8%)
Infection w/ unknown ANC, upper airway NOS	1/103 (1%)		0/120 (0%)
Infection w/gr 0-2 neut, blood	1/103 (1%)		0/120 (0%)
Injury, poisoning and procedural complications
Vascular assess, Thrombosis/Embolism	1/103 (1%)		0/120 (0%)
Investigations
Leukopenia	22/103 (21.4%)		27/120 (22.5%)
Neutropenia	28/103 (27.2%)		31/120 (25.8%)
Thrombocytopenia	2/103 (1.9%)		2/120 (1.7%)
Weight gain	0/103 (0%)		1/120 (0.8%)
Weight loss	0/103 (0%)		2/120 (1.7%)
Amylase increased	1/103 (1%)		0/120 (0%)
Lymphopenia	3/103 (2.9%)		9/120 (7.5%)
Metabolism and nutrition disorders
Anorexia	1/103 (1%)		1/120 (0.8%)
Dehydration	1/103 (1%)		1/120 (0.8%)
Hyperglycemia	0/103 (0%)		1/120 (0.8%)
Hypokalemia	1/103 (1%)		1/120 (0.8%)
Hyponatremia	0/103 (0%)		2/120 (1.7%)
Musculoskeletal and connective tissue disorders
Bone pain	1/103 (1%)		1/120 (0.8%)
Joint,pain	3/103 (2.9%)		8/120 (6.7%)
Muscle,pain	6/103 (5.8%)		4/120 (3.3%)
Nervous system disorders
CNS cerebrovascular Ischemia	1/103 (1%)		1/120 (0.8%)
Dizziness	0/103 (0%)		1/120 (0.8%)
Neuropathy-motor	0/103 (0%)		1/120 (0.8%)
Neuropathy-sensory	8/103 (7.8%)		10/120 (8.3%)
Syncope	0/103 (0%)		2/120 (1.7%)
Head/headache	1/103 (1%)		8/120 (6.7%)
Neuropathic,pain	0/103 (0%)		1/120 (0.8%)
Psychiatric disorders
Insomnia	0/103 (0%)		1/120 (0.8%)
Renal and urinary disorders
Proteinuria	2/103 (1.9%)		2/120 (1.7%)
Reproductive system and breast disorders
Irregular menses	0/103 (0%)		4/120 (3.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/103 (1.9%)		5/120 (4.2%)
Hypoxia	1/103 (1%)		0/120 (0%)
Voice changes/dysarthria	1/103 (1%)		0/120 (0%)
Skin and subcutaneous tissue disorders
Rash/desquamation	2/103 (1.9%)		0/120 (0%)
Hand-foot skin reaction	2/103 (1.9%)		1/120 (0.8%)
Vascular disorders
Hypertension	13/103 (12.6%)		13/120 (10.8%)
Hot flashes	1/103 (1%)		0/120 (0%)
Thrombosis/thrombus/embolism	1/103 (1%)		2/120 (1.7%)
Other (Not Including Serious) Adverse Events
	Arm A (ddBAC > BT > B)		Arm B (ddAC > BT > B)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	103/103 (100%)		120/120 (100%)
Blood and lymphatic system disorders
Anemia	51/103 (49.5%)		60/120 (50%)
Cardiac disorders
Left ventricular systolic dysfunction	19/103 (18.4%)		20/120 (16.7%)
Eye disorders
Vision-blurred	2/103 (1.9%)		8/120 (6.7%)
Tearing	6/103 (5.8%)		14/120 (11.7%)
Ocular-other	6/103 (5.8%)		2/120 (1.7%)
Gastrointestinal disorders
Constipation	36/103 (35%)		50/120 (41.7%)
Diarrhea w/o prior colostomy	37/103 (35.9%)		46/120 (38.3%)
Dry mouth	3/103 (2.9%)		9/120 (7.5%)
Dyspepsia	36/103 (35%)		43/120 (35.8%)
Muco/stomatitis (symptom), oral cavity	63/103 (61.2%)		62/120 (51.7%)
Muco/stomatitis (symptom), pharynx	15/103 (14.6%)		12/120 (10%)
Nausea	88/103 (85.4%)		100/120 (83.3%)
Taste disturbance	26/103 (25.2%)		37/120 (30.8%)
Vomiting	38/103 (36.9%)		40/120 (33.3%)
Oral activity, hemorrhage	7/103 (6.8%)		9/120 (7.5%)
Upper GI, hemorrhage NOS	6/103 (5.8%)		3/120 (2.5%)
Abonominal pain	6/103 (5.8%)		6/120 (5%)
Pain NOS	6/103 (5.8%)		3/120 (2.5%)
General disorders
Fatigue	86/103 (83.5%)		102/120 (85%)
Fever w/o neutropenia	6/103 (5.8%)		6/120 (5%)
Rigors/chills	8/103 (7.8%)		15/120 (12.5%)
Sweating	8/103 (7.8%)		16/120 (13.3%)
Edema limb	5/103 (4.9%)		13/120 (10.8%)
Pain-other	10/103 (9.7%)		9/120 (7.5%)
Hepatobiliary disorders
ALT increased	25/103 (24.3%)		23/120 (19.2%)
AST increased	18/103 (17.5%)		33/120 (27.5%)
Injury, poisoning and procedural complications
Radiation dermatitis	7/103 (6.8%)		6/120 (5%)
Investigations
Leukopenia	42/103 (40.8%)		41/120 (34.2%)
Lymphopenia	5/103 (4.9%)		12/120 (10%)
Neutropenia	28/103 (27.2%)		19/120 (15.8%)
Thrombocytopenia	25/103 (24.3%)		32/120 (26.7%)
Weight gain	12/103 (11.7%)		14/120 (11.7%)
Weight loss	32/103 (31.1%)		36/120 (30%)
Alkaline phosphatase increased	36/103 (35%)		37/120 (30.8%)
Bilirubin increased	0/103 (0%)		6/120 (5%)
Metabolism and nutrition disorders
Anorexia	43/103 (41.7%)		43/120 (35.8%)
Dehydration	6/103 (5.8%)		5/120 (4.2%)
Hyperglycemia	15/103 (14.6%)		9/120 (7.5%)
Hypokalemia	5/103 (4.9%)		11/120 (9.2%)
Hyponatremia	6/103 (5.8%)		6/120 (5%)
Musculoskeletal and connective tissue disorders
Back, pain	4/103 (3.9%)		10/120 (8.3%)
Bone pain	14/103 (13.6%)		20/120 (16.7%)
Extremity-limb,pain	4/103 (3.9%)		9/120 (7.5%)
Joint,pain	63/103 (61.2%)		75/120 (62.5%)
Muscle,pain	57/103 (55.3%)		76/120 (63.3%)
Nervous system disorders
Dizziness	9/103 (8.7%)		18/120 (15%)
Neuropathy-motor	7/103 (6.8%)		9/120 (7.5%)
Neuropathy-sensory	72/103 (69.9%)		89/120 (74.2%)
Head/headache	39/103 (37.9%)		51/120 (42.5%)
Psychiatric disorders
Insomnia	19/103 (18.4%)		24/120 (20%)
Anxiety	17/103 (16.5%)		5/120 (4.2%)
Depression	9/103 (8.7%)		12/120 (10%)
Renal and urinary disorders
Hemoglobinuria	3/103 (2.9%)		6/120 (5%)
Proteinuria	11/103 (10.7%)		23/120 (19.2%)
Reproductive system and breast disorders
Irregular menses	0/103 (0%)		6/120 (5%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	4/103 (3.9%)		14/120 (11.7%)
Nose, hemorrhage	39/103 (37.9%)		35/120 (29.2%)
Chest/thoracic pain NOS	8/103 (7.8%)		10/120 (8.3%)
Cough	20/103 (19.4%)		17/120 (14.2%)
Dyspnea	26/103 (25.2%)		30/120 (25%)
Voice changes/dysarthria	13/103 (12.6%)		2/120 (1.7%)
Skin and subcutaneous tissue disorders
Dry skin	3/103 (2.9%)		12/120 (10%)
Alopecia	93/103 (90.3%)		91/120 (75.8%)
Nail change	17/103 (16.5%)		28/120 (23.3%)
Pruritus/itching	6/103 (5.8%)		6/120 (5%)
Rash/desquamation	35/103 (34%)		31/120 (25.8%)
Hand-foot skin reaction	12/103 (11.7%)		9/120 (7.5%)
Vascular disorders
Hypertension	45/103 (43.7%)		43/120 (35.8%)
Hot flashes	24/103 (23.3%)		43/120 (35.8%)

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.