calgb/ctsu 40101 cyclophosphamide and doxorubicin (ca...

June 2009 Breast Committee CALGB 40101

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CALGB/CTSU 40101 Cyclophosphamide and doxorubicin (CA x 4 cycles) versus paclitaxel (4 cycles) as adjuvant therapy

for breast cancer in women with 0-3 positive axillary lymph nodes: A phase III randomized study

Activated: May 15, 2002 Study Chairpersons: L. Shulman CALGB Accrual as of 4/16/2009: 3520 S. Martino SWOG Projected Accrual: 4646 E. Perez NCCTG Projected Closure August 2012 R. O’Regan ECOG Coordinating Group: CALGB Statisticians: D. Berry CALGB Current Protocol Update: #9, August 15, 2008 C. Cirrincione CALGB Data Coordinator: C. Maher CALGB

SCHEMA

§ Administration of filgrastim, sargramostim or pegfilgrastim is recommended. ‡ Patients who have undergone lumpectomy must receive XRT according to local institutional standards. Patients who

have undergone mastectomy may receive chest wall and nodal XRT. * Aromatase inhibitors may be substituted for tamoxifen in postmenopausal women. Objectives Primary 1. To determine the equivalence of paclitaxel given

every 2 weeks with CA given every 2 weeks as adjuvant therapy for women with 0-3 positive axillary lymph nodes for disease-free survival.

2. To determine if longer therapy, 12 weeks, is superior to shorter therapy, 8 weeks, of either CA or paclitaxel for disease-free survival for women with primary breast cancer with 0-3 positive axillary lymph nodes.

Secondary 1. To determine the equivalence of paclitaxel given

every 2 weeks with CA given every 2 weeks, and the potential superiority of longer vs. shorter therapy, in relation to overall survival, local control (regardless of metastatic status) and time to distant metastases (regardless of local recurrence status).

2. To compare toxicities of short and long course CA and paclitaxel as adjuvant therapy for women with 0-3 positive axillary lymph node breast cancer.

3. To determine the effect of long and short course CA and paclitaxel on the induction of menopause for pre-menopausal patients.

4. To assess the discrepancy of myelosuppression among the common MDR1 haplotypes in the CA treatment arm.

5. To assess the effect of MDR1 haplotypes on DFS adjusted for treatment.

6. Exploratory analysis of the effect of CYP3A5, CYP2C8 and CYP2B6 polymorphisms on DFS and toxicity.


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Eligibility Criteria • Histologically confirmed invasive carcinoma of the

female breast • “High risk” node-negative breast cancer that

warrants chemotherapy • ER/PgR positive, negative or unknown • HER2 positive, negative, or unknown;

recommended that patients with HER2 positive disease receive trastuzumab

• Negative tumor margins for invasive cancer and DCIS; LCIS acceptable at the margin

• Multicentric breast cancer allowed if resected w/neg margins and axillary nodes negative

• Pts. must be registered < 84 days from MRM or lumpectomy

• No previous trastuzumab, chemo or hormonal therapy except for tamoxifen

• No locally advanced or inflammatory breast cancer or involvement of dermal lymphatics

• Bilateral, synchronous breast cancers are eligible • Disease free > 5 years for prior malignancies • Age > 18 years • CTC Performance Status 0-1 • Non-pregnant and not nursing • No concomitant exogenous hormone therapy • Tamoxifen or another selective estrogen receptor

modulator (SERM) for breast cancer prevention is allowed

• Adequate organ function; no active CHF; no MI < 6 months from the time of registration.

• Patients may be enrolled in adjuvant bisphosphonate or adjuvant hormonal studies concurrently with protocol therapy

Required Laboratory Values ANC >1000/mm3 Platelet Count > 100,000/mm3 Creatinine < 2.0 mg/dl Bilirubin < 1.5 x ULN Administrative Comments This is an intergroup study coordinated by the CALGB that was activated on May 15, 2002. It has also been opened within the CTSU. A study update in October 2005 broadened eligibility to include patients with 1-3 positive axillary nodes, and to allow patients with HER2-positive tumors a 52-week course of adjuvant trastuzumab. HER2 tumor status was therefore added as a stratification factor. In February 2008 accrual was closed to the two 6-cycle arms. Accrual continues with equally weighted randomization to the remaining two arms of 4 cycles each. The study schema and title have been modified to reflect this change.

Accrual As of April 16, 2009 the total enrollment was 3520 patients, of which the CTSU enrolled 1901 (54%). Accrual by Month 2002 2003 2004 2005 2006 2007 2008 2009 Total

Jan -- 47 72 62 48 32 31 29 321 Feb -- 37 75 59 48 38 18 32 307 Mar -- 44 67 70 59 46 24 24 334 Apr -- 39 71 68 46 42 37 18 321 May 0 42 71 69 50 54 26 -- 312 Jun 1 48 63 56 51 50 24 -- 293 Jul 6 47 54 54 38 33 23 -- 255 Aug 10 38 50 46 44 44 24 -- 256 Sep 16 45 54 63 40 33 23 -- 274 Oct 23 58 59 68 37 42 33 -- 320 Nov 20 45 56 39 27 30 18 -- 235 Dec 37 52 57 42 35 36 33 -- 292 Total 113 542 749 696 523 480 314 103 3520


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Accrual by Institution For Period 5/15/2002 Through 4/16/2009

Main/At-Large

Member Affiliate Total

BATI 0 1 1 CCHLTH 93 16 109 CHAPEL 38 51 89 CHICAGO 4 28 32 DARTMOUTH 10 23 33 DUKE 28 87 115 FARBER 47 100 147 GMOG 0 1 1 GRAND 10 19 29 GRENVIL 8 0 8 HOACNY 11 29 40 ILLINOIS 5 17 22 IORA 7 33 40 IOWA 5 5 10 KCCOP 6 0 6 MARYLAND 20 10 30 MGH 2 0 2 MIAMI 16 8 24 MINNESOTA 10 11 21 MO/EFCC 17 4 21 MOBAPT 16 8 24 MSH 2 55 57

Main/At-Large

Member Affiliate Total

MSKCC 17 0 17 MVCC 1 48 49 NCRF 0 25 25 NEBRASKA 6 93 99 NHOH 22 30 52 NICRC 9 12 21 OKLAHOMA 4 5 9 OSUMC 115 0 115 RIH 7 4 11 RPCI 15 3 18 SECCC 0 127 127 SIBLEY 7 0 7 SYRACUSE 7 7 14 UCSD 38 16 54 UMMS 9 6 15 UTEXAS 12 0 12 VCC 21 1 22 WASH-BARN 11 17 28 WEILL 0 2 2 WFUSM 28 0 28 WPENN 1 1 2 WRAMC 31 0 31 CALGB Total 716 903 1619 CTSU 1901 Total Accrual 3520


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Adverse Events A. During Protocol Therapy

The following table shows the highest grade of toxicity, which was possibly, probably or definitely due to treatment, which occurred during the interval from the start of protocol therapy to 6 weeks after ending protocol treatment. Data were available for 3292 patients. The incidence of any hematologic toxicity of Grade 3 or higher was considerably higher for the CA arms than for the T arms. The incidence of any non-hematologic toxicity of Grade 3 or higher was slightly higher for the 6-cycle regimens than for the 4-cycle arms. There were two Grade 5 (lethal) toxicities. Both patients died from cardiac-related causes; both were on CA regimens. The first patient died from a myocardial infarction (Grade 5 – Cardiac-other) 96 days after beginning CAx4, just after completing all protocol treatment. The second patient died four months after beginning CAx6 protocol therapy of Grade 5 left ventricular failure. There were few Grade 4 toxicities. The most frequent were neutropenia and leukopenia in the two CA arms. All other Grade 4 toxicities occurred with a frequency of ≤ 1%. The largest differences in the occurrence of Grade 3 or higher toxicities between the CA and T regimens were neutropenia, leukopenia, febrile neutropenia and sensory neuropathy.

Grade of Adverse Event Arm 3-Severe 4-LifeThr 5-Lethal Total

n (%) n (%) n (%) Hematologic Adverse Events Blood/Bone Marrow

Blood/Bone Marrow - Other CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Hemoglobin CAx4 29 ( 3%) 1 ( 0%) 0 ( 0%) 893 CAx6 47 ( 6%) 3 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 5 ( 1%) 1 ( 0%) 0 ( 0%) 753

Leukocytes (total WBC) CAx4 87 ( 10%) 84 ( 9%) 0 ( 0%) 893 CAx6 99 ( 13%) 103 ( 14%) 0 ( 0%) 748 Tx4 7 ( 1%) 3 ( 0%) 0 ( 0%) 898 Tx6 7 ( 1%) 0 ( 0%) 0 ( 0%) 753

Lymphopenia CAx4 10 ( 1%) 0 ( 0%) 0 ( 0%) 893 CAx6 10 ( 1%) 1 ( 0%) 0 ( 0%) 748 Tx4 5 ( 1%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Neutrophils/granulocytes (ANC/AGC) CAx4 76 ( 9%) 156 ( 17%) 0 ( 0%) 893 CAx6 81 ( 11%) 173 ( 23%) 0 ( 0%) 748 Tx4 18 ( 2%) 9 ( 1%) 0 ( 0%) 898 Tx6 15 ( 2%) 4 ( 1%) 0 ( 0%) 753


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n (%) n (%) n (%) Platelets CAx4 9 ( 1%) 4 ( 0%) 0 ( 0%) 893

CAx6 24 ( 3%) 8 ( 1%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Transfusion: Platelets CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Transfusion: pRBCs CAx4 4 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 13 ( 2%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 3 ( 0%) 0 ( 0%) 0 ( 0%) 753

SUMMARY Maximum Hematologic AE CAx4 94 ( 11%) 162 ( 18%) 0 ( 0%) 893

CAx6 100 ( 13%) 184 ( 25%) 0 ( 0%) 748 Tx4 28 ( 3%) 9 ( 1%) 0 ( 0%) 898 Tx6 26 ( 3%) 5 ( 1%) 0 ( 0%) 753

Non-Hematologic Adverse Events Allergy/Immunology

Allergic reaction/hypersensitivity CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 1 ( 0%) 0 ( 0%) 748 Tx4 15 ( 2%) 1 ( 0%) 0 ( 0%) 898 Tx6 11 ( 1%) 1 ( 0%) 0 ( 0%) 753

Cardiac Arrhythmia Cardiac Arrhythmia - Other CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 2 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 2 ( 0%) 2 ( 0%) 0 ( 0%) 753

Supraventricular and nodal arrhythmia CAx4 0 ( 0%) 1 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 1 ( 0%) 0 ( 0%) 753

Cardiac General Cardiac troponin T (cTnT) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Left ventricular systolic dysfunction CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 2 ( 0%) 2 ( 0%) 1 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898


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n (%) n (%) n (%) Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Restrictive cardiomyopathy CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Cardiovascular (Arrythmia Prolonged QTc interval (QTc > 0.48 seconds)

CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Vasovagal episode CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Cardiovascular (General) Cardiovascular/General-Other CAx4 0 ( 0%) 0 ( 0%) 1 ( 0%) 893

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Hypertension CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 5 ( 1%) 0 ( 0%) 0 ( 0%) 898 Tx6 5 ( 1%) 0 ( 0%) 0 ( 0%) 753

Hypotension CAx4 2 ( 0%) 1 ( 0%) 0 ( 0%) 893 CAx6 4 ( 1%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Constitutional Symptoms Constitutional Symptoms-Other CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Fatigue (asthenia, lethargy, malaise) CAx4 24 ( 3%) 0 ( 0%) 0 ( 0%) 893 CAx6 42 ( 6%) 3 ( 0%) 0 ( 0%) 748 Tx4 4 ( 0%) 1 ( 0%) 0 ( 0%) 898 Tx6 19 ( 3%) 0 ( 0%) 0 ( 0%) 753

Insomnia CAx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753


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n (%) n (%) n (%) Dermatology/Skin

Dermatology/Skin - Other CAx4 3 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Nail changes CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Pruritus CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 2 ( 0%) 0 ( 0%) 0 ( 0%) 753

Pruritus/itching CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Radiation dermatitis CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Rash/desquamation CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 6 ( 1%) 0 ( 0%) 0 ( 0%) 753

Rash: hand-foot skin reaction CAx4 3 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 8 ( 1%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Wound-infectious CAx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 4 ( 1%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Endocrine Hot flashes/flushes CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Gastrointestinal Anorexia CAx4 5 ( 1%) 0 ( 0%) 0 ( 0%) 893


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n (%) n (%) n (%) CAx6 3 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Colitis CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 2 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Constipation CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 2 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Dehydration CAx4 8 ( 1%) 1 ( 0%) 0 ( 0%) 893 CAx6 8 ( 1%) 1 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Diarrhea (patients without colostomy) CAx4 6 ( 1%) 1 ( 0%) 0 ( 0%) 893 CAx6 11 ( 1%) 0 ( 0%) 0 ( 0%) 748 Tx4 13 ( 1%) 0 ( 0%) 0 ( 0%) 898 Tx6 10 ( 1%) 0 ( 0%) 0 ( 0%) 753

Distension/bloating, abdominal CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Dysphagia esophagitis odynophagia CAx4 8 ( 1%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Dysphagia (difficulty swallowing) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Gastrointestinal-Other CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Heartburn/dyspepsia CAx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 3 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Mucositis/stomatitis (clinical exam) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893


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n (%) n (%) n (%) CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Mucositis/stomatitis (functional/symptomatic)

CAx4 11 ( 1%) 0 ( 0%) 0 ( 0%) 893

CAx6 18 ( 2%) 1 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Nausea CAx4 25 ( 3%) 1 ( 0%) 0 ( 0%) 893 CAx6 24 ( 3%) 0 ( 0%) 0 ( 0%) 748 Tx4 5 ( 1%) 1 ( 0%) 0 ( 0%) 898 Tx6 4 ( 1%) 0 ( 0%) 0 ( 0%) 753

Pancreatitis CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Typhlitis (inflammation of cecum) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Ulcer, GI CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Vomiting CAx4 23 ( 3%) 0 ( 0%) 0 ( 0%) 893 CAx6 19 ( 3%) 0 ( 0%) 0 ( 0%) 748 Tx4 3 ( 0%) 1 ( 0%) 0 ( 0%) 898 Tx6 2 ( 0%) 0 ( 0%) 0 ( 0%) 753

Hemorrhage Hemorrhage-Other CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Melena/GI bleeding CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Rectal bleeding/hematochezia CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753


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n (%) n (%) n (%) Vaginal bleeding CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 1 ( 0%) 0 ( 0%) 753

Hepatic Alkaline phosphatase CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Bilirubin CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

GGT (gamma-Glutamyl transpeptidase)

CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Hepatic-Other CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Infection Infection (documented clinically or microbially)

CAx4 5 ( 1%) 0 ( 0%) 0 ( 0%) 893

CAx6 2 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Infection with normal ANC or Grade 1 or 2 neutropenia

CAx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Infection with unknown ANC CAx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 2 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Infection/Febrile Febrile neutropenia (fever of unknown origin)

CAx4 43 ( 5%) 4 ( 0%) 0 ( 0%) 893

CAx6 47 ( 6%) 3 ( 0%) 0 ( 0%) 748


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n (%) n (%) n (%) Tx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Infection (documented clinically or microbiolly)

CAx4 11 ( 1%) 0 ( 0%) 0 ( 0%) 893

CAx6 18 ( 2%) 0 ( 0%) 0 ( 0%) 748 Infection with unknown ANC CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Infection without neutropenia CAx4 9 ( 1%) 0 ( 0%) 0 ( 0%) 893 CAx6 9 ( 1%) 0 ( 0%) 0 ( 0%) 748 Tx4 5 ( 1%) 0 ( 0%) 0 ( 0%) 898 Tx6 4 ( 1%) 0 ( 0%) 0 ( 0%) 753

Infection/Febrile Neutropenia-Other CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Metabolic/Laboratory ALT, SGPT (serum glutamic pyruvic transaminase)

CAx4 0 ( 0%) 1 ( 0%) 0 ( 0%) 893

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 6 ( 1%) 0 ( 0%) 0 ( 0%) 898 Tx6 6 ( 1%) 0 ( 0%) 0 ( 0%) 753

AST, SGOT(serum glutamic oxaloacetic transaminase)

CAx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Albumin, serum-low (hypoalbuminemia)

CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Creatinine CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Glucose serum-high (hyperglycemia) CAx4 5 ( 1%) 1 ( 0%) 0 ( 0%) 893 CAx6 4 ( 1%) 1 ( 0%) 0 ( 0%) 748 Tx4 17 ( 2%) 0 ( 0%) 0 ( 0%) 898 Tx6 19 ( 3%) 1 ( 0%) 0 ( 0%) 753

Glucose serum-low (hypoglycemia) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893


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n (%) n (%) n (%) CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Hyperkalemia CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Hypokalemia CAx4 8 ( 1%) 0 ( 0%) 0 ( 0%) 893 CAx6 5 ( 1%) 0 ( 0%) 0 ( 0%) 748 Tx4 3 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Hyponatremia CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 2 ( 0%) 0 ( 0%) 753

Lipase CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Musculoskeletal/Soft tissue Muscle weakness, generalized or specific area

CAx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 0 ( 0%) 1 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Myositis (inflammation/damage of muscle)

CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Neurology Arachnoiditis/meningismus/radiculitis CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Ataxia (incoordination) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Dizziness CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748


Breast - 13


n (%) n (%) n (%) Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Hallucinations CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Mood alteration CAx4 2 ( 0%) 1 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 3 ( 0%) 1 ( 0%) 0 ( 0%) 753

Neuropathy: motor CAx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 17 ( 2%) 1 ( 0%) 0 ( 0%) 898 Tx6 23 ( 3%) 1 ( 0%) 0 ( 0%) 753

Neuropathy: sensory CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 36 ( 4%) 0 ( 0%) 0 ( 0%) 898 Tx6 77 ( 10%) 1 ( 0%) 0 ( 0%) 753

Syncope (fainting) CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 2 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 6 ( 1%) 0 ( 0%) 0 ( 0%) 753

Ocular/Visual Ocular/Visual-Other CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Vision-photophobia CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Watery eye (epiphora tearing) CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Pain Arthralgia (joint pain) CAx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 3 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 20 ( 2%) 0 ( 0%) 0 ( 0%) 898 Tx6 19 ( 3%) 2 ( 0%) 0 ( 0%) 753


Breast - 14


n (%) n (%) n (%) Headache CAx4 5 ( 1%) 0 ( 0%) 0 ( 0%) 893

CAx6 7 ( 1%) 1 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 1 ( 0%) 0 ( 0%) 753

Neuropathic pain (e.g. jaw pain) CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 1 ( 0%) 0 ( 0%) 898 Tx6 4 ( 1%) 0 ( 0%) 0 ( 0%) 753

Pain CAx4 10 ( 1%) 0 ( 0%) 0 ( 0%) 893 CAx6 10 ( 1%) 0 ( 0%) 0 ( 0%) 748 Tx4 47 ( 5%) 1 ( 0%) 0 ( 0%) 898 Tx6 41 ( 5%) 3 ( 0%) 0 ( 0%) 753

Pain - Other CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 3 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 3 ( 0%) 0 ( 0%) 0 ( 0%) 753

Pulmonary Adult respiratory distress syndrome (ARDS)

CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 0 ( 0%) 1 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Cough CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Dyspnea (shortness of breath) CAx4 4 ( 0%) 1 ( 0%) 0 ( 0%) 893 CAx6 10 ( 1%) 1 ( 0%) 0 ( 0%) 748 Tx4 3 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 3 ( 0%) 1 ( 0%) 0 ( 0%) 753

Pneumonitis/pulmonary infiltrates CAx4 2 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 3 ( 0%) 2 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Pulmonary-Other CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Pulmonary/Upper Respiratory Hypoxia CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748


Breast - 15


n (%) n (%) n (%) Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Renal/Genitourinary Dysuria (painful urination) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Incontinence CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Renal/Genitourinary - Other CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Urinary frequency/urgency CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Sexual/Reproductive Irregular menses (change from baseline)

CAx4 4 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 4 ( 1%) 0 ( 0%) 0 ( 0%) 748 Tx4 3 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 4 ( 1%) 0 ( 0%) 0 ( 0%) 753

Sexual/Reproductive Function – Other CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Vascular Acute vascular leak syndrome CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 753

Thrombosis/embolism (vascular access-related)

CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 893

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 748 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

Thrombosis/thrombus/embolism CAx4 6 ( 1%) 1 ( 0%) 0 ( 0%) 893 CAx6 0 ( 0%) 5 ( 1%) 0 ( 0%) 748


Breast - 16


n (%) n (%) n (%) Tx4 1 ( 0%) 1 ( 0%) 0 ( 0%) 898 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 753

SUMMARY Maximum Non-Hematologic AE CAx4 152 ( 17%) 11 ( 1%) 1 ( 0%) 893

CAx6 178 ( 24%) 18 ( 2%) 1 ( 0%) 748 Tx4 162 ( 18%) 6 ( 1%) 0 ( 0%) 898 Tx6 181 ( 24%) 12 ( 2%) 0 ( 0%) 753

SUMMARY Maximum Overall AE CAx4 165 ( 18%) 166 ( 19%) 1 ( 0%) 893

CAx6 179 ( 24%) 195 ( 26%) 1 ( 0%) 748 Tx4 179 ( 20%) 13 ( 1%) 0 ( 0%) 898 Tx6 192 ( 25%) 17 ( 2%) 0 ( 0%) 753


Breast - 17

B. Adverse Events after Completing Protocol Therapy:

3210 patients have follow-up data which reported long-term or delayed toxicity after the completion of protocol therapy. One hundred thirty-two (132) of these 3210 patients reported adverse events of Grade 3 or higher severity during post-treatment follow-up. Four patients died of treatment-related causes (AML/MDS) secondary to protocol CA. Twenty-three (23) patients experienced significant LVEF toxicity during post-treatment follow-up. Four were randomized to the CAx4 regimen, 18 to the CAx6 regimen and one to the Tx6 regimen.

Grade of Adverse Event Arm 3-Severe 4-Life Threaten 5-Lethal Total

n (%) n (%) n (%) Allergy/Immunology Hypersensitivity NOS CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Blood/Bone marrow Hemoglobin CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 1 ( 1%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 768 Leukopenia NOS CAx4 1 ( 1%) 1 ( 1%) 0 ( 0%) 834 CAx6 0 ( 0%) 1 ( 1%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Lymphopenia CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Neutrophil count CAx4 1 ( 1%) 1 ( 1%) 0 ( 0%) 834 CAx6 0 ( 0%) 1 ( 1%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Packed red blood cells CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Platelet count decrease CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Cardiac/General Pulmonary hypertension CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768

Restrictive cardio-myopathy CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834


Breast - 18


n (%) n (%) n (%) CAx6 0 ( 0%) 2 ( 1%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Valvular heart disease CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 1 ( 1%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Cardiovascular (Arrythmia) Palpitations CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Sinus bradycardia CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768

Supraventricular arrhythmia CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 768 Ventricular arrhythmia CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 1 ( 1%) 0 ( 0%) 768 Cardiovascular (General) Hypertension NOS CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 768 Left ventricular failure CAx4 4 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 16 ( 3%) 2 ( 1%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 1 ( 1%) 0 ( 0%) 768 Myocardial ischaemia CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 2 ( 1%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Thrombosis CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 2 ( 1%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 3 ( 1%) 0 ( 0%) 0 ( 0%) 768 Not available CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Constitutional Symptoms Fatigue CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 3 ( 1%) 0 ( 0%) 0 ( 0%) 769


Breast - 19


n (%) n (%) n (%) Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Dermatology/Skin Culture wound negative CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Culture wound positive CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Enodcrine Hot flushes NOS CAx4 2 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 2 ( 1%) 0 ( 0%) 0 ( 0%) 768 Virilism CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Gastrointestinal Dehydration CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 1 ( 1%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Diarrhea NOS CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 768 Nausea CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Vomiting NOS CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Not Available CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 768 Hepatic Alanine aminotransferase CAx4 0 ( 0%) 1 ( 1%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 768

Aspartate amino-transferase CAx4 0 ( 0%) 1 ( 1%) 0 ( 0%) 834

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769


Breast - 20


n (%) n (%) n (%) Tx4 2 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768

Gamma-glutamyl-transferase CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 768 Hepatobilliary/Pancreas Not available CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Infection Febrile neutropenia CAx4 2 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 1 ( 1%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Not available CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Infection/Febrile neutropenia Infection NOS CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 2 ( 1%) 0 ( 0%) 0 ( 0%) 768 Lymphatics Lymphangiopathy NOS CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 2 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Metabolic/Laboratory

Glucose serum high (hyperglycemia) CAx4 0 ( 0%) 1 ( 1%) 0 ( 0%) 834

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Musculoskeletal/Soft tissue Seroma CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Not available CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Neurology Anxiety CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769


Breast - 21


n (%) n (%) n (%) Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 768 Cerebral ischaemia CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 1 ( 1%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Depression CAx4 0 ( 0%) 1 ( 1%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Extrapyramidal disorder CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Insomnia CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Memory impairment CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768

Peripheral motor neuropathy CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 4 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 2 ( 1%) 0 ( 0%) 0 ( 0%) 768

Peripheral sensory neuropathy CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834

CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 6 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 9 ( 2%) 0 ( 0%) 0 ( 0%) 768 Syncope CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Ocular/Visual Cataract CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 768 Pain Abdominal pain NOS CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 2 ( 1%) 0 ( 0%) 0 ( 0%) 768 Angina pectoris CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839


Breast - 22


n (%) n (%) n (%) Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Arthralgia CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 3 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 4 ( 1%) 0 ( 0%) 0 ( 0%) 768 Bone pain CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Chest pain CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Headache CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Headache NOS CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Myalgia CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 2 ( 1%) 0 ( 0%) 0 ( 0%) 768 Neuralgia NOS CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 2 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Pulmonary Dyspnea NOS CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Pulmonary fibrosis CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 1 ( 1%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Not Available CAx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Renal/Genitourinary Not Available CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 769 Tx4 1 ( 1%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Secondary Malignancy Secondary to cancer rx CAx4 0 ( 0%) 0 ( 0%) 1 ( 1%) 834


Breast - 23


n (%) n (%) n (%) CAx6 0 ( 0%) 0 ( 0%) 3 ( 1%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 Sexual/Reproductive Menstruation irregularity CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 834 CAx6 1 ( 1%) 0 ( 0%) 0 ( 0%) 769 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 839 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 768 SUMMARY Maximum Overall AE CAx4 16 ( 2%) 6 ( 1%) 1 ( 1%) 834 CAx6 34 ( 4%) 11 ( 1%) 3 ( 1%) 769 Tx4 27 ( 3%) 2 ( 1%) 0 ( 0%) 839 Tx6 30 ( 4%) 2 ( 1%) 0 ( 0%) 768

calgb/ctsu 40101 cyclophosphamide and doxorubicin (ca...

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