cyclophosphamide and doxorubicin (ca) (4 vs 6 cycles...

June 2006 Breast Committee CALGB 40101

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CALGB/CTSU 40101

Cyclophosphamide and Doxorubicin (CA) (4 vs 6 cycles) versus Paclitaxel (4 vs 6 cycles) as Adjuvant Therapy for Breast Cancer in Women with 0-3 Positive Axillary Lymph Nodes:

A 2X2 Factorial Phase III Randomized Study

Activated: May 15, 2002 Study Chairpersons: L. Shulman CALGB Accrual as of 3/24/2006: 2241 S. Martino SWOG Projected Accrual: 4646 E. Perez NCCTG Projected Closure March 2010 R. O’Regan ECOG Coordinating Group: CALGB Statisticians: D. Berry CALGB Current Protocol Update: #5, October 15, 2005 C. Cirrincione CALGB Data Coordinator: R. Heinze CALGB

SCHEMA


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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.

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.


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Accrual As of March 24, 2006 the total enrollment was 2241 patients of which the CTSU enrolled 1263 (56%). Accrual by Month

2002 2003 2004 2005 2006 Total

Jan -- 47 72 62 48 229 Feb -- 37 75 59 48 219 Mar -- 44 67 70 45 226 Apr -- 39 71 68 -- 178 May 0 42 71 69 -- 182 Jun 1 48 63 56 -- 168 Jul 6 47 54 54 -- 161 Aug 10 38 50 46 -- 144 Sep 16 45 54 63 -- 178 Oct 23 58 59 68 -- 208 Nov 20 45 56 39 -- 160 Dec 37 52 57 42 -- 188 Total 113 542 749 696 141 2241

Accrual by Institution For Period 5/15/2002 Through 3/24/2006

Main/At-Large Member Affiliate Total

CCHLTH 70 15 85 CHAPEL 18 28 46 CHICAGO 3 19 22 DARTMOUTH 5 19 24 DUKE 19 61 80 FARBER 16 70 86 GMOG 0 1 1 GRAND 10 12 22 GRENVIL 2 0 2 ILLINOIS 3 17 20 IORA 7 22 29 IOWA 4 5 9 KCCOP 5 0 5 MARYLAND 16 7 23 MGH 2 0 2 MIAMI 15 6 21 MINNESOTA 6 10 16 MO/EFCC 11 4 15 MOBAPT 15 4 19 MSH 2 16 18 MSKCC 5 0 5 MVCC 1 17 18 NCRF 0 12 12 NEBRASKA 0 46 46 NHOH 13 6 19 NICRC 7 10 17 OKLAHOMA 0 4 4 OSUMC 51 0 51 RIH 4 3 7 RPCI 13 0 13 SECCC 0 78 78 SYRACUSE 5 4 9 SYRHEM 0 29 29 UCSD 13 11 24 UMMS 7 4 11 UTEXAS 12 0 12 VCC 10 1 11 WASH-BARN 8 15 23 WEILL 0 2 2 WFUSM 17 0 17 WPENN 1 1 2 WRAMC 23 0 23 CALGB Total 419 559 978 CTSU 1263 Total Accrual 2241


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Adverse Events The following table shows Grades 3 and higher adverse events that were possibly, probably or definitely treatment related and which occurred during protocol treatment. Data were available for 1367 patients. Thus far, there have been two Grade 5 adverse events. 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 3 or 4 adverse events, either hematologic or non-hematologic in nature. The most frequent Grade 4 hematologic adverse events were neutropenia in the two CA arms (20%, 24%) compared to the two paclitaxel arms (each arm 1%) and leukopenia (CA arms: 8% and 14% versus none in the paclitaxel arms). All other Grade 4 toxicities occurred with a frequency of ≤ 1%. The largest differences between the CA and T regimens in the occurrence of Grade 3 or higher toxicities were neutropenia, leukopenia and febrile neutropenia in which the CA arms had a higher incidence than the T arms, and sensory neuropathy in which the T arms had a higher incidence than the CA arms.

Grade of Adverse Event

Arm 3-Severe 4-LifeThr 5-Lethal Total n (%) n (%) n (%)

Hematologic Adverse Events BLOOD/BONE MARROW

Hemoglobin CAx4 5 ( 1%) 0 ( 0%) 0 ( 0%) 348 CAx6 18 ( 5%) 2 ( 1%) 0 ( 0%) 340 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 1 ( 0%) 1 ( 0%) 0 ( 0%) 332

Leukocytes (total WBC) CAx4 39 ( 11%) 29 ( 8%) 0 ( 0%) 348 CAx6 41 ( 12%) 46 ( 14%) 0 ( 0%) 340 Tx4 3 ( 1%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Lymphopenia CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 3 ( 1%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Neutrophils/granulocytes (ANC/AGC) CAx4 32 ( 9%) 69 ( 20%) 0 ( 0%) 348 CAx6 37 ( 11%) 81 ( 24%) 0 ( 0%) 340 Tx4 8 ( 2%) 5 ( 1%) 0 ( 0%) 347 Tx6 6 ( 2%) 3 ( 1%) 0 ( 0%) 332

Platelets CAx4 7 ( 2%) 0 ( 0%) 0 ( 0%) 348 CAx6 7 ( 2%) 4 ( 1%) 0 ( 0%) 340 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Transfusion: Platelets CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Transfusion: pRBCs CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 6 ( 2%) 0 ( 0%) 0 ( 0%) 340


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

n (%) n (%) n (%) Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 332

SUMMARY Maximum Hematologic AE CAx4 37 ( 11%) 73 ( 21%) 0 ( 0%) 348

CAx6 44 ( 13%) 88 ( 26%) 0 ( 0%) 340 Tx4 10 ( 3%) 5 ( 1%) 0 ( 0%) 347 Tx6 8 ( 2%) 4 ( 1%) 0 ( 0%) 332

Non-Hematologic Adverse Events ALLERGY/IMMUNOLOGY

Allergic reaction/hypersensitivity (including

CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 0 ( 0%) 1 ( 0%) 0 ( 0%) 340 Tx4 3 ( 1%) 0 ( 0%) 0 ( 0%) 347 Tx6 7 ( 2%) 0 ( 0%) 0 ( 0%) 332

CARDIAC GENERAL Cardiac General - Other (Specify) CAx4 0 ( 0%) 0 ( 0%) 1 ( 0%) 348

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Cardiac troponin T (cTnT) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Hypertension CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 3 ( 1%) 0 ( 0%) 0 ( 0%) 347 Tx6 3 ( 1%) 0 ( 0%) 0 ( 0%) 332

Hypotension CAx4 1 ( 0%) 1 ( 0%) 0 ( 0%) 348 CAx6 3 ( 1%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Left ventricular systolic dysfunction CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 3 ( 1%) 1 ( 0%) 1 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

CONSTITUTIONAL SYM Constitutional Symptoms - Other (Specify __)

CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332


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n (%) n (%) n (%) Fatigue (asthenia lethargy malaise) CAx4 5 ( 1%) 0 ( 0%) 0 ( 0%) 348

CAx6 14 ( 4%) 1 ( 0%) 0 ( 0%) 340 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 8 ( 2%) 0 ( 0%) 0 ( 0%) 332

DERMATOLOGY/SKIN Dermatology/Skin - Other (Specify) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 2 ( 1%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Pruritus CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 332

Pruritus/itching CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 332

Rash/desquamation CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 3 ( 1%) 0 ( 0%) 0 ( 0%) 332

Rash: hand-foot skin reaction CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 5 ( 1%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Wound-infectious CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

GASTROINTESTINAL Anorexia CAx4 3 ( 1%) 0 ( 0%) 0 ( 0%) 348

CAx6 3 ( 1%) 0 ( 0%) 0 ( 0%) 340 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Constipation CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Dehydration CAx4 5 ( 1%) 1 ( 0%) 0 ( 0%) 348 CAx6 4 ( 1%) 0 ( 0%) 0 ( 0%) 340


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n (%) n (%) n (%) Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Diarrhea CAx4 2 ( 1%) 1 ( 0%) 0 ( 0%) 348 CAx6 6 ( 2%) 1 ( 0%) 0 ( 0%) 340 Tx4 8 ( 2%) 0 ( 0%) 0 ( 0%) 347 Tx6 7 ( 2%) 0 ( 0%) 0 ( 0%) 332

Esophagitis CAx4 4 ( 1%) 0 ( 0%) 0 ( 0%) 348 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Gastrointestinal - Other (Specify) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Heartburn/dyspepsia CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Mucositis/stomatitis (functional/symptomatic)

CAx4 4 ( 1%) 0 ( 0%) 0 ( 0%) 348

CAx6 5 ( 1%) 1 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Nausea CAx4 13 ( 4%) 1 ( 0%) 0 ( 0%) 348 CAx6 9 ( 3%) 0 ( 0%) 0 ( 0%) 340 Tx4 2 ( 1%) 1 ( 0%) 0 ( 0%) 347 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 332

Typhlitis (cecal inflammation) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Vomiting CAx4 13 ( 4%) 0 ( 0%) 0 ( 0%) 348 CAx6 6 ( 2%) 0 ( 0%) 0 ( 0%) 340 Tx4 3 ( 1%) 1 ( 0%) 0 ( 0%) 347 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 332

HEPATOBILIARY/PANC Hepatobiliary/Pancreas - Other (Specify)

CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332


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n (%) n (%) n (%) Pancreatitis CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

INFECTION Febrile neutropenia (fever of unknown origin

CAx4 16 ( 5%) 2 ( 1%) 0 ( 0%) 348

CAx6 17 ( 5%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Infection (documented clinically or microbiol

CAx4 6 ( 2%) 0 ( 0%) 0 ( 0%) 348

CAx6 5 ( 1%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Infection - Other (Specify) CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Infection with unknown ANC CAx4 3 ( 1%) 0 ( 0%) 0 ( 0%) 348 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 2 ( 1%) 0 ( 0%) 0 ( 0%) 332

Infection without neutropenia CAx4 5 ( 1%) 0 ( 0%) 0 ( 0%) 348 CAx6 4 ( 1%) 1 ( 0%) 0 ( 0%) 340 Tx4 3 ( 1%) 0 ( 0%) 0 ( 0%) 347 Tx6 2 ( 1%) 0 ( 0%) 0 ( 0%) 332

METABOLIC/LABORATO ALT SGPT (serum glutamic pyruvic transaminas

CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 3 ( 1%) 0 ( 0%) 0 ( 0%) 347 Tx6 3 ( 1%) 0 ( 0%) 0 ( 0%) 332

AST SGOT(serum glutamic oxaloacetic transami

CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Albumin serum-low (hypoalbuminemia)

CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347


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n (%) n (%) n (%) Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Creatinine CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Glucose serum-high (hyperglycemia) CAx4 3 ( 1%) 0 ( 0%) 0 ( 0%) 348 CAx6 2 ( 1%) 0 ( 0%) 0 ( 0%) 340 Tx4 6 ( 2%) 0 ( 0%) 0 ( 0%) 347 Tx6 10 ( 3%) 1 ( 0%) 0 ( 0%) 332

Lipase CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Potassium serum-low (hypokalemia) CAx4 5 ( 1%) 0 ( 0%) 0 ( 0%) 348 CAx6 3 ( 1%) 0 ( 0%) 0 ( 0%) 340 Tx4 2 ( 1%) 0 ( 0%) 0 ( 0%) 347 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 332

Sodium serum-low (hyponatremia) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 1 ( 0%) 0 ( 0%) 332

MUSCULOSKELETAL/SO Muscle weakness generalized or specific area

CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 0 ( 0%) 1 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Myositis (inflammation/damage of muscle)

CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

NEUROLOGY Arachnoiditis/meningismus/radiculitis CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Ataxia (incoordination) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332


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n (%) n (%) n (%) Dizziness CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Extrapyramidal/involuntary movement/restlessness

CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Mood alteration CAx4 2 ( 1%) 0 ( 0%) 0 ( 0%) 348 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 332

Neuropathy: motor CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 7 ( 2%) 1 ( 0%) 0 ( 0%) 347 Tx6 10 ( 3%) 0 ( 0%) 0 ( 0%) 332

Neuropathy: sensory CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 11 ( 3%) 0 ( 0%) 0 ( 0%) 347 Tx6 33 ( 10%) 0 ( 0%) 0 ( 0%) 332

Syncope (fainting) CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 332

OCULAR/VISUAL Vision-photophobia CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Watery eye (epiphora tearing) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

PAIN Headache CAx4 3 ( 1%) 0 ( 0%) 0 ( 0%) 348

CAx6 2 ( 1%) 1 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 1 ( 0%) 0 ( 0%) 332

Pain CAx4 5 ( 1%) 0 ( 0%) 0 ( 0%) 348 CAx6 6 ( 2%) 0 ( 0%) 0 ( 0%) 340


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n (%) n (%) n (%) Tx4 22 ( 6%) 2 ( 1%) 0 ( 0%) 347 Tx6 23 ( 7%) 4 ( 1%) 0 ( 0%) 332

Pain - Other (Specify) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 2 ( 1%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 2 ( 1%) 0 ( 0%) 0 ( 0%) 332

PULMONARY/UPPER RE Adult Respiratory Distress Syndrome (ARDS)

CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 0 ( 0%) 1 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Dyspnea (shortness of breath) CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 3 ( 1%) 1 ( 0%) 0 ( 0%) 340 Tx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 3 ( 1%) 0 ( 0%) 0 ( 0%) 332

Hypoxia CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 332

Pneumonitis/pulmonary infiltrates CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 2 ( 1%) 1 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Pulmonary/Upper Respiratory - Other (Specify)

CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 0 ( 0%) 1 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

RENAL/GENITOURINAR Dysuria (painful urination) CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Incontinence CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Renal/Genitourinary - Other (Specify) CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347


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n (%) n (%) n (%) Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

Urinary frequency/urgency CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348 CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

SECONDARY MALIGNAN Secondary Malignancy - possibly related to ca

CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 0 ( 0%) 1 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 332

SEXUAL/REPRODUCTIV Irregular menses (change from baseline)

CAx4 1 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 3 ( 1%) 0 ( 0%) 0 ( 0%) 347 Tx6 2 ( 1%) 0 ( 0%) 0 ( 0%) 332

Sexual/Reproductive Function - Other (Specify

CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 0 ( 0%) 0 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 332

VASCULAR Thrombosis/thrombus/embolism CAx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 348

CAx6 1 ( 0%) 1 ( 0%) 0 ( 0%) 340 Tx4 0 ( 0%) 0 ( 0%) 0 ( 0%) 347 Tx6 1 ( 0%) 0 ( 0%) 0 ( 0%) 332

SUMMARY Maximum Non-Hematologic AE CAx4 68 ( 20%) 4 ( 1%) 1 ( 0%) 348

CAx6 82 ( 24%) 10 ( 3%) 1 ( 0%) 340 Tx4 66 ( 19%) 3 ( 1%) 0 ( 0%) 347 Tx6 84 ( 25%) 7 ( 2%) 0 ( 0%) 332

SUMMARY Maximum Overall AE CAx4 73 ( 21%) 75 ( 22%) 1 ( 0%) 348

CAx6 82 ( 24%) 96 ( 28%) 1 ( 0%) 340 Tx4 73 ( 21%) 7 ( 2%) 0 ( 0%) 347 Tx6 87 ( 26%) 11 ( 3%) 0 ( 0%) 332

cyclophosphamide and doxorubicin (ca) (4 vs 6 cycles...

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