Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Bone Density Conservation Agents

All Drugs and Chemicals

Zoledronic Acid

Clodronic Acid

Diphosphonates

Ibandronic Acid

Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years.

Patients receive oral clodronate once daily for 35 months.

Patients receive oral ibandronate once daily for 35 months.

clodronate disodium

ibandronate sodium

zoledronic acid

Julie R. Gralow, MD

Robert B. Livingston, MD

James N. Ingle, MD

Carla I. Falkson, MD

Alexander H Paterson, MD, FRCP

Elizabeth C. Dees, MD

Mark J. Clemons, MD

RATIONALE: Zoledronate, clodronate, or ibandronate may delay or prevent bone metastases in patients with nonmetastatic breast cancer. It is not yet known whether zoledronate is more effective than clodronate or ibandronate in treating breast cancer.

PURPOSE: This randomized phase III trial is studying zoledronate to see how well it works compared to clodronate or ibandronate in treating women who have undergone surgery for stage I, stage II, or stage III breast cancer.

OBJECTIVES:

* Compare disease-free survival and overall survival of women with resected primary stage I-III adenocarcinoma of the breast treated with adjuvant zoledronate vs clodronate vs ibandronate.
* Compare the distributions of sites of first disease recurrence in patients treated with these drugs.
* Compare adverse events in patients treated with these drugs.
* Correlate parathyroid hormone related protein status and N-telopeptide levels at baseline with disease-free survival and sites of first recurrence in patients treated with these drugs.
* Investigate whether there is an association between inherited germ-line single nucleotide polymorphisms (SNP, rs2297480) in farnesyl diphosphate synthase (FDPS) and the adverse event of acute phase reactions in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 3 treatment arms.

* Arm I: Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years.
* Arm II: Patients receive oral clodronate once daily for 35 months.
* Arm III: Patients receive oral ibandronate once daily for 35 months. Treatment in all arms continues in the absence of disease recurrence or unacceptable toxicity.

After completion of study treatment, patients are followed every 6 months until disease recurrence and then annually for up to 10 years.

PROJECTED ACCRUAL: A total of 5,400 will be accrued for this study.

S0307 Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast Cancer.

Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast Cancer

Time from date of registration to date of first observation of recurrence or death due to any cause. Patients last known to be alive who have not experienced recurrence of disease are censored at their last contact date. The outcome for the disease-free survival will be presented as 5 year survival rate.

Time from date of registration to date of death due to any cause. Patients last known to be alive are censored at their last contact date. The outcome for overall survival will be presented as 5 year overall survival rate.

All sites of invasive disease documented within 30 days of first documentation of invasive recurrence.

Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.

National Cancer Institute (NCI)

North Central Cancer Treatment Group

Eastern Cooperative Oncology Group

NSABP Foundation Inc

Cancer and Leukemia Group B

NCIC Clinical Trials Group

SWOG Cancer Research Network

For Adverse Event assessment, we include patients who are eligible and evaluable for adverse events (e.g., received at least one dose of protocol treatment) in the analysis. For all-cause mortality, we include all eligible patients in the analysis.

Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years.

zoledronic acid: Given IV

Arm I Zoledronic Acid

Patients receive oral clodronate once daily for 35 months.

clodronate disodium: Given orally

Arm II Clodronate

Patients receive oral ibandronate once daily for 35 months.

ibandronate sodium: Given orally

Arm III Ibandronate

Arm I Zoledronate

Total

Age, Continuous

Age, Categorized

Age, Customized

Sex: Female, Male

Race (NIH/OMB)

Negative

Nodal Status

Negative (ER-, PR-)

Positive (ER+ or PR+)

ER/PR

HER2 negative

HER2 positive/equivocal

HER2 status

ER+ or PR+, HER2-

ER+ or PR+, HER2+

ER/PR-, HER2- (triple neg)

ER/PR-, HER2+ (triple neg)

Breast disease subtype

Stage I

Stage II

Stage III

Staging criterial is per AJCC 6th Edition, 2002. Higher staging means worse disease.

Stage

Not given or planned

Given or planned

Chemotherapy

Hormonal Therapy

Only eligible patients are included in the analysis.

SWOG statistician

Only eligible patients will be included in the analysis.

Disease-free Survival

Overall Survival

Statistical analysis for recurrence to bone

Local/Regional only

Contralateral only

Distant recurrence

Unknown location of recurrence

Bone as 1st site of distant recurrence

Bone only

Bone and nodes only

Bone and other distant sites (beside nodes)

Liver/lung/other visceral without bone recurrence

Brain/other CNS (+/- any other site)

Distributions of Sites of First Recurrence on the Three Arms.

ALT, SGPT (serum glutamic pyruvic transaminase)

AST, SGOT

Alkaline phosphatase

Allergic reaction/hypersensitivity

Anorexia

Arthritis (non-septic)

Auditory/Ear-Other (Specify)

Bilirubin (hyperbilirubinemia)

Blood/Bone Marrow-Other (Specify)

CNS cerebrovascular ischemia

Calcium, serum-low (hypocalcemia)

Cardiac General-Other (Specify)

Confusion

Constipation

Creatinine

Dehydration

Dental: periodontal disease

Dental: teeth

Diarrhea

Distention/bloating, abdominal

Dizziness

Dysphagia (difficulty swallowing)

Dyspnea (shortness of breath)

Edema: limb

Endocrine-Other (Specify)

Esophagitis

Extremity-upper (function)

Fatigue (asthenia, lethargy, malaise)

Febrile neutropenia

Fever in absence of neutropenia, ANC lt1.0x10e9/L

Flu-like syndrome

Fracture

Gastritis (including bile reflux gastritis)

Glucose, serum-high (hyperglycemia)

Heartburn/dyspepsia

Hemoglobin

Hemorrhage, GI - Rectum

Hemorrhage, GI - Stomach

Hot flashes/flushes

Hypertension

Hypotension

INR (of prothrombin time)

Incontinence, urinary

Inf (clin/microbio) w/Gr 3-4 neuts - Skin

Inf (clin/microbio) w/Gr 3-4 neuts - Soft tissue

Inf w/normal ANC or Gr 1-2 neutrophils - Bone

Inf w/normal ANC or Gr 1-2 neutrophils - Bronchus

Inf w/normal ANC or Gr 1-2 neutrophils - Dental

Infection with unknown ANC - Appendix

Infection with unknown ANC - Liver

Infection with unknown ANC - Skin (cellulitis)

Insomnia

Irregular menses (change from baseline)

Irritability (children lt3 years of age)

Joint-function

Left ventricular systolic dysfunction

Leukocytes (total WBC)

Lymphopenia

Magnesium, serum-high (hypermagnesemia)

Magnesium, serum-low (hypomagnesemia)

Masculinization of female

Memory impairment

Metabolic/Laboratory-Other (Specify)

Mood alteration - anxiety

Mood alteration - depression

Mood alteration - euphoria

Mucositis/stomatitis (clinical exam) - Oral cavity

Muscle weakness, not d/t neuropathy - Extrem-lower

Muscle weakness, not d/t neuropathy - Extrem-upper

Muscle weakness, not d/t neuropathy - body/general

Nausea

Neuropathy: motor

Neuropathy: sensory

Neutrophils/granulocytes (ANC/AGC)

Obesity

Opportunistic inf associated w/gt=Gr 2 lymphopenia

Osteonecrosis (avascular necrosis)

Pain - Abdomen NOS

Pain - Back

Pain - Bone

Pain - Chest wall

Pain - Chest/thorax NOS

Pain - Extremity-limb

Pain - Head/headache

Pain - Joint

Pain - Muscle

Pain - Neck

Pain - Neuralgia/peripheral nerve

Pain - Oral cavity

Pain - Pain NOS

Pain - Stomach

Pain - Throat/pharynx/larynx

Pain - Vagina

Pain-Other (Specify)

Pancreatitis

Perforation, GI - Duodenum

Phosphate, serum-low (hypophosphatemia)

Platelets

Potassium, serum-high (hyperkalemia)

Potassium, serum-low (hypokalemia)

Arm III Ibandronate

Patients receive oral ibandronate once daily for 35 months.

ibandronate sodium: Given orally

Patients who received at least one dose of protocol treatment.

Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
S0307 Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast Cancer.	NCT00127205	Breast Cancer	clodronate diso... ibandronate sod... zoledronic acid	18 Years -	SWOG Cancer Research Network
S0307A, Long-Term Bone Quality in Women With Breast Cancer Enrolled on Clinical Trial SWOG-S0307	NCT00873808	Breast Cancer	clodronate diso... demeclocycline ... ibandronate sod... tetracycline hy... zoledronic acid laboratory biom... adjuvant therap... computed tomogr... dual x-ray abso...	18 Years -	SWOG Cancer Research Network

Spots Global Cancer Trial Database for clodronate disodium