Clinical trial NCT00127205
Conditions: Breast Cancer
Keywords: stage I breast cancer stage II breast cancer stage IIIA breast cancer stage IIIB breast cancer stage IIIC breast cancer
Sponsor: SWOG Cancer Research Network
Start date: 2005-07-01; Completion date: 2021-03-29
Enrollment: 6097 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years. arm 2: Patients receive oral clodronate once daily for 35 months. arm 3: Patients receive oral ibandronate once daily for 35 months.
Interventions: intervention 1: clodronate disodium intervention 2: ibandronate sodium intervention 3: zoledronic acid
Intervention descriptions: intervention 1: Given orally intervention 2: Given orally intervention 3: Given IV

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
 
 
 
 
July 1, 2015 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (   ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
 
Reports: 
 
Dec. 8, 2014 
AE #2014179081 
May 26, 2015 
AE #2015262623 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
William E. Barlow, Ph.D. 
Yingkai Cheng – Bayer Healthcare 
 
Danika Lew, M.A. 
NCI Coop Coverage – Genentech 
 
Jean Barce 
Selin Hall – Genentech 
 
Jennie Barrett 
Margaret Sykes – Genentech 
 
Larry Kaye 
Carole Wishneski – Genentech 
 
Iris Syquia 
Jenna Marsano – Novartis 
 
 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
 
 
 
Distribution Date: 
February 1, 2015 
CTEP Submission Date:   
December 19, 2014 
 
 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
 
 
FROM: 
Megan M. Hardin, Protocol Coordinator (E-mail:  mhardin@swog.org) 
 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Chairs:  Drs. J. Gralow and R. Livingston. 
 
REVISION #12 
 
Study Chair:  Julie Gralow, M.D. 
Phone number:  206/288-7722 
E-mail:  pink@u.washington.edu 
 
IRB Review Requirements 
 
 (   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(   ) 
Expedited review allowed 
 
( √ ) 
No review required 
 
 
REVISION #12 
 
The protocol referenced above has been revised as follows: 
 
1. 
Pages 1 and 3, Title Page:  The version date has been updated.  The participant 
list has been moved from Page 1 to Page 3 and revised to be consistent with the 
new NCTN/CTSU guidelines. 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
 


 
 
 
 
 
 
July 15, 2014 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Report for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (   ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety report has been posted regarding an adverse event that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access this safety report via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
This safety report pertains to the following 
study: 
 
 
S0307 Breast 
 
Report: 
 
June 21, 2014 AE #2014076996 FU 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
William E. Barlow, Ph.D. 
Flavio Ewerton – Bayer Healthcare 
 
Danika Lew, M.A. 
NCI Coop Coverage – Genentech 
 
Jean Barce 
Margaret Sykes – Genentech 
 
Jennie Barrett 
Carole Wishneski – Genentech 
 
Larry Kaye 
Jenna Marsano – Novartis 
 
Iris Syquia 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
July 1, 2014 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (   ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
June 17, 2014 AE #2013037506 FU 
June 17, 2014 AE #2014087122 
June 18, 2014
AE #2014076996 FU
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
William E. Barlow, Ph.D. 
Silke Thiele – Bayer Healthcare 
 
Danika Lew, M.A. 
NCI Coop Coverage – Genentech 
 
Jean Barce 
Margaret Sykes – Genentech 
 
Jennie Barrett 
Carole Wishneski – Genentech 
 
Larry Kaye 
Jenna Marsano – Novartis 
 
Iris Syquia 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
June 15, 2014 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Report for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (   ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety report has been posted regarding an adverse event that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access this safety report via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
This safety report pertains to the following study: 
 
 
S0307 Breast 
Report: 
 
May 27, 2014 
AE #2014076996 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Syquia 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
NCI Coop – Genentech 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Larry Kaye 
Michelle Dubois – UVI, Inc. 
 


 
 
 
 
 
 
Distribution Date: 
May 1, 2014 
CTEP Submission Date:   
March 28.2014 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS, AND PATHOLOGISTS; CTSU.  Patient enrollments from 
institutions that are not aligned with SWOG will be conducted via the 
NCI Cancer Trials Support Unit (CTSU) and all data should be sent to 
the SWOG Data Operations as specified in the CTSU logistical 
appendix (See Section 19.1). 
 
FROM: 
Megan M. Hardin, Protocol Coordinator (E-mail:  mhardin@swog.org) 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Chairs:  Drs. J. Gralow and R. Livingston. 
 
REVISION #11 
 
Study Chair:  Julie Gralow, M.D. 
Phone number:  206/288-7722 
E-mail:  pink@u.washington.edu 
 
IRB Review Requirements 
 
 (   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(   ) 
Expedited review allowed 
 
( √ ) 
No review required 
 
 
REVISION #11 
 
The protocol referenced above has been revised as follows: 
 
1. 
Title Page:  The version date has been updated.  The version date has also been 
added to each page of the Model Consent Form (Pages 51-67). 
 
2. 
Page 31a, Section 8.7:  References to the Adverse Event Expedited Reporting 
System (AdEERS) have been changed to CTEP Adverse Event Reporting 
System (CTEP-AERS) in this section and throughout the protocol [Section 16.1 
(Pages 42-45a) and Appendix 19.1 (Page 86)].  Associated url’s have been 
updated on these pages as well. 
 
Please attach this memorandum to the front of your copy of the protocol.   
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
NOTE:  This study remains permanently closed. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
William E. Barlow, Ph.D. 
Jenna Marsano– Novartis  
Danika Lew, M.A. 
Selin Hall - Genentech 
Jean Barce 
Keiko Nakajima, M.D. – Bayer Healthcare 
Iris Syquia 
Silke Thiele – Bayer Healthcare 
Jennie Barrett 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
September 1, 2013 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Report for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (   ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety report has been posted regarding an adverse event that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access this safety report via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
This safety report pertains to the following 
study: 
 
 
S0307 Breast 
 
Report: 
 
Aug. 15, 2013 AE #2013098005 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Syquia 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
Clinical Operations – Genentech 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Larry Kaye 
Michelle Dubois – UVI, Inc. 
 


 
 
 
 
 
August 15, 2013 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (   ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
 
Reports: 
 
July 29, 2013 
AE #2013091230 
July 29, 2013 
AE #2013091248 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Syquia 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
Clinical Operations – Genentech 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Larry Kaye 
Michelle Dubois – UVI, Inc. 
 


 
 
 
 
 
 
June 15, 2013 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (   ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Feb. 4, 2013 
AE #2012122211(3) FU 
Mar. 18, 2013 AE #2013031381 
Mar. 28, 2013 AE #2013037506 
Apr. 5, 2013 
AE #2013031381(1) FU 
May 29, 2013
AE #2013066106
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Syquia 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
Clinical Operations – Genentech 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Nicole Castillo 
Michelle Dubois – UVI, Inc. 
 
Larry Kaye 


 
 
 
 
 
 
January 15, 2013 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
 
Reports: 
 
Dec. 11, 2012 AE #2012130075 
Dec. 14, 2012 AE #2012114410 FU 
Dec. 18, 2012 AE #2012122211 FU 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Syquia 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
Clinical Operations – Genentech 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Nicole Castillo 
Michelle Dubois – UVI, Inc. 
 
Larry Kaye 


 
 
 
 
 
 
December 1, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
 
S0307 Breast 
Reports: 
 
Nov. 16, 2012 AE #2012118376 
Nov. 23, 2012 AE #2012122211 
Nov. 23, 2012 AE #2012122249 
Nov. 26, 2012 AE #2012123754 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Syquia 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
Clinical Operations – Genentech 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Nicole Castillo 
Michelle Dubois – UVI, Inc. 
 
Larry Kaye 


 
 
 
 
 
 
November 15, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
 
S0307 Breast 
Reports: 
 
Oct. 29, 2012 AE #2012022802 FU 
Nov. 2, 2012 AE #2012114410 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Syquia 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
Selin Hall – Genentech 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Nicole Castillo 
Michelle Dubois – UVI, Inc. 
 
Larry Kaye 


 
 
 
 
 
 
October 1, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
 
Reports: 
 
Aug. 30, 2012 AE #2012089597 
Sep. 4, 2012 AE #2012091067 
Sep. 4, 2012 AE #2012090774 
Sep. 6, 2012 AE #2011057639 FU 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Syquia 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
Selin Hall – Genentech 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 
 
Larry Kaye 


 
 
 
 
 
 
September 15, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Aug. 30, 2012 AE #2012089597 
Sep. 4, 2012 AE #2012091067 
Sep. 4, 2012 AE #2012090774 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
September 1, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Aug. 7, 2012 AE #2012079512 
Aug. 10, 2012 AE #2012080442 
 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
 
 
Distribution Date: 
June 15, 2012 
CTEP Submission Date:   
May 29, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS, AND PATHOLOGISTS; CTSU.  Patient enrollments from 
institutions that are not aligned with SWOG will be conducted via the NCI 
Cancer Trials Support Unit (CTSU) and all data should be sent to the SWOG 
Data Operations as specified in the CTSU logistical appendix (See Section 
19.1). 
 
FROM: 
Megan M. Hardin, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
REVISION #10 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone number:  206/288-7722 
E-mail:  pink@u.washington.edu 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) 
Expedited review allowed 
 
(    ) 
No review required 
 
 
REVISION #10 
 
Institutions do not need to update their local consent forms to include the changes to the 
Model Consent Form unless required by the local Institutional Review Board (IRB).  
 
Patients currently receiving and patients who have completed treatment with zoledronic 
acid (Zometa®) need not be informed of these changes unless required by the local 
Institutional Review Board (IRB).  
 
The protocol referenced above has been amended as follows: 
 
1. 
Title Page:  The version date has been updated 
 
2. 
Page 16a, Section 3.1g.3b:  The contact information for Kristen White at Novartis 
Pharmaceuticals has been replaced with a reference to the S0307 abstract page 
of the SWOG website, which is where the contact information is now located. 


 
S0307 
 
Revision #10 (contd.) 
 
Page 2 
 
 
 
3. 
Page 58, Model Consent Form, What side effects or risks can I expect from 
being in the study?:  Under the "Rare but Serious" section of risks for zoledronic 
acid, “atypical bone fractures” has been added.   
 
Please attach this memorandum to the front of your copy of the protocol.   
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
NOTE:  This study remains permanently closed. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
William E. Barlow, Ph.D. 
 
Danika Lew, M.A. 
 
Jean Barce 
 
Iris Syquia 
 
Jennie Barrett 
Jeri Jardine 
Jenna Marsano– Novartis  
Selin Hall - Genentech 
Keiko Nakajima, M.D. – Bayer Healthcare 
Silke Thiele – Bayer Healthcare 
Michelle Dubois – UVI, Inc. 
 
 


 
 
 
 
 
 
June 1, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Report for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety report has been posted regarding an adverse event that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access this safety report via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
This safety report pertains to the following study: 
 
 
S0307 Breast 
Report: 
 
May 7, 2012 
AE #2012042926 
 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
May 15, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Apr. 5, 2012 
AE #2012032297 
Apr. 24, 2012 AE #2012039215 
Apr. 27, 2012 AE #2012032297 FU 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
 
May 1, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS, AND PATHOLOGISTS; CTSU.  Patient enrollments from 
institutions that are not aligned with SWOG will be conducted via the NCI 
Cancer Trials Support Unit (CTSU) and all data should be sent to the SWOG 
Data Operations as specified in the CTSU logistical appendix (See Section 
19.1). 
 
FROM: 
Megan M. Hardin, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone number:  206/288-7722 
E-mail:  pink@u.washington.edu 
 
IRB Review Requirements 
 
 (   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (   ) 
Expedited review allowed 
 
( √ ) 
No review required 
 
 
MEMORANDUM 
 
The purpose of this memorandum is to remind sites that an incremental payment of 
$496.00 was awarded to help offset the cost of the end of study bone scan, Month 2, 3, 5 
and 6 creatinine blood draws, specimen collection and specimen submission.  The funds 
have been automatically distributed from SWOG-CTI based on accrual.  This information 
can be found on the S0307 funding memo which can be accessed from the S0307 
abstract page on the SWOG website (www.swog.org).               
 
Please contact Kati Stoermer at Laszlo@med.umich.edu with any questions or 
concerns.   
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
NOTE:  This study remains permanently closed. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
William E. Barlow, Ph.D. 
Jenna Marsano– Novartis  
Danika Lew, M.A. 
Selin Hall - Genentech 
Jean Barce 
Keiko Nakajima, M.D. – Bayer Healthcare 
Iris Syquia 
Silke Thiele – Bayer Healthcare 
Jennie Barrett 
Michelle Dubois – UVI, Inc. 
Larry Kaye 


 
 
 
 
 
 
May 1, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Mar. 20, 2012 AE #2012022802 FU 
Mar. 28, 2012 AE #2012009073 FU 
Mar. 28, 2012 AE #2012029657 
Mar. 29, 2012 AE #201030788NA FU 
Apr. 5, 2012 
AE #2010001740 FU 
Apr. 5, 2012 
AE #2012033102 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
April 1, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Feb. 28, 2012 AE #2012019312 
Mar. 6, 2012 AE #2012021567 
Mar. 9, 2012 AE #2012022802 FU 
 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
March 15, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Report for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(   ) 
No review required 
 
 
MEMORANDUM 
 
The following new safety report has been posted regarding an adverse event that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access this safety report via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
This safety report pertains to the following 
study: 
 
 
S0307 Breast 
Report: 
 
 
Feb. 16, 2012 AE #2012009073 FU 
 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
February 15, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
 
Jan. 23, 2012 AE #200935806NA FU 
Jan. 24, 2012 AE 201030788NA FU 
Jan. 24, 2012 AE #2011123505 FU 
Jan. 31, 2012 AE #2012009073 
 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
January 15, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via study’s abstract page or the safety report link on 
the SWOG website https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Dec. 28, 2011 AE #2011123505 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
January 1, 2012 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Nov. 29, 2011 AE #2011112939 FU 
Nov. 30, 2011 AE #2011105692 FU 
Dec. 1, 2011 AE #2011114944 
Dec. 15, 2011 AE #2011034189 FU 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
 
 
 
December 15, 2011 
 
 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS, AND PATHOLOGISTS; CTSU.  Patient enrollments from 
institutions that are not aligned with SWOG will be conducted via the NCI 
Cancer Trials Support Unit (CTSU) and all data should be sent to the SWOG 
Data Operations as specified in the CTSU logistical appendix (See Section 
19.1). 
 
 
FROM: 
Megan M. Wardeski, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone number:  206/288-7722 
E-mail:  pink@u.washington.edu 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(   ) 
Expedited review allowed 
 
( √ ) 
No review required 
 
 
MEMORANDUM 
 
The purpose of this memorandum is to inform sites of the holiday shipment schedule for 
Uintavision, Inc. (UVI).  UVI will not ship drug on the following days:  
 
Monday, December 26, 2011 
Monday, January 2, 2012 
 
UVI will be open December 26 and January 2 to provide customer assistance but will not 
have shipment capabilities.  Any submitted non-refrigerated orders will be processed 
Friday, December 23 and Friday, December 30, 2011.  Please note that if a site needs 
refrigerated goods during this time, those orders should be placed by Thursday, 
December 22 and Thursday, December 29.   
 


 
S0307 
 
Memorandum (contd.) 
 
Page 2 
 
 
 
Please contact Michelle Dubois at 800/370-2508 me with any questions or concerns.   
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
NOTE:  This study remains permanently closed. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
William E. Barlow, Ph.D. 
 
Danika Lew, M.A. 
 
Jean Barce 
 
Iris Syquia 
 
Jennie Barrett 
Jeri Jardine 
Jenna Marsano– Novartis  
Selin Hall - Genentech 
Keiko Nakajima, M.D. – Bayer Healthcare 
Silke Thiele – Bayer Healthcare 
Michelle Dubois – UVI, Inc. 
 
 


 
 
 
 
 
 
December 15, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Nov. 21, 2011 AE #2011109917 FU 
Nov. 24, 2011 AE #2011112939 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
December 1, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Oct. 26, 2011 AE #201017651NA FU 
Oct. 26, 2011 AE #2011029627 FU 
Oct. 31, 2011 AE #2011104922 
Oct. 31, 2011 AE #2011104959 
Nov. 4, 2011 AE #2011105692 
Nov. 16, 2011 AE #2011104922 FU 
Nov. 16, 2011 AE #2011109917 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
November 15, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Oct. 21, 2011 
AE #2011081397 FU 
Oct. 21, 2011 
AE #2011099069 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
November 1, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Report for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety report has been posted regarding an adverse event that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access this safety report via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
This safety report pertains to the following 
study: 
 
 
S0307 Breast 
Report: 
 
Oct. 4, 2011 
AE #2011061835 FU 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
 
 
Distribution Date: 
November 1, 2011 
CTEP Submission Date:   
October 11, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS, AND PATHOLOGISTS; CTSU.  Patient enrollments from 
institutions that are not aligned with SWOG will be conducted via the NCI 
Cancer Trials Support Unit (CTSU) and all data should be sent to the SWOG 
Data Operations as specified in the CTSU logistical appendix (See Section 
19.1). 
 
FROM: 
Megan M. Wardeski, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
REVISION #9 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone number:  206/288-7722 
E-mail:  pink@u.washington.edu 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) 
Expedited review allowed 
 
(    ) 
No review required 
 
 
REVISION #9 
 
Institutions should update their local consent forms to include the changes to the Model 
Consent Form. 
 
SWOG considers that the Model Consent Form changes do not represent an alteration 
in risk-benefit ratio.  Therefore, local accrual does not need to be suspended pending 
implementation of these changes.   
 
Patients currently receiving zoledronic acid (Zometa®) need not be informed of these 
changes unless required by the local Institutional Review Board (IRB).  
 
 


 
S0307 
 
Revision #9 (contd.) 
 
Page 2 
 
 
 
The protocol referenced above has been amended as follows: 
 
1. 
Title Page:  The version date has been updated.  “Southwest Oncology Group” 
has been updated to “SWOG” above the title and in the participant’s list. 
 
2. 
Pages 14-16b, Section 3.1:  The drug information for Zoledronic Acid has been 
updated.  Therefore this section has been replaced with new standard language. 
Page 16b was added to prevent extensive repagination. 
 
3. 
Page 32, Section 9.0:  The “δ” footnote has been added to the “End of 
Treatment” column in the “Bone scan or roentgenological exam” row.  The 
footnote reads, “Only a bone scan is acceptable at End of Treatment (see 
Section 7.10).” 
 
4. 
Page 57, Model Consent Form, What side effects or risks can I expect from 
being in the study?:  Under the "Likely" section of risks for zoledronic acid, 
“fatigue or tiredness” has been added.  This risk was added to the “Less Likely” 
section in Revision #8.  However, it should have been added to the “Likely” 
section.  “Fever” was added to the “Less Likely” section in Revision #8.  Because 
it was already correctly located in the “Likely” section, it has been removed from 
the “Less Likely” section. 
 
Please attach this memorandum to the front of your copy of the protocol.   
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
NOTE:  This study remains permanently closed. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
William E. Barlow, Ph.D. 
 
Danika Lew, M.A. 
 
Jean Barce 
 
Iris Syquia 
 
Jennie Barrett 
Jeri Jardine 
Jenna Marsano– Novartis  
Selin Hall - Genentech 
Keiko Nakajima, M.D. – Bayer Healthcare 
Silke Thiele – Bayer Healthcare 
Michelle Dubois – UVI, Inc. 
 
 


 
 
 
 
 
 
September 15, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the 
following study: 
 
 
S0307 Breast 
Reports: 
 
Aug. 18, 2011 AE #2011061835 FU 
Aug. 19, 2011 AE #2011028903 
Aug. 23, 2011 AE #2010002638 FU 
Aug. 24, 2011 AE #2011029627 
Aug. 24, 2011 AE #2011017224 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
September 1, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
 (     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the 
following study: 
 
 
S0307 Breast 
Reports: 
 
July 26, 2011 
AE #2011033511 FU 
July 27, 2011 
AE #2011061835 
July 27, 2011 
AE #2011062225 
July 29, 2011 
AE #2011048943 FU 
Aug. 1, 2011 
AE #2011063879 
Aug. 3, 2011 
AE #200928049NA FU 
Aug. 3, 2011 
AE #201030788NA FU 
Aug. 3, 2011 
AE #2011067170 
Aug. 10, 2011 AE #2011033511 FU 
Aug. 12, 2011 AE #2011067170 FU 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
 
 
Distribution Date: 
September 1, 2011 
E-mailed Date:   
August 23, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS, AND PATHOLOGISTS; CTSU.  Patient enrollments from 
institutions that are not aligned with SWOG will be conducted via the NCI 
Cancer Trials Support Unit (CTSU) and all data should be sent to the SWOG 
Data Operations as specified in the CTSU logistical appendix (See Section 
19.1). 
 
FROM: 
Megan M. Wardeski, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone number:  206/288-7722 
E-mail:  pink@u.washington.edu 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(   ) 
Expedited review allowed 
 
( √ ) 
No review required 
 
 
MEMORANDUM 
 
The August 15, 2011 safety report memo has been withdrawn.  The reports were 
distributed in error and please disregard. 
 
Please attach this memorandum to the front of your copy of the protocol.   
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
NOTE:  This study remains permanently closed. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
William E. Barlow, Ph.D. 
Larry Kaye 
Danika Lew, M.A. 
Jenna Marsano– Novartis  
Jean Barce 
Keiko Nakajima, M.D. – Bayer Healthcare 
Iris Syquia 
Silke Thiele – Bayer Healthcare 
Jennie Barrett 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
August 1, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the 
following study: 
 
 
S0307 Breast 
Reports: 
 
July 12, 2011 
AE #2011056748 
July 12, 2011 
AE #2011057639 
July 13, 2011 
AE #2011058737 
July 14, 2011 
AE #2011044227 FU 
July 15, 2011 
AE #2011060302 
July 18, 2011 
AE #2011057605 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 


 
 
 
 
 
 
July 15, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the 
following study: 
 
 
S0307 Breast 
Reports: 
 
July 4, 2011 
AE #201020451NA FU 
July 4, 2011 
AE #2011017730 FU 
July 4, 2011 
AE #2011037975 FU 
July 6, 2011 
AE #2011054922 
July 8, 2011 
AE #2011017125 FU 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 
 


 
 
 
 
 
 
July 1, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
June 14, 2011 AE #2011048943 
June 15, 2011 AE #2011048213 
June 22, 2011 AE #2011048213 FU 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 
 


 
 
 
 
 
 
June 15, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
May 27, 2011 AE #2011041929 
May 30, 2011 AE #2011026058 FU 
June 7, 2011 AE #2011026058 FU 
June 9, 2011 AE #2011044227 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Larry Kaye 
 
William E. Barlow, Ph.D. 
Iris Syquia 
 
Danika Lew, M.A. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Jean Barce 
Silke Thiele – Bayer Healthcare 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 
 


 
 
 
 
 
 
 
 
Distribution Date: 
June 1, 2011 
CTEP Submission Date:   
April 21, 2011 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  
Patient enrollments from institutions that are not aligned with SWOG will 
be conducted via the NCI Cancer Trials Support Unit (CTSU) and all data 
should be sent to the SWOG Data Operations as specified in the CTSU 
logistical appendix (See Section 19.1). 
 
FROM: 
Megan M. Wardeski, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
REVISION #8 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone number:  206/288-7722 
E-mail:  pink@u.washington.edu 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign  
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) 
Expedited review allowed 
 
(    ) 
No review required 
 
 
REVISION #8 
 
Institutions must update their local consent forms to include the changes to the Model 
Consent Form. 
 
SWOG considers that the Model Consent Form changes do not represent an alteration 
in risk-benefit ratio.  Therefore, local accrual does not need to be suspended pending 
implementation of these changes.   
 
Patients currently receiving zoledronic acid (Zometa®) must be informed of these 
changes.  The manner by which this notification takes place is at the discretion of the 
local institution.  At a minimum, the patients must be notified at the next visit and this 
notification process must be documented in the patient chart.   
 
 


 
S0307 
 
Revision #8 (contd.) 
 
Page 2 
 
 
 
The protocol referenced above has been amended as follows: 
 
1. 
Title Page:  The version date has been updated. 
 
2. 
Page 15, Section 3.1b, Toxicology Background:  The zoledronic acid (Zometa®) 
drug information section has been updated to be consistent with the most recent 
zoledronic acid package insert.  The labeling changes in the toxicology section 
include pyrexia, asthenia, fatigue and malaise persisting for greater than 30 days.  
These have been added to this section respectively. 
 
3. 
Page 16, Section 3.1c:  This section has been updated to include new standard 
language for drug returns and drug accountability.  This change has also been 
made to Section 3.2c (Page 19) and Section 3.3c (Page 22).  Handling/Disposal 
information referencing consideration of OSHA procedures has been removed 
from Sections 3.2c and 3.3c.  Pages 16a and 22a were added to prevent 
extensive repagination. Information in Section 3.2c (Drug Accountability) has 
been reworded for clarity. 
 
4. 
Page 29, Section 7.3:  The following definition of monthly has been added to this 
section:  If treatment begins on the first of the month, then the subsequent doses 
are given on the first of each month thereafter. 
 
5. 
Page 31, Section 7.12:  The length of time for delay of protocol treatment has 
been changed from greater than 4 weeks to greater than 3 months to allow more 
flexibility.  This change has also been made to Section 8.4 (Page 31a). 
 
6. 
Page 31a, Section 8.7:  This section has been updated to include new standard 
language for AE reporting.  Unexpected or fatal toxicities has been replaced with 
toxicities that meet the expedited reporting criteria.  The remainder of the section 
has been reworded for clarity but the content was not affected. 
 
7. 
Page 32, Section 9.0:  Study Calendar:  A reference to Section 7.3 for the 
definition of monthly has been added to the "Ω" footnote. 
 
8. 
Page 42, Section 16.0:  This section has been updated to reflect new standard 
language for drug accountability.  Specific accountability language has been 
removed and this section now refers sites to the Code of Federal Regulations 21 
CFR 312 for procedures and requirements of drug accountability. 
 
9. 
Page 45a, Section 16.1h:  The guidelines for reporting secondary AML/ALL/MDS 
have been updated to the most current NCI guidelines which require 
second/secondary AML/ALL/MDS to be reported via AdEERS instead of the 
NCI/CTEP Secondary AML/ALL/MDS Report Form.  Instructions for reporting in 
CTCAE Version 3.0 and Version 4.0 have been included separately. 
 
10. 
Page 57, Model Consent Form, What side effects or risks can I expect from 
being in the study?:  Under the "Less Likely" section of risks for zoledronic acid, 
the following new risks have been added as provided by the FDA MedWatch 
Safety program: 
 
• 
Fever 
• 
Fatigue or tiredness 
 
Please attach this memorandum to the front of your copy of the protocol.   
 


 
S0307 
 
Revision #8 (contd.) 
 
Page 3 
 
 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
NOTE:  This study remains permanently closed. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
William E. Barlow, Ph.D. 
 
Danika Lew, M.A. 
 
Jean Barce 
 
Iris Syquia 
 
Jennie Barrett 
Jeri Jardine 
Jenna Marsano– Novartis  
Selin Hall - Genentech 
Keiko Nakajima, M.D. – Bayer Healthcare 
Silke Thiele – Bayer Healthcare 
Michelle Dubois – UVI, Inc. 
 
 


 
 
 
 
 
 
June 1, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
May 11, 2011 AE #2011038309 
May 14, 2011 AE #2011038733 
May 18, 2011 AE #2011041572 
May 19, 2011 AE #2011040272 
May 21, 2011 AE #2011038069 FU 
May 21, 2011 AE #2011038309 FU 
May 21, 2011 AE #2011039087 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Syquia 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
Selin Hall – Genentech 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 
 
Larry Kaye 
 


 
 
 
 
 
 
May 15, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Apr. 28, 2011 AE #2011033463 
Apr. 29, 2011 AE #2011035555 
May 2, 2011 
AE #2011034683 
May 2, 2011 
AE #2011036333 
May 4, 2011 
AE #2011034494 
May 4, 2011 
AE #2011037975 
May 5, 2011 
AE #2011035321 
May 9, 2011 
AE #2011033511 FU 
May 9, 2011 
AE #2011038069 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Syquia 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
Selin Hall – Genentech 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 
 
Larry Kaye 
 


 
 
 
 
 
 
May 1, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following new safety reports have been posted regarding adverse events that 
occurred in association with the drug Bonefos® (clodronate disodium tetrahydrate). 
Please access these safety reports via the safety report link in the member section of the 
SWOG website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Apr. 11, 2011 AE #2011026058 
Apr. 11, 2011 AE #2011026058 FU 
Apr. 21, 2011 AE #2011033462 
Apr. 25, 2011 AE #2011034189 
Apr. 28, 2011 AE #2011033511 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Syquia 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
Selin Hall – Genentech 
 
Jennie Barrett 
Jenna Marsano – Novartis 
 
Jeri Jardine 
Michelle Dubois – UVI, Inc. 
 
Larry Kaye 
 


 
 
 
 
 
 
April 1, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in 
association with the drug Bonefos® (clodronate disodium tetrahydrate).  Please access 
these safety reports via the safety report link in the member section of the SWOG 
website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Mar. 14, 2011 AE #2011011929* 
Mar. 15, 2011 AE #2011020038 
Mar. 15, 2011 AE #2011020044 
Mar. 15, 2011 AE #2011020045 
Mar. 17, 2011 AE #2011020656 
* 
The initial report for this AE dated February 21, 2011 was circulated to sites in both the 
March 1, 2011 and March 15, 2011 SWOG distributions. Please disregard the second 
notification. 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
William E. Barlow, Ph.D. 
Silke Thiele – Bayer Healthcare 
 
Danika Lew, M.A. 
Selin Hall – Genentech 
 
Jean Barce 
Jenna Marsano – Novartis 
 
Jennie Barrett 
Michelle Dubois – UVI, Inc. 
Jeri Jardine 
 
Iris Syquia 


 
 
 
 
 
 
 
March 15, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in 
association with the drug Bonefos® (clodronate disodium tetrahydrate).  Please access 
these safety reports via the safety report link in the member section of the SWOG 
website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Feb. 21, 2011 AE #2011011929 
Feb. 24, 2011 AE #2011014149 
Feb. 24, 2011 AE #2011017125 
Mar. 1, 2011 AE #2011015886 
Mar. 7, 2011 AE #2011017125 
Mar. 8, 2011 AE #2011017730 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
William E. Barlow, Ph.D. 
Silke Thiele – Bayer Healthcare 
 
Danika Lew, M.A. 
Selin Hall – Genentech 
 
Jean Barce 
Jenna Marsano – Novartis 
 
Jennie Barrett 
Michelle Dubois – UVI, Inc. 
Jeri Jardine 
 
Iris Syquia 


 
 
 
 
 
 
 
March 1, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in 
association with the drug Bonefos® (clodronate disodium tetrahydrate).  Please access 
these safety reports via the safety report link in the member section of the Southwest 
Oncology Group website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Feb. 7, 2011 AE #2011009105 
Feb. 8, 2011 AE #2011011544 
Feb. 11, 2011 AE #2011011544 
Feb. 16, 2011 AE #2011011928 
Feb. 21, 2011 AE #2011011929 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
William E. Barlow, Ph.D. 
Silke Thiele – Bayer Healthcare 
 
Danika Lew, M.A. 
Selin Hall – Genentech 
 
Jean Barce 
Lixian Jin – Novartis 
 
Jennie Barrett 
Michelle Dubois – UVI, Inc. 
Jeri Jardine 
 
Iris Syquia 


 
 
 
 
 
 
 
Distribution Date: 
February 15, 2011 
CTEP Submission Date: 
February 1, 2011 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  
Patient enrollments from institutions that are not aligned with SWOG will 
be conducted via the NCI Cancer Trials Support Unit (CTSU) and all data 
should be sent to the SWOG Data Operations as specified in the CTSU 
logistical appendix (See Section 19.1). 
 
FROM: 
Megan M. Wardeski, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
Attached here is a Dear Doctor Letter which addresses the recent presentation of the 
AZURE clinical trial findings presented at the 33rd Annual San Antonio Breast Cancer 
Symposium and their implications on S0307.  SWOG is not mandating that any 
information be conveyed to patients at this time.  Investigators may choose to discuss 
these issues with their patients at their own discretion and subject to the guidance of their 
local IRB. 
 
This protocol remains permanently closed to accrual. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: PROTOCOL & INFORMATION OFFICE Jennie Barrett 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
Michael Dubois – UVI, Inc. 
 
Iris Buchanan   
Lixian Jin - Novartis 
 
Jeri Jardine   
Selin Hall - Genentech 
 
 


 
 
 
 
 
 
 
 
Date: 
February 2, 2011 
 
To: 
Investigators participating in the SWOG clinical trial S0307 
 
From: Julie Gralow, M.D. on behalf of SWOG 
 
 
This letter addresses the recent presentation of the AZURE clinical trial findings 
presented at the San Antonio Breast Cancer Symposium in December (Coleman RE et 
al, abstract S4-5) and the implications regarding S0307. The co-PIs of the S0307 trial met 
at San Antonio to review the safety data from S0307 and to discuss the implications of 
the AZURE presentation on S0307. As a result, we are encouraging continuation of the 
S0307 trial as planned.  
 
The AZURE trial randomized 3360 women with Stage II/III breast cancer receiving 
systemic therapy to zoledronic acid or not. The dosing of zoledronic acid used in this trial 
was 4 mg every 3-4 weeks for 6 doses, then every 3 months x 8, followed by every 6 
months x 5, to complete 5 total years of treatment.  Ninety-six percent received 
chemotherapy, only 152 patients received endocrine therapy alone. Serious adverse 
events were similar in both arms, and to date 14 cases of osteonecrosis of the jaw (ONJ) 
have occurred, all in the zoledronic acid arm. For the primary endpoint of disease-free 
survival (DFS) with a median follow-up of 59 months, the study shows no significant 
effect of zoledronic acid. In a preplanned subset analysis, a significant effect on both 
recurrence and overall survival was reported in women with well-established menopause 
(defined as more than 5 years after menopause, n=1101). This finding is unexpected and 
hypothesis-generating, requiring further investigation. 
 
The AZURE presentation is in contrast to other previously reported adjuvant 
bisphosphonate trials suggesting clinical benefit.  The ABCSG-12 study (Gnant M et al, 
NEJM 2009; ASCO 2010, abstract #533) demonstrated a 32% risk reduction in DFS 
events with zoledronic acid (4 mg every 6 months for 3 years) in a cohort of 
premenopausal women treated with endocrine therapy (including ovarian suppression) 
without chemotherapy at 62 months median follow-up.  A randomized, placebo-controlled 
trial of daily oral clodronate for 2 years (Powles T et al, Breast Cancer Res 2006) in 1,069 
patients with stage I-III breast cancer reported a reduction in bone relapse and improved 
survival. It is understood that this trial will be retrospectively evaluated with respect to 
menopausal status in the near future. The NSABP B-34 of clodronate versus placebo for 
3 years in early stage breast cancer patients has not yet reported. The SWOG Breast 
Committee leadership feels strongly that the combined evidence of these trials, and not 
just a single trial, must be considered before making a definitive conclusion regarding the 
benefit of adjuvant bisphosphonates in specific breast cancer patient populations. 
 
S0307 is a randomized clinical trial of 3 different bisphosphonates in Stage I-III breast 
cancer patients receiving adjuvant systemic therapy. The randomization is between a 
dosing schedule of zoledronic acid similar to AZURE (4 mg intravenously monthly for 6 
months, then every 3 months) versus oral ibandronate (50 mg po daily) versus oral 
clodronate (1,600 mg po daily), all given for 3 years.  S0307 was activated November 15, 
2005 and completed accrual February 1, 2010. All 6,097 patients have been followed for 
at least a year, and no patients remain in the monthly dosing portion of the zoledronic 
therapy.  
 


 
S0307 
 
 Dear Doctor letter (contd.) 
 
Page 2 
 
 
 
No unexpected safety signals have emerged on study to date. Among 5,498 patients 
assessed for toxicity, 17 patients experienced Grade 4 toxicities, and an additional 7% 
have experienced Grade 3 events, primarily musculoskeletal pain. There have been 20 
reported cases of ONJ, or about one case per 500 patients followed for a year.  
 
Some important differences exist between the AZURE trial design and enrollment and 
S0307. S0307 delivers zoledronic acid in a similar “intensive” regimen, although it 
additionally evaluates two other oral bisphosphonates in the protocol. The duration of 
therapy in S0307 is 3 years, compared to 5 years in AZURE. The percentage of patients 
who did not receive chemotherapy is much higher in S0307 (20% versus about 4% in 
AZURE), which may impact benefit of bisphosphonates. S0307 mandates an end of 
study bone scan to provide a single time point at which bone metastases can be 
evaluated, with the thought that these high dose bisphosphonates might mask pain and 
other symptoms of bone involvement. S0307 has additional substudies evaluating 
fracture rates on high dose bisphosphonates, the impact of statin therapy on recurrence, 
and important biological correlates (using baseline tissue, serum and DNA) including 
predictors of bone metastases and toxicities from these drugs. We are looking carefully at 
the incidence and risk factors for ONJ in this study. The first interim analysis of S0307 is 
likely to occur in 2012 and then will occur annually thereafter.  The analysis of S0307 will 
include analyses in subsets defined by age, menopausal status, tumor stage, and other 
characteristics measured at baseline to determine if treatment effects are consistent over 
these factors.  
 
In conclusion, the data so far are conflicting. The discrepant results of previously 
presented/published trials, including ABCSG-12 and AZURE, have generated 
hypotheses, but no compelling direction. We strongly believe that the role of adjuvant 
bisphosphonates in early stage breast cancer to reduce recurrences and deaths is 
unclear. There are no emerging safety issues in S0307 that should impact patients’ 
decisions to continue to participate in the trial. There is undoubtedly a bone 
density/osteoporosis benefit to these patients, who are at increased risk of bone loss due 
to their therapy. The correlative science components of S0307 are important to 
understand the effect of the various bisphosphonates and perhaps identify biomarkers of 
benefit. We ask you to continue your support of S0307 to help resolve the current 
controversy by encouraging your patients to stay on study to complete their intended 
treatment. Results from ongoing trials, including S0307, will help define this important 
issue. 
 
 
Julie Gralow, M.D. 


 
 
 
 
 
 
 
February 15, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Report for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following safety report has been posted regarding an adverse event that occurred in 
association with the drug Bonefos® (clodronate disodium tetrahydrate).  Please access 
this safety report via the safety report link in the member section of the Southwest 
Oncology Group website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
This safety report pertains to the following study: 
 
 
S0307 Breast 
Report: 
 
Feb. 7, 2011 AE #2011009105 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
William E. Barlow, Ph.D. 
Silke Thiele – Bayer Healthcare 
 
Danika Lew, M.A. 
Selin Hall – Genentech 
 
Jean Barce 
Lixian Jin – Novartis 
 
Jennie Barrett 
Michael Dubois – UVI, Inc. 
 
Iris Syquia 
 
Jeri Jardine 
 


 
 
 
 
 
 
 
February 1, 2011 
 
TO: 
ALL SWOG MEMBER, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, 
SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Report for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following safety report has been posted regarding an adverse event that occurred in 
association with the drug Bonefos® (clodronate disodium tetrahydrate).  Please access 
this safety report via the safety report link in the member section of the Southwest 
Oncology Group website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
This safety report pertains to the following study: 
 
 
S0307 Breast 
Report: 
 
Jan. 6, 2010 
AE #201101168 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: PROTOCOL & INFORMATION OFFICE Jeri Jardine 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
Joyce Mull – NSABP 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 
Iris Buchanan 
 
 


 
 
 
 
 
 
 
January 15, 2011 
 
TO: 
ALL SWOG, CCOP AND AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS 
AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in 
association with the drug Bonefos® (clodronate disodium tetrahydrate).  Please access 
these safety reports via the safety report link in the member section of the SWOG 
website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Dec. 8, 2010 
AE #2010001255 
Dec. 9, 2010 
AE #2010001008 
Dec. 13, 2010 
AE #2010001538 
Dec. 13, 2010 
AE #2010001740 
Dec. 13, 2010 
AE #2010002638 
Dec. 13, 2010 
AE #201044429GPV 
Dec. 22, 2010 
AE #2010004720 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE Jeri Jardine 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
Joyce Mull – NSABP 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 
Iris Buchanan 


 
 
 
 
 
 
 
 
January 1, 2011 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Report for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following safety report has been posted regarding an adverse event that occurred in 
association with the drug Bonefos® (clodronate disodium tetrahydrate).  Please access 
this safety report via the safety report link in the member section of the Southwest 
Oncology Group website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
This safety report pertains to the following study: 
 
 
S0307 Breast 
Report: 
 
Dec. 3, 2010 AE #201013586NA 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: PROTOCOL & INFORMATION OFFICE Jeri Jardine 
 
William E. Barlow, Ph.D. 
Keiko Nakajima, M.D. – Bayer Healthcare 
 
Danika Lew, M.A. 
Silke Thiele – Bayer Healthcare 
 
Jean Barce 
Joyce Mull – NSABP 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 
Iris Buchanan 
 


 
 
 
 
 
 
 
December 15, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
SWOG Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in 
association with the drug Bonefos® (clodronate disodium tetrahydrate).  Please access 
these safety reports via the safety report link in the member section of the Southwest 
Oncology Group website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Nov. 17, 2010 
AE #201017693GPV 
Nov. 25, 2010 
AE #201040920NA 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
 
 
cc: PROTOCOL & INFORMATION OFFICE Iris Buchanan 
 
William E. Barlow, Ph.D. 
Jeri Jardine 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 


 
 
 
 
 
 
 
December 1, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in 
association with the drug Bonefos® (clodronate disodium tetrahydrate).  Please access 
these safety reports via the safety report link in the member section of the Southwest 
Oncology Group website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following 
study: 
 
 
S0307 Breast 
Reports: 
 
Nov. 4, 2010 
AE #201025921NA 
Nov. 4, 2010 
AE #201036783NA 
Nov. 4, 2010 
AE #20104405GPV 
Nov. 5, 2010 
AE #201043226GPV 
Nov. 12, 2010 
AE #200835032NA 
Nov. 12, 2010 
AE #201013586NA 
Nov. 12, 2010 
AE #201039369NA 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in these reports if it is deemed necessary by 
your institution.  Please append this notice and these reports to your copy of the protocol 
and forward copies to your Institutional Review Board (IRB) as required by your local 
policies and procedures. Should any further information regarding these adverse events 
be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: PROTOCOL & INFORMATION OFFICE Iris Buchanan 
 
William E. Barlow, Ph.D. 
Jeri Jardine 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Jennie Barrett 
Ellen Antonio – CTSU 


 
 
 
 
 
 
 
November 15, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Report for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
The following safety report has been posted regarding an adverse event that occurred in 
association with the drug Bonefos® (clodronate disodium tetrahydrate).  Please access 
this safety report via the safety report link in the member section of the Southwest 
Oncology Group website (https://swog.org/SafetyReports/SafetyReports.asp). 
 
This safety report pertains to the following study:
 
 
S0307 Breast 
Report: 
 
Oct. 28, 2010 AE #201043226GPV 
 
Protocol amendments are not necessary at this time, but your consent form may be 
revised to include the information provided in this report if it is deemed necessary by your 
institution.  Please append this notice and this report to your copy of the protocol and 
forward a copy to your Institutional Review Board (IRB) as required by your local policies 
and procedures. Should any further information regarding this adverse event be made 
available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: PROTOCOL & INFORMATION OFFICE Iris Buchanan 
 
William E. Barlow, Ph.D. 
Jeri Jardine 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 


 
 
 
 
 
 
November 1, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Oct. 19, 2010 
AE 201041755GPV 
Oct. 19, 2010 
AE 201041769GPV 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures. Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Buchanan 
 
William E. Barlow, Ph.D. 
Jeri Jardine 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 
 
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
October 15, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Sep. 28, 2010 AE 201033616NA 
Sep. 28, 2010 AE 201014956NA 
Sep. 29, 2010 AE 200919383NA 
Sep. 29, 2010 AE 201034050NA 
Sep. 30, 2010 AE 200938484NA 
Oct. 5, 2010 
AE 201039272GPV 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures. Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Buchanan 
 
William E. Barlow, Ph.D. 
Jeri Jardine 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
October 1, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Sep. 15, 2010 AE 201032707NA 
Sep. 20, 2010 AE 200927870NA 
Sep. 20, 2010 AE 201030791NA 
Sep. 20, 2010 AE 201039272GPV 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures. Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Buchanan 
 
William E. Barlow, Ph.D. 
Jeri Jardine 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
Distribution Date: 
September 15, 2010 
CTEP Submission Date: 
August 30, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  
Patient enrollments from institutions that are not aligned with SWOG will 
be conducted via the NCI Cancer Trials Support Unit (CTSU) and all data 
should be sent to the SWOG Data Operations as specified in the CTSU 
logistical appendix (See Section 19.1).  
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
REVISION #7 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
 
 (   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
 (    ) No review required 
 
 
REVISION #7 
 
The protocol referenced above has been amended as follows: 
 
1. 
Title Page:  The version date has been updated. 
 
2. 
Page 31-31a, Section 8.1:  The criteria for reporting Adverse Events have been 
updated.  Effective October 1, 2010 the CTCAE Version 4.0 will be utilized for SAE 
reporting.  The CTCAE Version 3.0 will continue to be utilized for routine toxicity 
reporting.   
 
3. 
Page 41, Section 15.4d:  The e-mail address for Miguel Martinez (the contact at 
the 
SWOG 
Solid 
Tumor 
Tissue 
Bank) 
has 
been 
changed 
to 
miguel.martinez@ucdenver.edu.  
 
Please attach this memorandum to the front of your copy of the protocol.       
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
NOTE:  This study remains permanently closed. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
William E. Barlow, Ph.D. 
Istvan Molnar - Bayer Schering Pharma Oy 
Danika Lew, M.A. 
Diep Tran - Novartis 
Jean Barce 
Benedicte Marion - Hoffman - Laroche, Ltd. 
Iris Buchanan 
 
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
September 15, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Aug. 18, 2010 AE 201031813GPV 
Aug. 24, 2010 AE 201030788NA 
Aug. 25, 2010 AE 201028721NA 
Aug. 25, 2010 AE 201030791NA 
Aug. 26, 2010 AE 201024770NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures. Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Buchanan 
 
William E. Barlow, Ph.D. 
Jeri Jardine 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
September 1, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Aug. 13, 2010 AE 201029240NA 
Aug. 13, 2010 AE 201031813GPV 
Aug. 16, 2010 AE 201023699NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures. Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Iris Buchanan 
 
William E. Barlow, Ph.D. 
Jeri Jardine 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 
 
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
August 15, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain 
to the following study: 
 
S0307 Breast 
Reports: 
 
July 15, 2010 AE 201031813GPV July 20, 2010 AE 201020681NA 
July 15, 2010 AE 201026892NA 
July 20, 2010 AE 201027733NA 
July 15, 2010 AE 201026764NA 
July 20, 2010 AE 200836438NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures. Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Joyce Mull – NSABP 
 
Jean Barce 
Maddy Balois – CTSU 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 
Iris Buchanan 
 
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
August 1, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain 
to the following study: 
 
S0307 Breast 
Reports: 
 
June 29, 2010 AE 200925055NA 
June 30, 2010 AE 201025675NA 
June 29, 2010 AE 201024765NA 
June 30, 2010 AE 201025786NA 
June 29, 2010 AE 201024770NA 
June 30, 2010 AE 201025921NA 
June 29, 2010 AE 201025200NA  
July 5, 2010 
AE 201028474GPV 
June 29, 2010 AE 201025458NA 
July 5, 2010 
AE 201026135NA 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Joyce Mull – NSABP 
 
Jean Barce 
Maddy Balois – CTSU 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 
Iris Buchanan 
 
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
July 15, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
June 9, 2010 
AE 201012401NA 
June 16, 2010 
AE 201023699NA 
June 16, 2010 
AE 201024770NA 
June 16, 2010 
AE 201027595GPV 
June 16, 2010 
AE 201028474GPV 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Joyce Mull – NSABP 
 
Jean Barce 
Maddy Balois – CTSU 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 
Iris Buchanan 
 
 
 
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
July 1, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain 
to the following study: 
 
S0307 Breast 
Reports: 
 
May 12, 2010 AE 201021257NA 
May 27, 2010 AE 200716245NA 
May 17, 2010 AE 201021912NA 
May 27, 2010 AE 201014471NA 
May 18, 2010 AE 200929525NA 
May 27, 2010 AE 201022634NA 
May 21, 2010 AE 201025523GPV May 31, 2010 AE 201023391NA 
May 27, 2010 AE 201021912NA 
May 31, 2010 AE 201023699NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Joyce Mull – NSABP 
 
Jean Barce 
Maddy Balois – CTSU 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 
Iris Buchanan 
 
 
 
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
June 15, 2010 
 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE 
MEDICAL 
ONCOLOGISTS, 
SURGEONS, 
AND 
PATHOLOGISTS; CTSU.  Patient enrollments from institutions that are 
not aligned with SWOG will be conducted via the NCI Cancer Trials 
Support Unit (CTSU) and all data should be sent to the SWOG Data 
Operations as specified in the CTSU logistical appendix (See Section 
19.1). 
 
FROM: 
Amanda Vidlak, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
 (   ) Expedited review allowed 
 
 ( √  ) 
No review required 
 
 
MEMORANDUM 
 
UVI, Inc., the drug distributor for the S0307 trial, will be closed for business on Monday, 
July 5, 2010 in observance of the July 4th holiday.  As a result UVI will not be processing 
drug shipments on July 5, 2010.  Please plan your drug orders accordingly.  We apologize 
for any inconvenience this may cause. 
 
This protocol remains permanently closed to accrual. 
 
Please attach this memorandum to the front of your copy of the protocol.   
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jeannie Barrett 
 
 William E. Barlow, Ph.D. 
Istvan Molnar– Bayer Schering Pharma Oy 
 Danika Lew, M.A. 
Maddy Balois– CTSU 
 Jean Barce 
Michelle Dubois – UVI, Inc. 
Iris Buchanan 
Lixian Jin - Novartis 
Jeri Jardine 
 
 
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
June 1, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain 
to the following study: 
 
S0307 Breast 
Reports: 
 
May 4, 2010 
AE 200929525NA 
May 6, 2010 
AE 201020341NA 
May 4, 2010 
AE 201019766NA 
May 6, 2010 
AE 201020678NA 
May 4, 2010 
AE 201020451NA 
May 6, 2010 
AE 201020681NA 
May 5, 2010 
AE 201020683NA 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Joyce Mull – NSABP 
 
Jean Barce 
Maddy Balois – CTSU 
 
Jennie Barrett 
Ellen Antonio – CTSU 
 
Iris Buchanan 
 
 
 
 
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
May 15, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain 
to the following study: 
 
S0307 Breast 
Reports: 
 
Apr. 6, 2010 
AE 201016159NA 
Apr. 16, 2010 AE 201018522NA 
Apr. 6, 2010 
AE 201017651NA 
Apr. 26, 2010 AE 201017889NA 
Apr. 12, 2010 AE 201011319NA 
Apr. 26, 2010 AE 201019766NA 
Apr. 12, 2010 AE 201017889NA 
Apr. 27, 2010 AE 201019773NA 
Apr. 14, 2010 AE 201016369NA 
Apr. 28, 2010 AE 201022066GPV 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Lisa Gavigan 
 
William E. Barlow, Ph.D. 
Jeri Jardine 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Jennie Barrett 
Maddy Balois – CTSU 
 
Iris Buchanan 
Ellen Antonio – CTSU 
 
 
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
April 15, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain 
to the following study: 
 
S0307 Breast 
Reports: 
 
Feb. 26, 2010 AE 201014472NA 
Mar. 16, 2010 AE 201018181GPV 
Feb. 26, 2010 AE 201016672GPV 
Mar. 18, 2010 AE 201015688NA 
Mar. 2, 2010 
AE 201014471NA 
Mar. 18, 2010 AE 201016159NA 
Mar. 4, 2010 
AE 201014475NA 
Mar. 24, 2010 AE 200835032NA 
Mar. 4, 2010 
AE 201014672NA 
Mar. 24, 2010 AE 201014471NA 
Mar. 11, 2010 AE 201014472NA 
Mar. 24, 2010 AE 201016369NA 
Mar. 11, 2010 AE 201014956NA 
Mar. 31, 2010 AE 201017173NA 
Mar. 16, 2010 AE 200920427NA 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jennie Barrett 
 
William E. Barlow, Ph.D. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Joyce Mull – NSABP 
 
Jean Barce 
Maddy Balois – CTSU 
 
Lisa Gavigan 
Ellen Antonio – CTSU 
 
Jeri Jardine 
 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
March 15, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Feb. 17, 2010 
AE 201011714GPV 
Feb. 19, 2010 
AE 201013586NA 
Feb. 24, 2010 
AE 201011811NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jennie Barrett 
 
William E. Barlow, Ph.D. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Joyce Mull – NSABP 
 
Jean Barce 
Maddy Balois – CTSU 
 
Lisa Gavigan 
Ellen Antonio – CTSU 
 
Jeri Jardine 
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
March 1, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Feb. 8, 2010 
AE 201012174NA 
Feb. 8, 2010 
AE 201012401NA 
Feb. 8, 2010 
AE 201012714NA 
Feb. 12, 2010 
AE 201012616NA 
Feb. 12, 2010 
AE 201013185NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jennie Barrett 
 
William E. Barlow, Ph.D. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Joyce Mull – NSABP 
 
Jean Barce 
Maddy Balois – CTSU 
 
Lisa Gavigan 
Ellen Antonio – CTSU 
 
Jeri Jardine 
 
 
Operations Office 
4201 Medical Drive, Suite 250 • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
Distribution Date: 
February 15, 2010 
CTEP Submission Date: 
January 21, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  
Patient enrollments from institutions that are not aligned with SWOG will 
be conducted via the NCI Cancer Trials Support Unit (CTSU) and all data 
should be sent to the SWOG Data Operations as specified in the CTSU 
logistical appendix (See Section 19.1).  
 
FROM: 
Amanda Vidlak, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
REVISION #6 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
REVISION #6 
 
1. 
Title Page – The version date has been updated. 
 
2. 
Page 3: The contact information for Dr. Clemons has been updated. 
 
3. 
Page 16, Section 3.1.c: For zolendronic acid drug returns, the incorrect contact 
information has been deleted.  See the memorandum distributed 10/15/09 for 
current contact information. 
 
4. 
Page 29, Sections 7.3 and 7.4:  A note regarding dosing of zoledronic acid has 
been added to this section for clarification purposes.  The table in Section 7.3 was 
modified; the interval for oral bisphosphonates was changed from 3 years to 35 
months as the oral bisphosphonates are discontinued on Day 1 of Month 36.  The 
SWOG Operations Office phone number has been updated. 
 
5. 
Page 30, Section 7.10: Language has been inserted to clarify that all end of 
treatment evaluations are done on Day 1 of Month 36.  The SWOG Operations 
office phone number has been updated.  
 
 
 
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
S0307 
 
Revision #6 (contd.) 
 
Page 2 
 
 
 
6. 
Page 32, Section 9.0: The reference regarding bone scans related to the footnote 
“£” in the study calendar has been corrected from Section 5.9 to Section 5.10.  The 
footnote “Ω” has been corrected to say that zolendronic acid can be given ± 2-day 
interval for the first six months.  A note regarding dosing of zoledronic acid has 
been added to this section for clarification purposes.  The footnote “€” has been 
added to clarify that all end of treatment evaluations are done on Day 1 of Month 
36.  In the column for Month 36, the X’s have been deleted from the clodronate and 
ibandronate rows because these are to be discontinued on Day 1 of Month 36.  
The associated footnotes have been revised accordingly. 
 
7. 
Page 33-34, Section 11.0:  This section was modified, as requested by the NCI, to 
stratify the analysis by time period of randomization.  In Section 11.2 the time a 
patient is followed was also corrected to 10 years from randomization. 
 
8. 
Page 35, Section 13.3a:  The SWOG Operations Office phone number has been 
updated. 
 
9. 
Page 36, Section 14.3:  The SWOG Operations Office phone number has been 
updated. 
 
10. 
Page 37, Section 14.7:  The S0307 Serum Creatinine Reporting Form has been 
added to the list of forms submitted within 14 days of discontinuation of treatment. 
 
11. 
Page 43, Section 16.1e:  The SWOG Operations Office phone number has been 
updated. 
 
12. 
Pages 45-45a, Section 16.1:  A section on instructions and exceptions to AdEERS 
expedited reporting requirements has been added as section 16.1.f.  The 
subsequent sections have been renumbered.  In Section 16.1g and 16.1h the 
SWOG Operations Office phone and FAX number has been updated as well as the 
address.  Page 45a has been inserted to prevent extensive repagination. 
 
13. 
Page 56, Model Consent Form:  The time a patient will be in this study has been 
clarified to 10 years from randomization. 
 
14. 
Page 83, Section 19.0:  Appendix 19.4, the S0307 Statistical Analysis Plan, was 
added to the Appendix section of the protocol. 
 
15. 
Pages 100-104, Appendix 19.4:  This section has been inserted. 
 
The Southwest Oncology Group considers that the Model Consent Form change does not 
represent an alteration in risk-benefit ratio.  Patients currently on treatment need  not be 
informed of this change unless required by the responsible Institutional Review Board 
(IRB). 
 
Please attach this memorandum to the front of your copy of the protocol.       
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
NOTE:  This study remains permanently closed. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jennie Barrett 
William E. Barlow, Ph.D. 
Istvan Molnar - Bayer Schering Pharma Oy 
Danika Lew, M.A. 
Diep Tran - Novartis 
Jean Barce 
Benedicte Marion - Hoffman - Laroche, Ltd. 
Lisa Gavigan 
Maddy Balois - CTSU 
Jeri Jardine 
 
 


 
 
 
 
 
Distribution Date: 
February 15, 2010 
E-mailed Date: 
February 9, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  
Patient enrollments from institutions that are not aligned with SWOG will 
be conducted via the NCI Cancer Trials Support Unit (CTSU) and all data 
should be sent to the SWOG Data Operations as specified in the CTSU 
logistical appendix (See Section 19.1). 
 
FROM: 
Amanda Vidlak, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
 (   ) Expedited review allowed 
 
 ( √  ) No review required 
 
 
MEMORANDUM 
 
UVI, Inc., drug distributor for the S0307 trial, has confirmed that they are experiencing a 
temporary shortage of clodronate tablets.  The clodronate tablets continue to be 
manufactured by Bayer Schering Pharma Oy; however, a new shipment is not expected in 
the UVI warehouse for up to three weeks. 
 
We anticipate that this shortage will last no longer than three weeks and we hope that 
registered patients on the clodronate arm have necessary supplies on hand.  There may be 
instances where an interruption in treatment may be experienced.  If a treatment 
interruption occurs, please contact UVI, Inc., so that clodronate re-supply orders can be 
expedited once the shortage is resolved. 
 
Note:    Any treatment interruption due to the drug shortage will not be considered a 
protocol deviation; however, institutions should document in the research record 
the reason for the interruption. 
 
The ibandronate shortage which was announced in a memorandum distributed 2/4/2010 
has been resolved.  All pending orders will be released from UVI, Inc., today, February 9, 
2010. 
 
This protocol remains permanently closed to accrual. 
 
Please attach this memorandum to the front of your copy of the protocol.   
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jeannie Barrett 
 
 William E. Barlow, Ph.D. 
Istvan Molnar– Bayer Schering Pharma Oy 
 Danika Lew, M.A. 
Maddy Balois– CTSU 
 Jean Barce 
Michelle Dubois – UVI, Inc. 
Lisa Gavigan 
Lixian Jin - Novartis 
Jeri Jardine 
 
 
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
Distribution Date: 
February 15, 2010 
E-mailed Date: 
February 4, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  
Patient enrollments from institutions that are not aligned with SWOG will 
be conducted via the NCI Cancer Trials Support Unit (CTSU) and all data 
should be sent to the SWOG Data Operations as specified in the CTSU 
logistical appendix (See Section 19.1). 
 
FROM: 
Amanda Vidlak, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
 (   ) Expedited review allowed 
 
 ( √  ) No review required 
 
 
MEMORANDUM 
 
UVI, Inc., drug distributor for the S0307 trial, has confirmed that they are experiencing a 
temporary shortage of ibandronate tablets.  The ibandronate tablets continue to be 
manufactured by Roche; however, a new shipment is not expected in the UVI warehouse 
until next week. 
 
While we anticipate that this shortage will only last a week, we hope that registered 
patients on the ibandronate arm have necessary supplies on hand.  There may be 
instances where an interruption in treatment may be experienced.  If a treatment 
interruption occurs, please contact UVI, Inc., so that ibandronate re-supply orders can be 
expedited once the shortage is resolved. 
 
Note:    Any treatment interruption due to the drug shortage will not be considered a 
protocol deviation; however, institutions should document in the research record 
the reason for the interruption. 
 
This protocol remains permanently closed to accrual. 
 
Please attach this memorandum to the front of your copy of the protocol.   
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jeannie Barrett 
 
 William E. Barlow, Ph.D. 
Istvan Molnar– Bayer Schering Pharma Oy 
 Danika Lew, M.A. 
Maddy Balois– CTSU 
 Jean Barce 
Michelle Dubois – UVI, Inc. 
Lisa Gavigan 
Lixian Jin - Novartis 
Jeri Jardine 
 
  
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
February 15, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Jan. 5, 2010 
AE 200943195NA 
Jan. 18, 2010 
AE 201010540NA 
Jan. 22, 2010 
AE 201011106GPV 
Jan. 22, 2010 
AE 201011319NA 
Jan. 27, 2010 
AE 201011811NA 
Jan. 28, 2010 
AE 201011714GPV 
Jan. 28, 2010 
AE 201013164GPV 
Jan. 29, 2010 
AE 201011741NA 
Jan. 29, 2010 
AE 201011940NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jennie Barrett 
 
William E. Barlow, Ph.D. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Joyce Mull – NSABP 
 
Jean Barce 
Maddy Balois – CTSU 
 
Lisa Gavigan 
Ellen Antonio – CTSU 
 
Jeri Jardine 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
January 15, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  
Patient enrollments from institutions that are not aligned with SWOG will 
be conducted via the NCI Cancer Trials Support Unit (CTSU) and all data 
should be sent to the SWOG Data Operations as specified in the CTSU 
logistical appendix (See Section 19.1). 
 
FROM: 
Amanda Vidlak, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston 
 
STATUS NOTICE 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
( √  ) Expedited review allowed 
 
(   ) No review required 
 
 
PERMANENT CLOSURE 
 
The study referenced above has reached its accrual goal and will be permanently closed 
effective February 1, 2010.  Registration will be open until 11:59 p.m. PST on Monday 
February 1, 2010. 
 
Please attach this notice to the front of your copy of the protocol.   
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
 William E. Barlow, Ph.D. 
 
 Danika Lew, M.A. 
 
 Jean Barce 
 
Lisa Gavigan 
 
Jeri Jardine 
 
Jeannie Barrett 
 
Istvan Molnar– Bayer Schering Pharma Oy 
Maddy Balois– CTSU 
Michelle Dubois – UVI, Inc. 
Diep Tran - Novartis 
     
Operations Office 
4201 Medical Drive (Suite 250) •San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
January 15, 2010 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Dec. 15, 2009 
AE 200942044NA 
Dec. 16, 2009 
AE 200933062NA 
Dec. 18, 2009 
AE 200942141NA 
Dec. 23, 2009 
AE 200942675NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jennie Barrett 
 
William E. Barlow, Ph.D. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Joyce Mull – NSABP 
 
Jean Barce 
Maddy Balois – CTSU 
 
Lisa Gavigan 
Ellen Antonio – CTSU 
 
Jeri Jardine 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
December 15, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Nov. 16, 2009 
AE 200937511GPV 
Nov. 16, 2009 
AE 200938156NA 
Nov. 16, 2009 
AE 200938484NA 
Nov. 19, 2009 
AE 200924223LA 
Nov. 19, 2009 
AE 200939069NA 
Nov. 20, 2009 
AE 200938931NA 
Nov. 30, 2009 
AE 200941024NA 
Nov. 30, 2009 
AE 200938484NA 
Dec. 4, 2009 
AE 200933062NA 
Dec. 7, 2009 
AE 200939069NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jennie Barrett 
 
William E. Barlow, Ph.D. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Joyce Mull – NSABP 
 
Jean Barce 
Maddy Balois – CTSU 
 
Lisa Gavigan 
Ellen Antonio – CTSU 
 
Jeri Jardine 
 
Operations Office 
4201 Medical Drive (Suite 250) • San Antonio, TX 78229 • Telephone 210-614-8808 • FAX 210-614-0006 • http://swog.org 


 
 
 
 
 
 
December 1, 2009 
 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Nov. 4, 2009 
AE 200937014NA 
Nov. 5, 2009 
AE 200937723NA 
Nov. 6, 2009 
AE 200936680NA 
Nov. 9, 2009 
AE 200937511GPV 
Nov. 9, 2009 
AE 200937700GPV 
Nov. 9, 2009 
AE 200938156NA 
Nov. 11, 2009 
AE 200935806NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
Ellen Antonio – CTSU 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
November 15, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Oct. 19, 2009 
AE 200935806NA 
Oct. 26, 2009 
AE 200936074GPV 
Oct. 26, 2009 
AE 200936680NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
Ellen Antonio – CTSU 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
November 1, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Oct. 5, 2009 
AE 200932010NA(1) 
Oct. 7, 2009 
AE 200931478NA(1) 
Oct. 9, 2009 
AE 200934396GPV 
Oct. 15, 2009 
AE 200922983NA(1) 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
Distribution Date: 
October 15, 2009 
E-mailed Date: 
October 8, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  
Patient enrollments from institutions that are not aligned with SWOG will 
be conducted via the NCI Cancer Trials Support Unit (CTSU) and all data 
should be sent to the SWOG Data Operations as specified in the CTSU 
logistical appendix (See Section 19.1). 
 
FROM: 
Amanda Vidlak, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
(   ) Expedited review allowed 
 
( √  ) No review required 
 
 
MEMORANDUM 
 
This memorandum serves to notify sites that the Novartis contact for drug returns for 
zoledronic acid has changed.  The telephone and Fax numbers in the last paragraph of 
Section 3.1c are no longer correct.  For drug returns and disposals, please request a 
zoledronic acid drug return form by contacting Kristen White (kristen.white@novartis.com) 
from Novartis at phone number: 862-778-2969 or Fax: 973-781-3322. 
 
Please attach this memorandum to the front of your copy of the protocol.   
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
 William E. Barlow, Ph.D. 
 
 Danika Lew, M.A. 
 
 Jean Barce 
 
Lisa Gavigan 
 
Jeri Jardine 
 
Jeannie Barrett 
 
Istvan Molnar– Bayer Schering Pharma Oy 
Maddy Balois– CTSU 
Michelle Dubois – UVI, Inc. 
Diep Tran - Novartis 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
October 15, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Sep. 28, 2009 
AE 200933062NA 
Sep. 30, 2009 
AE 200931701NA(1) 
Oct. 2, 2009 
AE 200933353NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
October 1, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  
Patient enrollments from institutions that are not aligned with SWOG will 
be conducted via the NCI Cancer Trials Support Unit (CTSU) and all data 
should be sent to the SWOG Data Operations as specified in the CTSU 
logistical appendix (See Section 19.1). 
 
FROM: 
Amanda Vidlak, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
(   ) Expedited review allowed 
 
( √  ) No review required 
 
 
MEMORANDUM 
 
This memorandum serves to clarify questions regarding Revision #5 and the Model 
Consent Form.  The current consent form states that patients will be randomized to an arm 
of the study that has not met its accrual goal.  The ibandronate arm (Arm 3) has reached its 
accrual maximum of 1,400 patients and is now closed.  The clodronate and zoledronic acid 
arms have returned to their original accrual maximums of 2,000 patients and are still 
accruing.  To make this abundantly clear in the Informed Consent Form, SWOG is allowing 
sites with the approval of their local IRB to add language to their local consent forms stating 
the ibandronate arm is closed and patients will not have a chance to be randomized to that 
arm of the study.  The study design has not been changed, therefore SWOG will not be 
removing ibandronate from the Model Consent Form, protocol or Fast Facts Sheet.  Sites 
must also keep this information in their local consent forms. 
 
If you have any further questions, please contact the Southwest Oncology Group 
Operations Office at 210/450-8808. 
 
Please attach this memorandum to the front of your copy of the protocol.   
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 William E. Barlow, Ph.D. 
Jeannie Barrett  
 Danika Lew, M.A. 
Istvan Molnar– Bayer Schering Pharma Oy 
 Jean Barce 
Maddy Balois– CTSU 
Lisa Gavigan 
Michelle Dubois – UVI, Inc. 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
October 1, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  
Patient enrollments from institutions that are not aligned with SWOG will 
be conducted via the NCI Cancer Trials Support Unit (CTSU) and all data 
should be sent to the SWOG Data Operations as specified in the CTSU 
logistical appendix (See Section 19.1). 
 
FROM: 
Amanda Vidlak, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
(   ) Expedited review allowed 
 
( √  ) No review required 
 
 
MEMORANDUM 
 
The purpose of this memorandum is to clarify follow-up laboratory test requirements 
conducted for S0307.  The Southwest Oncology Group Quality Assurance Department has 
expressed that there have been multiple deficiencies for failure to obtain magnesium and 
phosphate when conducting follow-up lab tests to assess for toxicity.  Please be aware that 
these tests are required for patient safety as stated in the FDA label for zoledronic acid 
even though they may not be routinely included in institution’s chemistry panel.  Failure to 
obtain these tests will be noted as a Deficiency upon audit.  If you have any questions, 
please contact the Southwest Oncology Group Operations Office at 210/450-8808. 
 
Please attach this memorandum to the front of your copy of the protocol.   
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
 William E. Barlow, Ph.D. 
 
 Danika Lew, M.A. 
 
 Jean Barce 
 
Lisa Gavigan 
 
Jeri Jardine 
Jeannie Barrett 
 
Istvan Molnar– Bayer Schering Pharma Oy 
Maddy Balois– CTSU 
Michelle Dubois – UVI, Inc. 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
October 1, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Aug. 25, 2009 
AE 200924334NA(2) 
Aug. 25, 2009 
AE 200929525NA 
Aug. 26, 2009 
AE 200923557NA (1) 
Aug. 31, 2009 
AE 200929599GPV 
Sep. 2, 2009 
AE 200929996NA 
Sep. 3, 2009 
AE 200929582GPV 
Sep. 7, 2009 
AE 200929599GPV(1) 
Sep. 9, 2009 
AE 200931859NA 
Sep. 9, 2009 
AE 200929996NA(1) 
Sep. 10, 2009 
AE 200931478NA 
Sep. 11, 2009 
AE 200931701NA 
Sep. 15, 2009 
AE 200932010NA 
Sep. 16, 2009 
AE 200930721NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
September 1, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  
Patient enrollments from institutions that are not aligned with SWOG will 
be conducted via the NCI Cancer Trials Support Unit (CTSU) and all data 
should be sent to the SWOG Data Operations as specified in the CTSU 
logistical appendix (See Section 19.1). 
 
FROM: 
Amanda Vidlak, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston 
 
STATUS NOTICE 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(   ) No review required 
 
 
RE-ACTIVATION 
 
The above referenced protocol is now re-activated for accrual, effective immediately.  
Please disregard the statement at the end of the Revision #5 memorandum saying accrual 
does not need to be suspended pending implementation of these changes. 
 
Sites must have IRB approval of Revision #5 within 90 days of release of this 
memorandum.  Please submit proof of IRB approval of Revision #5 to: 
 
Coalition for National Cancer Cooperative Groups 
1818 Market Street 
Suite 1100 
Philadelphia, PA 19103 
FAX:  215/569-0206 
E-mail:  CTSURegulatory@ctsu.coccg.org 
 
IRB approval must be submitted prior to registering further patients. 
 
Randomization has been changed to two arms.  The ibandronate arm has met its accrual 
goal, and accrual will not be extended due to contractual limitations.  The clodronate and 
zoledronic acid arms have been allowed to return to the original accrual size of 2000 
patients.  If you have any questions or concerns, please contact the Southwest Oncology 
Group Operations Office at 210/450-8808 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
S0307 
 
Re-Activation (contd.) 
 
Page 2 
 
 
 
 
 
 
 
 
 
 
Please attach this memorandum to the front of your copy of the protocol.   
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
 William E. Barlow, Ph.D. 
 
 Danika Lew, M.A. 
 
 Jean Barce 
 
Lisa Gavigan 
 
Jeri Jardine 
Jeannie Barrett 
 
Istvan Molnar– Bayer Schering Pharma Oy 
Maddy Balois– CTSU 
Michelle Dubois – UVI, Inc. 
 


 
 
 
 
 
Distribution Date: 
September 1, 2009 
CTEP Submission Date: July 13, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  
Patient enrollments from institutions that are not aligned with SWOG will 
be conducted via the NCI Cancer Trials Support Unit (CTSU) and all data 
should be sent to the SWOG Data Operations as specified in the CTSU 
logistical appendix (See Section 19.1).  
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
REVISION #5 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
REVISION #5 
 
The primary purpose of Revision #5 is to increase the study's sample size to take 
advantage of the increasing accrual rate to allow greater power for the statistical 
comparisons planned in the study.  Another purpose is to add a pharmacogenomic 
translational medicine study to the protocol.  Details related to these changes and 
additional protocol clarifications are outlined below:   
 
Face page:  The version date of the protocol has been updated. 
 
Page 2:  Dr. Catherine Van Poznak was added as a co-coordinator for pharmacogenomics. 
 
Objectives, Page 6:  Objective 1.7 was added to incorporate the primary study objective for 
the pharmacogenomic study:  
 
"To investigate whether there is an association between inherited germ-line single 
nucleotide polymorphisms (SNP, rs2297480) in farnesyl diphosphate sythase (FDPS) 
and the adverse event of acute phase reactions in this cohort of patients (see 
Appendix 19.3)." 
 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
S0307 
 
Revision #5 
 
Page 2 
 
 
 
 
 
Section 2.0, Page 13:  Background on pharmacogenomics as well as a reference to the 
pharmacogenomic studies appendix (Appendix 19.3) were added.  The paragraph on 
serum banking was updated to include WBC banking. 
 
Section 2.0, Page 13a:  The accrual table documenting the inclusion of race and ethnic 
subsets was updated to accommodate the new projected accrual numbers. 
 
Section 3.2c and Section 3.3c, Pages 19 and 22:  Handling and disposal/Drug returns – 
these sections have been updated to indicate that drug returns should be noted in the 
patient record (rather than the drug accountability ledger). 
 
Section 5.3, Page 26:  This section has been clarified by adding "…for the cancer." to the 
end of the second sentence regarding surgery timing.  In the third sentence, "completion" 
was clarified as "the last administration". 
 
Section 5.4, Page 26:  The collection of whole blood was added to the specimens 
referenced in this section. 
 
Section 7.3, Page 29:  An editorial error was corrected.  During the first six months of 
dosing, it is suggested that infusions of zoledronic acid be given within ± 2 days (rather 
than ± 7 days). 
 
Section 7.7, Page 30 :  This section was revised to ensure consistency with the drug 
information instructions.  Oral bisphosphonates should be taken at least one hour (rather 
than 30 minutes) before the first food or drink of the day other than water. 
 
Section 7.10, Page 30 and Section 9.0, "£" footnote, Page 32:  A sentence was added to 
clarify that "Patients who have had a bone scan within 6 months prior to ending treatment 
will not be required to have the scan repeated." 
 
Section 7.12a, Page 31:  The first criterion for removal from protocol treatment was clarified 
to exclude the diagnosis of a second non-breast primary as a reason for removal from 
protocol treatment and to clarify that diagnosis of DCIS without an invasive component is 
not considered to be a recurrence or second primary. 
 
Section 8.3, Page 31:  The first sentence of this section was revised to clarify the levels of 
creatinine increase requiring action. 
 
Section 8.4, Page 31:  This section has been updated to clarify timing of treatment, and 
treatment delays and rescheduling on zoledronic acid arm of the study.  Page 31a was 
added to prevent extensive repagination. 
 
Section 9.0 (Study Calendar), Page 32:  The Study Calendar was revised to delete the 
"End of Treatment" column as for most patients the end of treatment will occur at Month 36.  
The requirements for the end of treatment dental exam and bone scan were moved to 
Month 36.  The "Ψ" and "α" footnotes were edited to delete the phase "for 36 months" 
because the oral drug treatment actually ends on the first day of Month 36.  The "ƒ" 
footnote was edited to change the section reference from 7.8 to 7.11.  The whole blood 
specimen collection and an associated "β" footnote was added. 
 
Sections 10.1 and 10.2, Page 33:  These sections were updated to clarify that DCIS 
without an invasive component is not considered to be a recurrence. 
 
Sections 11.1, 11.2 and 11.4-11.6, Pages 33-34b:  The Statistical Considerations were 
updated to accommodate the increased sample size for the study.  The overall planned 
accrual of eligible patients will be 5,400 (2,000 to receive zoledronic acid, 2,000 to receive 
clodronate and 1,400 to receive ibandronate).  Page 34b was added to prevent extensive 
repagination. 
 
Sections 15.1 and 15.4 (Pages 38 and 40):  These sections were revised to incorporate the 
submission of a single whole blood specimen per patient  


 
S0307 
 
Revision #5 
 
Page 3 
 
 
 
 
 
 
Tables 16.1 and 16.2 (Pages 44 and 45):  The title of Table 16.1 was edited.  Footnote "3" 
in Table 16.1 and footnote "c" in Table 16.2 were both updated to indicate that 
osteonocrosis of the jaw (regardless of grade, attribution or expectedness) is to be reported 
in an expedited fashion. 
 
Section 17.0, Page 46:  Bibliography entry #16 was corrected. 
 
Model Informed Consent Form:  Under "How Many People will take part in the study?" 
Page 53, the number of participants was updated from 4,500 to 5,400.  A bullet item was 
added to page 54 to describe the optional collection of whole blood.  Also on page 54 the 
description of the randomization process was updated to match the current accrual plan.  
Page 54a was added to prevent extensive repagination. 
 
A new question related to optional participation in the submission of a whole blood 
specimen for DNA analysis was added to the optional studies questions on Page 62.  A 
reference to "whole blood" was added into the list of the types of specimens applicable to 
the "Consent Form for Use of Specimens for Research on Page 63. 
 
The S0307 Registration Form has been updated to collect the answer to the consent 
question related to the submission of whole blood.  The form number has been changed 
from #63147 to #46563.  This change is also reflected in Section 18.2a, Page 50.  The 
S0307 Adverse Event Summary Form has been updated to add details regarding the 
reporting of osteonocrosis of the jaw.  The form number has been changed from #11983 to 
#22831.  This change is also reflected in Sections 14.5, 14.7 and 14.9 (Page 37), as well 
as Section 18.2d (Page 50). 
 
Appendix 19.3 has been inserted (Pages 89-95) and has been added to the appendix list 
on Page 83. 
 
Institutions must update their local consent forms to reflect these changes for future 
registrations and are expected to have received IRB approval of these consent form 
changes within 90 days after distribution of this revision.  It is strongly recommended that 
patients already registered to the protocol (including those who have been removed 
from protocol treatment) as well as newly registered patients be given the 
opportunity to consent to submission of a whole blood specimen prior to the time of 
their next blood draw for routine laboratory testing so that the specimen may be 
collected at the same time.  The whole blood specimen may be drawn at any time during 
the patient's clinical care or planned phlebotomy and at any time during study participation 
or follow-up.  Patients need not be on protocol treatment at the time of this draw.  Patients 
currently registered to the protocol need not be informed of the accrual requirement 
changes unless required by the local Institutional Review Board (IRB).   
 
The Southwest Oncology Group considers that the Model Consent Form changes do not 
represent an alteration in risk-benefit ratio.  Therefore, local accrual does not need to be 
suspended pending implementation of these changes.  
 
Please attach this memorandum to the front of your copy of the protocol.       
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jennie Barrett 
William E. Barlow, Ph.D. 
Istvan Molnar - Bayer Schering Pharma Oy 
Danika Lew, M.A. 
Diep Tran - Novartis 
Jean Barce 
Benedicte Marion - Hoffman - Laroche, Ltd. 
Lisa Gavigan 
Maddy Balois - CTSU 
Jeri Jardine 
 
 
 
 
 


 
 
 
 
 
Distribution Date: September 1, 2009 
Emailed Date: 
August 20, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  
Patient enrollments from institutions that are not aligned with SWOG will 
be conducted via the NCI Cancer Trials Support Unit (CTSU) and all data 
should be sent to the SWOG Data Operations as specified in the CTSU 
logistical appendix (See Section 19.1). 
 
FROM: 
Amanda Vidlak, Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
(   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
(   ) Expedited review allowed 
 
( √  ) No review required 
 
 
MEMORANDUM 
 
UVI, Inc., drug distributor for the S0307 trial, has confirmed that they are experiencing a 
temporary shortage of clodronate tablets.  The clodronate tablets continue to be manufactured 
by Bayer Schering Pharma Oy; however, a new shipment is not expected in the UVI warehouse 
until early next week. 
 
While we anticipate that this shortage will only last a week, please contact UVI, Inc. at 800/370-
2508 before registering a patient to check on available clodronate supplies and to adjust 
registration plans and/or treatment start dates accordingly.  While it is our hope that registered 
patients on the clodronate arm have necessary supplies on hand, there may be instances where 
an interruption in treatment may be experienced.  If a treatment interruption occurs, please 
contact UVI, Inc. so that clodronate re-supply orders can be expedited once the shortage is 
resolved. 
 
Note:  Any delay in the treatment start date or treatment interruption due to the drug 
shortage will not be considered a protocol deviation; however institutions should 
document in the research chart the reason for the delay/interruption. 
 
Please attach this memorandum to the front of your copy of the protocol.   
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 William E. Barlow, Ph.D. 
Jeannie Barrett  
 Danika Lew, M.A. 
Istvan Molnar– Bayer Schering Pharma Oy 
 Jean Barce 
Maddy Balois– CTSU 
Lisa Gavigan 
Michelle Dubois – UVI, Inc. 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
September 1, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
Aug. 6, 2009 
AE 200928049NA 
Aug. 7, 2009 
AE 200928622NA 
Aug. 10, 2009 
AE 200925618NA(1) 
Aug. 11, 2009 
AE 200927439GPV 
Aug. 17, 2009 
AE 200927923NA(1) 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
August 15, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
July 29, 2009 
AE 200926222GPV 
July 31, 2009 
AE 200927870NA 
Aug. 5, 2009 
AE 200927923NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
Mailed:   August 1, 2009 
Emailed: July 24, 2009 
 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  Patient 
enrollments from institutions that are not aligned with SWOG will be 
conducted via the NCI Cancer Trials Support Unit (CTSU) and all data should 
be sent to the SWOG Data Operations as specified in the CTSU logistical 
appendix (See Section 19.1). 
 
FROM: Southwest Oncology Group Operations Office 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast 
Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
STATUS NOTICE 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
 
(   )    Full board review required.  Reason: 
(   )   Initial activation (should your institution choose to participate) 
(   )   Increased risk to patient 
(   )   Complete study redesign 
(   )   Addition of tissue banking requirements 
(   )   Study closure due to new risk information 
 
( √ )    Expedited review allowed  
 
(   )    No review required  
 
 
TEMPORARY CLOSURE 
 
The study referenced above will be temporarily closed, effective August 24, 2009, due to 
significant protocol changes currently under development.   
 
Please attach this memorandum to the front of your copy of the protocol and insert the 
replacement pages.  
 
This memorandum serves to inform the Southwest Oncology Group Statistical Center and the 
NCI. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 William E. Barlow, Ph.D. 
 Danika Lew, M.A. 
 Jean Barce 
 Lisa Gavigan 
 Jeri Jardine 
Jennie Barrett 
Istvan Molnar – Bayer Schering Pharma Oy 
Diep Tran – Novartis  
Benedicte Marion – Hoffman-LaRoche, Ltd. 
Maddy Balois – CTSU 
Michelle Dubois - UVI 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
July 1, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
May 27, 2009 
AE #200920113GPV(1) 
May 28, 2009 
AE #200920420GPV(1) 
June 1, 2009 
AE #200921670NA 
June 3, 2009 
AE #200911902BNE 
June 3, 2009 
AE #200913597NA(1) 
June 3, 2009 
AE #200921359NA* 
June 8, 2009 
AE #200920427NA(1) 
June 10, 2009 
AE #200913597NA(2) 
June 12, 2009 
AE #200922309NA 
June 15, 2009 
AE #200922677GPV 
June 16, 2009 
AE #200923025NA 
June 17, 2009 
AE #200921359NA(1)* 
June 18, 2009 
AE #200922882GPV 
June 19, 2009 
AE #200915232NA(1) 
June 19, 2009 
AE #200911902BNE(1) 
June 22, 2009 
AE #200922983NA 
June 22, 2009 
AE #200923344GPV 
June 22, 2009 
AE #200923338GPV 
June 22, 2009 
AE #200923273GPV 
June 22, 2009 
AE #200923327GPV 
June 22, 2009 
AE #200923211GPV* 
* Note:    The numbering system differs from the numbering noted on the manufacturer’s report.   
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
June 15, 2009 
  
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
April 29, 2009 
AE #200918353NA 
May 7, 2009 
AE #2006032513(6) 
May 11, 2009 
AE #200919383NA 
May 11, 2009 
AE #200919936GPV 
May 11, 2009 
AE #200920113GPB 
May 13, 2009 
AE #200920420GPV 
May 21, 2009 
AE #200917399NA(1) 
May 25, 2009 
AE #200920427NA 
 
* Note:    The numbering system differs from the numbering noted on the manufacturer’s report.   
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
   
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
 
 
 
 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
June 1, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE MEDICAL 
ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  Patient enrollments 
from institutions that are not aligned with SWOG will be conducted via the NCI 
Cancer Trials Support Unit (CTSU) and all data should be sent to the SWOG Data 
Operations as specified in the CTSU logistical appendix (See Section 19.1). 
 
FROM: 
Gilbert R. Carrizales, M.S., Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast 
Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
 
(    )    Full board review required.  Reason: 
(    )   Initial activation (should your institution choose to participate) 
(    )   Increased risk to patient 
(    )   Complete study redesign 
(    )   Addition of tissue banking requirements 
(    )   Study closure due to new risk information 
 
(    )    Expedited review allowed  
 
( √ )    No review required  
 
 
MEMORANDUM 
 
UVI, Inc., drug distributor for the S0307 trial, has confirmed that they are experiencing another 
temporary shortage of clodronate tablets.  The clodronate tablets continue to be manufactured by 
Bayer Schering Pharma Oy; however, a new shipment is not expected to be released for shipment 
until next week.   
 
While we anticipate that this shortage will only last approximately 1-2 weeks, please contact UVI, 
Inc. at 800/370-2508 before registering a patient to check on available clodronate supplies and to 
adjust registration plans and/or treatment start dates accordingly.  While it is our hope that 
registered patients on the clodronate arm have necessary supplies on hand, there may be 
instances where an interruption in treatment may be experienced.  If a treatment interruption 
occurs, please contact UVI, Inc. so that clodronate re-supply requests will be expedited once the 
shortage is resolved.   
 
Note:  Any delay in the treatment start date or treatment interruption due to the drug 
shortage will not be considered a protocol deviation; however institutions should document 
in the research chart the reason for the delay/interruption.   
 
Please attach this memorandum to the front of your copy of the protocol.       
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 William E. Barlow, Ph.D. 
 
Jeannie Barrett  
 Danika Lew, M.A. 
 
Istvan Molnar– Bayer Schering Pharma Oy 
 Jean Barce 
 
Maddy Balois– CTSU 
 
 
 Lisa Gavigan 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
May 15, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(   ) 
Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(   ) 
No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
April 14, 2009 
AE #200916443NA(1) 
April 15, 2009 
AE #200916901NA 
April 17, 2009 
AE #200917399NA 
April 20, 2009 
AE #2006032513(5)* 
 
* Note:    The numbering system differs from the numbering noted on the manufacturer’s report.   
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
April 15, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
March 18, 2009 
AE #200914480NA 
March 19, 2009 
AE #200916296GPV 
March 24, 2009 
AE #200915232NA 
March 27, 2009 
AE #200815097NA(3) 
April 1, 2009 
AE #200916443NA 
April 1, 2009 
AE #200916112NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
April 1, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
March 2, 2009 
AE #200913597NA 
March 2, 2009 
AE #2007006800(2)* 
March 3, 2009 
AE #200913939GPV* 
March 6, 2009 
AE #200912953NA(1) 
 
* Note:    The numbering system differs from the numbering noted on the manufacturer’s report.   
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
Distribution Date: 
March 15, 2009 
E-mailed Date: 
March 10, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE MEDICAL 
ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  Patient enrollments 
from institutions that are not aligned with SWOG will be conducted via the NCI 
Cancer Trials Support Unit (CTSU) and all data should be sent to the SWOG Data 
Operations as specified in the CTSU logistical appendix (See Section 19.1). 
 
FROM: 
Gilbert R. Carrizales, M.S., Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast 
Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
 
(    )    Full board review required.  Reason: 
(    )   Initial activation (should your institution choose to participate) 
(    )   Increased risk to patient 
(    )   Complete study redesign 
(    )   Addition of tissue banking requirements 
(    )   Study closure due to new risk information 
 
(    )    Expedited review allowed  
 
( √ )    No review required  
 
 
MEMORANDUM 
 
UVI, Inc., drug distributor for the S0307 trial, has confirmed that they are experiencing another 
temporary shortage of clodronate tablets.  The clodronate tablets continue to be manufactured by 
Bayer Schering Pharma Oy; however, a new shipment is not expected to be released for shipment 
until next week.   
 
While we anticipate that this shortage will only last a few days, please contact UVI, Inc. at 800/370-
2508 before registering a patient to check on available clodronate supplies and to adjust 
registration plans and/or treatment start dates accordingly.  While it is our hope that registered 
patients on the clodronate arm have necessary supplies on hand, there may be instances where an 
interruption in treatment may be experienced.  If a treatment interruption occurs, please contact 
UVI, Inc. so that clodronate re-supply requests will be expedited once the shortage is resolved.   
 
Note:  Any delay in the treatment start date or treatment interruption due to the drug 
shortage will not be considered a protocol deviation; however institutions should document 
in the research chart the reason for the delay/interruption.   
 
Please attach this memorandum to the front of your copy of the protocol.       
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 William E. Barlow, Ph.D. 
 
Jeannie Barrett  
 Danika Lew, M.A. 
 
Istvan Molnar– Bayer Schering Pharma Oy 
 Jean Barce 
 
Maddy Balois– CTSU 
 
 
 Lisa Gavigan 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
March 15, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
February 12, 2009 
AE #200812671NA(3) 
February 16, 2009 
AE #200815097NA(2) 
February 20, 2009 
AE #200913537GPV 
February 23, 2009 
AE #200913715GPV 
February 23, 2009 
AE #200912953NA 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
February 15, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
January 6, 2009 
AE #200833071NA(1) 
January 6, 2009 
AE #200836438NA(1) 
January 8, 2009 
AE #200839971NA(2)* 
January 19, 2009 AE #200910081NA* 
 
*  Note:    This is a follow-up report  which differs from the numbering noted on the manufacturer’s report. 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Jens Kuhlmann – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
January 15, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
December 24, 2008 
AE #200831463NA 
December 31, 2008 
AE #200839971NA* 
*  Note:    This is a follow-up report  which differs from the numbering noted on the manufacturer’s report. 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Jens Kuhlmann – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Megan Rossmann – CTSU 
 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
January 1, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
December 3, 2008 
AE #200812671NA(2) 
December 3, 2008 
AE #200837950NA(1) 
December 3, 2008 
AE #200831128GPV 
December 5, 2008 
AE #200831457GPV 
December 11, 2008 
AE #200839971NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Jens Kuhlmann – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Megan Rossmann – CTSU 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
December 15, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
November 3, 2008 
AE #200828012GPV(2) 
November 3, 2008 
AE #200836245NA 
November 6, 2008 
AE #200835467NA(1) 
November 6, 2008 
AE #200836438NA 
November 6, 2008 
AE #200829635GPV 
November 19, 2008 
AE #200823590GPV(1) 
November 21, 2008 
AE #200829635GPV(1) 
November 21, 2008 
AE #200837950NA 
November 21, 2008 
AE #200838304NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Jens Kuhlmann – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Megan Rossmann – CTSU 
                             
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
November 15, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
October 9, 2008 
AE #200834239NA 
October 9, 2008 
AE #200835032NA 
October 17, 2008 
AE #200828012GPV 
October 21, 2008 
AE #200835467NA 
October 22, 2008 
AE #200824407NA(2) 
October 22, 2008 
AE #200834239NA(1) 
October 22, 2008 
AE #200828565GPV 
October 27, 2008 
AE #2007006800(1)* 
October 27, 2008 
AE #200828012GPV(1) 
*  Note:    This is a follow-up report  which differs from the numbering noted on the manufacturer’s report.   
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Jens Kuhlmann – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Megan Rossmann – CTSU 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
October 15, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
September 5, 2008 
AE #2007041732(1) 
September 5, 2008 
AE #200829546NA(1) 
September 23, 2008 
AE #200833071NA 
October 1, 2008 
AE #200824407NA(1) 
October 1, 2008 
AE #200833892NA 
October 3, 2008 
AE #200826944GPV 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Jens Kuhlmann – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Megan Rossmann – CTSU 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
October 1, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
August 8, 2008 
AE #200823590GPV 
August 14, 2008 
AE #200829546NA 
August 20, 2008 
AE #200816114GPV(1) 
August 28, 2008 
AE #200824957GPV 
August 29, 2008 
AE #200831463NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Jens Kuhlmann – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Megan Rossmann – CTSU 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
Distribution Date: 
September 15, 2008 
CTEP Submission Date: 
July 25, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  Patient 
enrollments from institutions that are not aligned with SWOG will be 
conducted via the NCI Cancer Trials Support Unit (CTSU) and all data should 
be sent to the SWOG Data Operations as specified in the CTSU logistical 
appendix (See Section 19.1). 
 
FROM: Gilbert R. Carrizales, M.S., Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast 
Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
REVISION #4 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
 
(    )    Full board review required.  Reason: 
(    )   Initial activation (should your institution choose to participate) 
(    )   Increased risk to patient 
(    )   Complete study redesign 
(    )   Addition of tissue banking requirements 
(    )   Study closure due to new risk information 
 
( √ )    Expedited review allowed  
 
(    )    No review required  
 
 
REVISION #4 
 
The protocol referenced above has been amended as follows: 
 
1. 
(Title page):  The version date has been updated (version 07/25/08).   
 
2. 
(Page 9a, Section 2.0, Background):  Recent information regarding the use of 
adjuvant bisphosphonate therapy has been added.   
 
3. 
(Page 26, Section 5.6, Eligibility Criteria):  The first sentence has been revised.   
 
"Patients must not be co-enrolled on protocols that have bone density as an endpoint, 
such as NCIC-CTG study MA.27." 
 
Has been changed to: 
 
"Patients must not be co-enrolled on protocols that have bone density as an 
endpoint." 
 
(Rationale:  With the recent closure of the bone density substudy, MA.27B, S0307 
patients are allowed to co-enroll in MA.27.) 
 
 
 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


S0307 
Revision #4 (contd.) 
Page 2 
 
 
 
 
4. 
(Page 30, Section 7.10, Treatment Plan):  Following the 2nd sentence, the following 
additional sentence regarding the end of treatment dental exam has been added for 
clarification: 
 
 
"The end of treatment dental examination must be performed regardless of how long 
the patient was on treatment (including one month or less)." 
 
5. 
(Page 32, Section 9.0, Study Calendar):  The first sentence of the "λ" footnote has 
been revised for clarification purposes.   
 
 
"Dental exam should be performed at the beginning and end of the treatment." 
 
 
Has been changed to: 
 
 
"Dental exam should be performed at the beginning and end of the treatment 
(regardless of how long the patient was on protocol treatment, see Section 7.10)." 
 
6. 
(Pages 36-37, Section 14.0, Data Submission Schedule):  The following changes 
have been made to this section: 
 
• Section 14.3b:  The following information regarding the submission of faxed data 
has been added at the end of this section: 
 
"Please make sure that each page of all faxed data includes the SWOG patient 
number, study ID, and patient initials." 
 
• Section 14.6:  The data submission instructions have been revised to be consistent 
with the end of treatment evaluation schedule as outlined in Section 7.10:  
 
"WITHIN 90 DAYS OF DISCONTINUATION OF TREATMENT" 
 
Has been changed to: 
 
"WITHIN 6 MONTHS OF DISCONTINUATION OF PROTOCOL TREATMENT" 
 
7. 
(Pages 44-45, Section 16.1, Adverse Event Reporting Guidelines):  The following 
changes have been made to this section: 
• Table 16.1:  This table has been updated to reflect additional reporting instructions 
for possible cases of osteonecrosis of the jaw associated with the commercial 
agent zoledronic acid (Arm 1).  More specifically, an additional footnote ("3") has 
been added to Table 16.1 stating the following: 
 
"Protocol-specific reporting requirements:  The adverse events listed below 
also require expedited monitoring for this trial:  Osteonecrosis of the jaw, occurring 
in Arm 1 patients who have received zoledronic acid.  All other adverse events on 
Arm 1 patients should be reported per guidelines in Table 16.2." 
 
• Table 16.2:  This table has been updated to reflect additional reporting instructions 
for possible cases of osteonecrosis of the jaw.  More specifically, an additional 
footnotes ("c & d") have been added to Table 16.2 stating the following, 
respectively: 
 
"Protocol-specific expedited reporting requirements: The adverse events listed 
below also require expedited monitoring for this trial:  Osteonecrosis of the jaw 
(see Table 16.1)" 
 
"Any Group-specific instructions. The SWOG Operations Office will notify 
Novartis as required." 


S0307 
Revision #4 (contd.) 
Page 3 
 
 
 
 
 
8. 
(Page 49, Section 17.0, Bibliography):  The bibliography section has been updated.  
References #66-67 have been added.   
 
9. 
(Page 50, Section 18.2, Master Forms Set):  The following changes have been made 
to this section: 
• Section 18.2a:  The S0307 Registration Form has been updated from Form 
#50085 to Form #63147.   
• Sections 18.2f & 18.2l:  The 6/1/08 version date has been included next to each 
form number. 
 
10. 
(Page 54, Model Consent Form, During the study...):  Under the paragraph that begins 
"You will need these tests and procedures...", the first bullet regarding PTHrP testing 
has been revised for editorial purposes. 
 
 
"Tumor block for PTHrP testing and banking:  a sample of tumor from the original 
biopsy will be removed and analyzed for parathyroid hormone related protein (PTHrP) 
to see if the breast cancer has spread to the bones.  If you consent, any remaining 
sample will be stored frozen for future scientific studies." 
 
Has been changed to: 
 
"Tumor block for PTHrP testing and banking:  a sample of your tumor from the original 
biopsy will be removed and analyzed for parathyroid hormone related protein (PTHrP) 
to see if this predicts the risk of your breast cancer spreading to the bones.  If you 
consent, any remaining sample will be stored frozen for future scientific studies." 
 
11. 
(Page 54, Model Consent Form, During the study...):  The paragraph that begins, "If 
you are in Group 1 (often called "Arm 1")...", has been revised to be consistent with 
the current treatment plan for zoledronic acid. 
 
"...every 4 weeks for the first six months..."  
 
Has been changed to: 
 
"...every month for the first six months..." 
 
12. 
(Page 59a, Model Consent Form, Are there benefits to taking part in the study?):  An 
additional paragraph relating to the recent information regarding the use of adjuvant 
bisphosphonate therapy has been added: 
 
"Some small trials of clodronate have suggested some possible benefit for that drug, 
although with conflicting results, and now a study with zoledronic acid showed benefit 
for dosing twice a year in pre-menopausal women, with estrogen-receptor positive 
breast cancer receiving ovarian suppression and not chemotherapy.  However, at 
present, it is not standard of care to give these drugs in the majority of breast cancer 
patients."   
 
13. 
Page 62, Model Consent Form, Additional research studies):  The following editorial 
changes have been made to each of the yes/no questions relating to tissue/blood 
testing: 
 
• 
Tissue 
 
"I agree to submit a tissue specimen...to see if this predicts the risk of your breast 
cancer spreading to the bones." 
 
Has been changed to: 
 
"I agree to submit a tissue specimen...to see if this predicts the risk of my breast 
cancer spreading to the bones." 


S0307 
Revision #4 (contd.) 
Page 4 
 
 
 
 
 
• 
Blood 
 
"I agree to submit a blood sample...to see if high levels will predict the risk of your 
breast cancer spreading to the bones." 
 
Has been changed to: 
 
"I agree to submit a blood sample...to see if high levels will predict the risk of my 
breast cancer spreading to the bones." 
 
• 
Formatting changes were made throughout the section which did not affect 
content.   
 
Institutions should update their Model Consent Forms to include the above information 
for future registrations. Patients currently being treated on this study should be 
informed of these changes in the manner determined by the local institutional review 
board (IRB). 
 
The Southwest Oncology Group considers that the changes in the Model Consent Form 
that are associated with this revision are solely administrative and editorial in nature 
and do not significantly impact the risk/benefit ratio for participants on this study.  
Local accrual to the study does not need to be suspended pending implementation of 
these changes. 
 
Please attach this memorandum to the front of your copy of the protocol and insert the 
replacement pages.  
 
This memorandum serves to inform the Southwest Oncology Group Statistical Center and the 
NCI. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 William E. Barlow, Ph.D. 
 
 Danika Lew, M.A. 
 
 Jean Barce 
 
 Lisa Gavigan 
 
 Jeri Jardine 
Jennie Barrett 
Lars H. Breimer – Bayer Schering Pharma Oy 
Diep Tran – Novartis  
Edward McKenna – Roche 
Megan Rossmann – CTSU 
 
 
 


 
 
 
 
 
September 1, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 ( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
July. 31, 2008 
AE 200816556GPB(1) 
August. 4, 2008 
AE 200822387NA(1) 
August. 4, 2008 
AE 200828478NA 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Jennie Barrett 
 
Danika Lew, M.A. 
Istvan Molnar – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Maddy Balois – CTSU 
 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
August 1, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
June 27, 2008 
AE #200825602NA 
June 27, 2008 
AE #200715313NA(2) 
July 14, 2008 
AE #200825602NA(1) 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Christine McLeod 
 
Danika Lew, M.A. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Megan Rossmann – CTSU 
 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
July 1, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
June 10, 2008 
AE #200815097NA(1) 
June 11, 2008 
AE #200824407NA 
June 12, 2008 
AE #200811207LA(1) 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 
William E. Barlow, Ph.D. 
Christine McLeod 
 
Danika Lew, M.A. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Jean Barce 
Joyce Mull – NSABP 
 
Lisa Gavigan 
Megan Rossmann – CTSU 
 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
June 15, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
May 14, 2008 
AE #200821861NA 
May 14, 2008 
AE #200821886NA 
May 16, 2008 
AE #200822387NA 
May 20, 2008 
AE #200820008NA(2) 
May 29, 2008 
AE #200818891GPV 
May 30, 2008 
AE #200818690GPV 
May 30, 2008 
AE #200812671NA(1) 
June 3, 2008 
AE #200819168GPV 
June 4, 2008 
AE #200715313NA(1) 
June 5, 2008 
AE #200811207LA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Diep Tran - Novartis 
 
Jean Barce 
Marie-Paule Schoerlin – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
June 1, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
April 22, 2008 
AE #200816643GPV 
April 23, 2008 
AE #200816556GPV 
April 23, 2008 
AE #200820008NA 
May 1, 2008 
AE #200820008NA(1) 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Diep Tran - Novartis 
 
Jean Barce 
Marie-Paule Schoerlin – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
Distribution Date: 
June 1, 2008 
CTEP Submission Date: March 11, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  Patient 
enrollments from institutions that are not aligned with SWOG will be 
conducted via the NCI Cancer Trials Support Unit (CTSU) and all data should 
be sent to the SWOG Data Operations as specified in the CTSU logistical 
appendix (See Section 19.1). 
 
FROM: Gilbert R. Carrizales, M.S., Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast 
Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
AMENDMENT #2 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
 
( √ )   Full board review required.  Reason: 
(    )   Initial activation (should your institution choose to participate) 
( √ )   Increased risk to patient 
(    )   Complete study redesign 
(    )   Addition of tissue banking requirements 
(    )   Study closure due to new risk information 
 
(   )  Expedited review allowed  
 
(   )   No review required  
 
 
AMENDMENT #2 
 
The protocol referenced above has been amended as follows: 
 
1. 
(Amendment #1, distributed 10/15/07, item #7, page 2):  A typo in the change was 
incorrectly described as Section 3.2a.  The correct section should be Section 3.2c.    
 
2. 
(Fast Fact Sheet):  The following changes have been made to this page: 
• Treatment (Arm 1 – Zoledronic acid):  "q 4 weeks for 6 months…" has been 
changed to "q monthly for 6 months".   
• Prestudy requirements:  The timeframe for the prestudy pregnancy test has 
corrected.  "≤ 24-72 hours" has been changed to ""≤ 72 hours".   
 
(Reason:  The prestudy requirement and treatment sections have been changed to 
match the modifications to the eligibility criteria and treatment plan, Sections 5.0 and 
7.0, respectively.  See also items #6 and #9 below.) 
 
3. 
(Title page):  The following changes have been made to this page: 
• The version date has been updated (version 03/11/08).   
• Under the participant list, the bolded statement "Patient enrollments…should be 
sent to the SWOG Data Operations unless otherwise specified…" has been 
changed to: "Patient enrollments…should be sent to the SWOG Data Operations 
Center as specified…" 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


S0307 
Amendment #2 (contd.) 
Page 2 
 
 
 
 
 
4. 
(Page 4, CTSU Contact Information):  In the patient enrollment column, the following 
updated CTSU information has been added: 
• The CTSU office hours have changed from 8:00 am – 8:00 pm EST to 9:00 am – 
5:30 pm EST. 
• The statement in brackets that begins "For CTSU patient enrollments that must be 
completed within approximately one hour…" has been replaced with the following:   
 
"Registrations received after 5:00 pm EST will be handled the next business day.  
For CTSU enrollments that must be completed within approximately one hour, or 
other extenuating circumstances, call 301/704-2376 between 9:00 am – 5:30 pm 
EST." 
 
5. 
(Page 15, Section 3.1b, Background):  The zoledronic acid (Zometa®) drug 
information section has been modified to include new adverse event information.  
Particularly important are the new labeling changes in the toxicology section 
regarding musculoskeletal pain, ocular adverse events, and hypersensitivity 
reactions.  (Reason:  This section was updated to be consistent with the most recent 
zoledronic acid package insert.)  Page 15a has been added to prevent extensive 
repagination. 
 
6. 
(Page 27, Section 5.12, Eligibility Criteria):  The last sentence has been amended.  
"Women of child-bearing potential must have a pregnancy test within 24-72 hours 
prior to initiation of treatment" has been changed to "Women of child-bearing potential 
must have a pregnancy test within 72 hours prior to initiation of treatment".  (Reason:  
This change was made in order to allow pregnancy tests to be performed on Friday 
preceding treatment the following Monday.) 
 
7. 
(Page 28, Section 7.1, Good Medical Practice):  The following changes have been 
made to this section: 
• Section 7.1d:  Magnesium testing has been added.  (Reason:  This change was 
made to provide consistency as magnesium testing is listed in the study calendar, 
Section 9.0.) 
• Section 7.1e:  The electrolyte chemical names for "Na+, K+, Cl-, HCO3
-" have been 
changed to "sodium, potassium, chloride, and bicarbonate", respectively.  (Reason:  
This change was made for editorial purposes.) 
 
8. 
(Page 28, Section 7.2, Treatment Plan):  This section has been titled "Pre-Treatment 
Guidelines."  In the second bolded paragraph, "Women of child-bearing potential must 
have a pregnancy test performed within 24-72 hours prior to initiation of treatment" 
has been changed to "Women of child-bearing potential must have a pregnancy test 
performed within 72 hours prior to initiation of treatment".  (Reason:  See item #6 
above.) 
 
9. 
(Page 29, Section 7.3, Treatment Plan):  The following changes have been made to 
this page: 
• This title of this section, "Treatment Plan" has been changed to "Treatment 
Schedule".  (Reason:  This change was made for editorial purposes.)   
• The following dosing instructions have been amended: 
 
"For patients receiving zoledronic acid, peripheral or central intravenous access 
may be used.  Every effort should be made to administer zoledronic acid to 
patients in Arm 1 every 4 weeks during the first 6 months of dosing, however minor 
deviances from these dosing intervals are acceptable.  It is suggested that the 
infusions be given within ± 2 days (2 days earlier or later).  During the remaining 
period of dosing, zoledronic acid may be given within ± 7 days (7 days earlier or 
later). The last dose of zoledronic acid in Arm 1 should be administered at Month 
33. Oral bisphosphonates given in Arms 2 and 3 are to continue daily until the first 
day of Month 36 and are then discontinued." 
 


S0307 
Amendment #2 (contd.) 
Page 3 
 
 
 
 
 
Has been changed to: 
 
"For patients receiving zoledronic acid, peripheral or central intravenous access 
may be used.  During the first 6 months of dosing, zoledronic acid should be 
administered to patients in Arm 1 monthly, however, minor deviances from this 
dosing interval are acceptable.  It is suggested that the infusions be given within ± 
1 week (7 days earlier or later).  During the remaining period of dosing, zoledronic 
acid may be given within ± 1 week (7 days earlier or later).  The last dose of 
zoledronic acid in Arm 1 should be administered at Month 33. Oral 
bisphosphonates given in Arms 2 and 3 are to continue daily until the first day of 
Month 36 and are then discontinued."  (Reason:  This change from q 4 weeks to q 
monthly was made to provide consistency with the schema of the trial.)  
 
• Treatment table:  The interval of zoledronic acid dosing has been changed from "q 
4 weeks x 6 months…" to "q monthly x 6 months…"  (Reason:  This change from q 
4 weeks to q monthly was made to provide consistency with the schema of the 
trial.) 
 
10. 
(Page 29, Section 7.4, Treatment Plan):  The section has been titled "Dental 
Examination".  (Reason:  This change was made for editorial purposes.)   
 
11. 
(Page 30, Section 7.9, Treatment Evaluations):  A new Section 7.9 titled "Treatment 
Evaluations" has been included that clarifies the timing of physical exams and lab 
testing while on protocol treatment as follows (subsequent sections have been re-
organized): 
 
"Physical exams and labs (including CBC, electrolytes, calcium, phosphate, 
magnesium, albumin, and LFTs) should be performed prior to dosing (ideally Day 1) of 
Month 2, 4, 6, then q 3 months until Month 36. 
 
For Arm 1, serum creatinine testing must be performed within 7 days prior to 
administering subsequent zoledronic acid dosing q monthly for Months 2-6, then q 3 
months until Month 36. 
 
For Arms 2 & 3, serum creatinine testing should be performed ± 7 days (7 days earlier 
or later) q monthly for Months 2-6, then q 3 months until Month 36."   
 
Page 30a has been added to prevent extensive repagination. 
 
12. 
(Page 30, Section 7.10, End of Treatment Evaluation):  The first sentence has been 
amended.  "A bone scan will be obtained in all patients…" has been changed to "An 
end of treatment physical examination and a bone scan will be obtained in all 
patients…" (Reason:  This change was made to highlight the end of treatment 
physical examination that is required upon study completion in addition to the bone 
scan and final dental examination.)   
 
13. 
(Page 31, Section 8.2, Toxicities to be Monitored):  Patient removal instructions have 
been amended as follows:    
 
"Any Grade 3 or greater toxicity (that is attributed to the bisphosphonate by the 
treating physician) will require removal of the patient from protocol treatment." 
 
Has been changed to: 


S0307 
Amendment #2 (contd.) 
Page 4 
 
 
 
 
 
"Bisphosphonate therapy must be held for any Grade 3 or greater toxicity (that is 
attributed to the bisphosphonate by the treating physician).  If toxicity has not resolved 
within 4 weeks, then the patient must be removed from protocol treatment.  If toxicity 
resolves (Grade 0-1) within 4 weeks, the protocol treatment should be restarted.  If 
Grade 3 or greater toxicity reoccurs, then the patient must be removed from protocol 
treatment."   
 
(Reason:  This change was made to allow patients to remain on bisphosphonate 
treatment after resolution of Grade 3 or greater toxicity.) 
 
14. 
(Page 32, Section 9.0, Study Calendar):  The following changes have been made to 
this page: 
• Ω footnote:  The instructions for the zoledronic acid treatment footnote have been 
amended.   
 
"Zoledronic acid will be administered by IV on Day 1 q 4 weeks for the first 6 
months, however minor deviations are acceptable.  It is suggested that the 
infusions be given within ± 2 days (2 days earlier or later).  During the remaining 
period of dosing, zoledronic acid may be given within ± 7 days (7 days earlier or 
later)." 
 
Has been changed to: 
 
"Zoledronic acid will be administered by IV on Day 1 q monthly for the first 6 
months, however minor deviations are acceptable.  It is suggested that the 
infusions be given within ± 1 week (7 days earlier or later).  During the remaining 
period of dosing, zoledronic acid may be given within ± 1 week (7 days earlier or 
later)." 
 
• ƒ footnote:  The instructions for the patient follow-up footnote have been amended.   
 
"Patients off treatment prior to recurrence should return for disease assessments at 
least every 6 months for 5 years…" 
 
Has been changed to: 
 
"All patients including patients off treatment prior to recurrence should return for 
disease assessments at least every 6 months for 5 years…" 
 
• ◊ footnote:  The instructions for the serum creatinine footnote have been amended.   
 
"To be performed within 7 days prior to registration, and within 7 days prior to 
administering all subsequent doses."…" 
 
Has been changed to: 
 
"Arm 1:  To be performed within 7 days prior to registration, and within 7 days prior 
to administering all subsequent doses.  Arm 2/Arm 3:  To be performed within 7 
days prior to registration, and within ± 7 days (7 days earlier or later) of q monthly 
for Months 2-6 and q 3 month patient visits." 
 
(Reason:  Study calendar changes were made provide consistency with the 
protocol changes as noted above.) 
 


S0307 
Amendment #2 (contd.) 
Page 5 
 
 
 
 
15. 
(Page 37, Section 14.0, Data Submission Schedule):  The following changes have 
been made to this section:   
 
• Section 14.5:  A new S0307 Serum Creatinine Reporting Form (Form #60188) has 
been added.  This form should be submitted during treatment at 6 months, and 
Year 1, 2 and 3. 
 
• Section 14.7:  The data submission instructions have been amended as follows: 
 
WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT: 
 
Submit the Off Treatment Notice Form (Form #8756) and S0307 Supplementary 
Off-Treatment Form (Form #24801).   
 
Has been changed to:   
 
"WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT: 
 
Submit copies of the following: 
  
a. 
Off Treatment Notice (Form #8756)  
b. 
S0307 Supplementary Off Treatment Form (Form #24801)  
c. 
Final S0307 Treatment Form (Form #31453) for current reporting period  
d. 
Final S0307 Adverse Event Summary Form (Form #11093)" 
 
• Section 14.8:  The S0307 Supplementary Follow-Up Form (Form #9679) has been 
replaced with Form #36846.   
  
• Section 14.9:  The data submission instructions have been amended as follows: 
 
WITHIN 14 DAYS OF PROGRESSION/RELAPSE: 
 
Submit the Follow-Up Form (Form #64587) and S0307 Supplementary Follow-Up 
Form (Form #9679).   
 
Has been changed to:   
 
"WITHIN 14 DAYS OF PROGRESSION/RELAPSE: 
 
Submit copies of the following: 
  
a. 
Follow-up Form (Form #64587) documenting date, site and method for 
determining malignancy  
b. 
S0307 Supplementary Follow-Up Form (Form #36846)  
c. 
If patient was still on treatment, final S0307 Treatment Form (Form 
#31453) for current reporting period  
d. 
If patient was still on treatment, final S0307 Adverse Event Summary Form 
(Form #11093)" 
 
Page 37a was added to prevent extensive repagination. 
 
16. 
(Page 38, Section 15.2c, Special Instructions):  In the paragraph that begins, "To 
report technical problems with Specimen Tracking…", the website link for the 
Specimen 
Tracking 
system 
has 
been 
changed 
from 
"http://dnet.crab.org/SpecTrack/Documents/SpecTPrimer-Insts.pdf" 
to 
"https://gill.crab.org/SpecTrack/Documents/Instructions.pdf".   


S0307 
Amendment #2 (contd.) 
Page 6 
 
 
 
 
 
17. 
(Pages 39 & 41, Sections 15.3e & 15.4d, respectively, Special Instructions):  The 
room number for shipping specimens to the SWOG Solid Tumor Bank has changed 
from "L18-5104" to "L18-5400A".  Also, the zip code has been updated from "80010" 
to "80045". 
 
18. 
(Page 42, Section 16.1, Adverse Event Reporting Requirements):  The following 
changes have been made to this section: 
• Section 16.1b:  CTEP no longer accepts phone or fax notification of SAEs which 
require 24-hour reporting. All such reports must now be submitted via AdEERS. In 
addition, use of AdEERS paper templates as a substitute for on-line AdEERS 
reporting is no longer allowed.  Thus, the ADEERS reporting instructions have 
been updated as follows:   
 
"This study requires that expedited adverse event reporting use the NCI’s Adverse 
Event Expedited Reporting System (AdEERS). The NCI’s guidelines for AdEERS 
can be found at http://ctep.cancer.gov. An AdEERS report must be submitted to the 
Southwest Oncology Group Operations Office electronically via the AdEERS Web-
based application located at http://ctep.cancer.gov." 
 
• Section 16.1c:  The following instructions have been amended.  "When the adverse 
event requires expedited reporting, submit the report within 7 working days of 
learning of the event" has been changed to "When the adverse event requires 
expedited reporting, submit the report within the number of calendar days of 
learning of the event as specified in Table 16.1 or 16.2, as applicable."  (Reason:  
This change was made to provide consistency with the ADEERS reporting 
instructions as specified in Tables 16.1 and 16.2.) 
 
19. 
(Page 45, Section 16.0, Adverse Event Reporting Requirements):  The following 
changes have been made to this section: 
• Table 16.1:  Table 16.1 has been updated to reflect changes in Southwest 
Oncology Group Policy No. 23.  More specifically, an additional footnote ("b") has 
been added to Table 16.1 stating that following an AdEERS report, supporting data 
need not be submitted unless specifically requested by SWOG.  
• Section 16.1f:  The instructions for reporting secondary AML/MDS to the 
Investigational Drug Branch have been updated.   
 
"All cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that 
occur in patients on NCI-sponsored trials following chemotherapy for cancer must be 
reported using the NCI/CTEP Secondary AML/MDS Report Form in lieu of AdEERS. 
The following supporting documentation must also be submitted within 30 days." 
 
Has been changed to: 
 
"All cases of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and 
myelodysplastic syndrome (MDS) that occur in patients on NCI-sponsored trials 
following chemotherapy for cancer must be reported using the NCI/CTEP Secondary 
AML/MDS Report Form in lieu of AdEERS. The form can be downloaded at 
http://ctep.cancer.gov/forms/33-AML_20Form_20v1.pdf. The following supporting 
documentation must also be submitted within 30 days."   
 
20. 
(Page 50, Section 18.0, Master Forms Set):  The following changes have been made 
to this section: 
 
• Section 18.2f:  The S0307 Supplementary Follow-Up Form (Form #9679) has been 
replaced with Form #36846.   
• Section 18.2l:  The S0307 Serum Creatinine Reporting Form (Form #60188) has 
been added.   


S0307 
Amendment #2 (contd.) 
Page 7 
 
 
 
 
 
21. 
(Page 53, Model Consent Form, Before you being the study…):  The last bullet has 
been amended.  "Women …must have a pregnancy test performed within 24-72 
hours…" has been changed to "Women…must have a pregnancy test performed 
within 72 hours…" (Reason:  See item #6 above.) 
 
22. 
(Page 55, Model Consent Form, Study Chart):  The timing of pregnancy testing in the 
first column, fourth row, has been updated.  "Within 24-72 hours prior to starting 
study" has been changed to "Within 72 hours prior to starting study".  (Reason:  See 
item #6 above.) 
 
23. 
(Page 56, Model Consent Form, When you are finished taking study drugs…):  "You 
will need to see your study doctor for a physical examination and bone scan.  
Additionally, you will need to have a dental examination within 90 days of completing 
treatment" has been changed to "You will need to see your study doctor for a physical 
examination and bone scan.  Additionally, you will need to have a dental examination 
within 6 months of completing treatment or being removed from study."  (Reason:  
This change was made for editorial purposes.) 
 
24. 
(Page 58, Model Consent Form, What side effects or risks can I expect from being in 
the study?):  The following changes have been made to this section: 
• Zoledronic Acid:  Under the rare, but serious category of risks for zoledronic acid 
the following new risks related to inflammation of the eyes and allergic reaction 
have been added as provided by the FDA MedWatch Safety Program: 
• 
Inflammation of the eyes can occur with zoledronic acid use.  Symptoms can 
include red eye, eye pain, and/or decreased/blurry vision.  In some cases, 
these events did not improve until the zoledronic acid was discontinued. 
• 
Allergic reaction:  There have been rare reports of allergic reaction with 
intravenous zoledronic acid including swelling in the mouth or throat making it 
difficult to breath.  Very rare cases of anaphylactic reaction/shock have also 
been reported. 
 
25. 
(Page 59, Model Consent Form, What side effects or risks can I expect from being in 
the study?):  A new paragraph regarding severe bone pain has been included to 
address recent toxicity information regarding the incidence of severe bone pain while 
on bisphosphonate treatment:   
 
Severe bone pain:  Rare reports of severe and occasionally disabling bone, joint, 
and/or muscle pain has been reported with bisphosphonate use.  The severe bone, 
joint, and/or muscle pain may occur within days, months, or years after starting a 
bisphosphonate. Some patients have reported complete relief of symptoms after 
discontinuing the bisphosphonate, whereas others have reported slow or incomplete 
recovery. The risk factors that contribute to severe bone, joint, and/or muscle pain 
associated with bisphosphonates are unknown. 
 
Page 59a was added to prevent extensive repagination.   
 
26. 
(Page 63, Model Consent Form, Consent Form for Use of Specimens for Research):  
The room number for the SWOG Solid Tumor Bank has changed from "L18-5104" to 
"L18-5400A" and the zip code has been changed from "80010" to "80045".     
 
27. 
(Page 85, Section 19.1, CTSU Participation Procedures):  Under the "CTSU 
Procedures for Patient Enrollment" section, item #3, the CTSU office hours have 
changed from 8:00 a.m. and 8:00 p.m. to 9:00 a.m. and 5:30 p.m.   
 
 
 


S0307 
Amendment #2 (contd.) 
Page 8 
 
 
 
 
 
Institutions must update their local consent form to include the above information.  
Patients currently being treated on this study must be informed of these changes at 
their next scheduled visit and the notification process documented.   
 
Please attach this memorandum to the front of your copy of the protocol and insert the 
replacement pages.  
 
This memorandum serves to inform the Southwest Oncology Group Statistical Center and the 
NCI. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
 
 William E. Barlow, Ph.D. 
 
 Danika Lew, M.A. 
 
 Jean Barce 
 
 Lisa Gavigan 
 
 Jeri Jardine 
 
Christine McLeod 
Lars H. Breimer – Bayer Schering Pharma Oy 
Diep Tran – Novartis  
Edward McKenna – Roche 
Megan Rossmann – CTSU 
 
 
 


 
 
 
 
 
 
May 1, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
April 9, 2008 
AE #200810824GPV(1) * 
April 10, 2008 
AE #200816114GPV 
 
* Bayer's F/U #1 and F/U #2 were issued within days of each other. Instead of issuing both reports, F/U #2 was issued since 
it was the most current report (and inclusive of all information known to date).  Therefore, this report is considered F/U #1 
since this was the first time we were issuing a follow-up report for Bayer #200810824GPV. 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Diep Tran - Novartis 
 
Jean Barce 
Marie-Paule Schoerlin – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
April 15, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp). 
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
March 3, 2008 
AE #200711360BNE(3) 
March 3, 2008 
AE #200813940GPV 
March 6, 2008 
AE #200715690NA(1) 
March 11, 2008 
AE #200814162GPV 
March 11, 2008 
AE #200815097NA 
March 14, 2008 
AE #200816063NA 
March 14, 2008 
AE #200816075NA 
March 21, 2008 
AE #200813940GPV(1) 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Diep Tran - Novartis 
 
Jean Barce 
Marie-Paule Schoerlin – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
March 15, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate).  Please access these safety reports via the safety 
report 
link 
in 
the 
member 
section 
of 
the 
Southwest 
Oncology 
Group 
website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
February 20, 2008 
AE #200813728NA 
February 21, 2008 
AE #200813730NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Diep Tran - Novartis 
 
Jean Barce 
Marie-Paule Schoerlin – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
March 1, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
January 21, 2008 
AE #200810824GPV 
January 30, 2008 
AE #200811720GPV 
February 8, 2008 
AE #200812652NA 
February 8, 2008 
AE #200812671NA 
February 13, 2008 
AE #200813174NA 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Diep Tran - Novartis 
 
Jean Barce 
Marie-Paule Schoerlin – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
January 15, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
December 19, 2007 
AE #200718095GPV 
December 20, 2007 
AE #200715690NA 
December 24, 2007 
AE #200716245NA 
January 3, 2008 
AE #200711360BNE(1) 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Simone Lake - Novartis 
 
Jean Barce 
Marie-Paule Schoerlin – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
January 1, 2008 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
November 21, 2007 
AE #2007042893 
December 4, 2007 
AE #200714883NA 
December 11, 2007 
AE #200715679NA 
December 12, 2007 
AE #200715313NA(1) 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Simone Lake - Novartis 
 
Jean Barce 
Marie-Paule Schoerlin – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
December 15, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
November 9, 2007 
AE #2007040750 
November 9, 2007 
AE #2007041732 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Simone Lake - Novartis 
 
Jean Barce 
Marie-Paule Schoerlin – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
December 15, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  Patient 
enrollments from institutions that are not aligned with SWOG will be conducted 
via the NCI Cancer Trials Support Unit (CTSU) and all data should be sent to the 
SWOG Data Operations unless otherwise specified in the CTSU logistical 
appendix (See Section 19.1). 
 
FROM: 
Gilbert R. Carrizales, M.S., Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone number:  206/288-7722 
E-mail:  pink@u.washington.edu 
 
IRB Review Requirements 
 
 (   ) Full board review required.  Reason: 
 
(   ) 
Initial activation (should your institution choose to participate) 
 
(   ) 
Increased risk to patient 
 
(   ) 
Complete study redesign 
 
(   ) 
Addition of tissue banking requirements 
 
(   ) 
Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(   ) No review required 
 
 
MEMORANDUM 
 
In order to familiarize advocacy groups with current Southwest Oncology Group (SWOG) clinical 
trials and to help with accrual to these trials, the SWOG Lay Advocate Committee will be 
disseminating trial and study information to advocacy groups.  We encourage you to print the 
attached patient information sheet regarding the S0307 trial (approved by the NCI Central IRB, 
August 29, 2007) in newsletters and/or to distribute in any other manner to your constituencies. 
 
Please attach this memorandum to the front of your copy of the protocol.       
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE Christine McLeod 
 William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 Danika Lew, M.A. 
Simone Lake – Novartis  
 Jean Barce 
Marie-Paule Schoerlin – Roche 
 Lisa Gavigan 
Megan Rossmann – CTSU 
 Jeri Jardine 
 
 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


S0307
This document does not take the place of the informed consent or information provided by your study doctor.
Research Study of Bisphosphonate Therapy
for Breast Cancer
This study is investigational and is being done to find out if adding a drug (called a
bisphosphonate) to hormonal therapy and/or chemotherapy will help prevent cancer from
spreading to the bones or other parts of the body.
If you choose to participate in this study, a computer will assign you by chance to 1 of
the 3 groups below.  This research study is being done to see if there is any difference
between the 3 different bisphosphonate drugs.
Group 1 (or Arm 1):
You will be given a 4 mg
infusion of zoledronic
acid through a needle in
your vein.  This drug will
be given for
15 minutes once every
4 weeks for the first
6 months and then once
every 3 months after that
for 30 more months (36
months total).
Group 2 (or Arm 2):
You will take 1600 mg of
clodronate by mouth
once every day for
36 months
Group 3 (or Arm 3):
You will take 50 mg of
ibandronate by mouth
once every day for
36 months
All 3 groups will be asked to take bisphosphonates for 3 years.  Throughout the 3-year period,
you will visit your study doctor on a regular basis (see schedule on next page).  After you are
finished taking bisphosphonates, your study doctor will ask you to visit the office for follow-up
exams every year for a length of 10 years.  You can stop your participation at any time by
contacting your study doctor to discuss how to stop safely.
Your study doctor will discuss the specific risks of each treatment.
Side Effects:
You may have side effects while on the study.  Everyone taking part in the study will be
watched carefully for any side effects; however, doctors don’t know all the side effects that
may happen.  Side effects may be mild or very serious.  Common side effects associated with
bisphosphonates include nausea, vomiting, reflux, and diarrhea.  Uncommon, but serious, side
effects include the possibility of a specific type of damage to the jawbone (a condition called
osteonecrosis of the jaw) and damage to an unborn baby or a baby who is breastfeeding.
Bisphosphonates are drugs that prevent bone from breaking
down.  Low doses of bisphosphonate drugs are used to treat
osteoporosis; higher doses of bisphosphonate drugs are used to
treat cancer that has spread to the bone.  Higher doses of
bisphosphonate drugs will be used in this study in the amounts
listed above for Group 1, Group 2, or Group 3.


S0307
This document does not take the place of the informed consent or information provided by your study doctor.
Research Study of Bisphosphonate Therapy
for Breast Cancer
If you choose to participate in this study, a computer will assign you by chance to 1 of the
3 groups listed below.  There is no “placebo” in this study.
zoledronic acid (4 mg, given by infusion once a month for 6 months, then once every
3 months for a total of 3 years)
clodronate (1600 mg, given as 2 pills taken daily for 3 years)
ibandronate (50 mg, given as 1 pill taken daily for 3 years)
The drugs used in this study have been tested in research studies around the world.
If using zoledronic acid, you will receive an infusion in your
vein at your study doctor’s office
If using clodronate, you will begin taking the medication
If using ibandronate, you will begin taking the medication
Day 1:
Month 1
Months
2, 4, 6
After
completing
the study
Physical exams with your study doctor every 6 months for
5 years then yearly until Year 10
Prior to study
Routine exams (including dental exam), tests, and procedures to
find out if you can be in the study
Brief Study Schedule
Months
3, 5
Serum creatinine blood tests (to be sure your kidneys are
working properly)
Months
9, 12, 15, 18,
21, 24, 27,
30, 33, 36
Routine blood tests
Physical examination (x-ray and scans as needed for disease
assessment)
Serum creatinine blood tests (to be sure your kidneys are
working properly)
End of study
drug
treatment
Physical examination
Dental exam
Bone scan
Routine blood tests
Physical examination (x-ray and scans as needed for disease
assessment)
Serum creatinine blood tests (to be sure your kidneys are
working properly)


S0307
This document does not take the place of the informed consent or information provided by your study doctor.
Osteonecrosis of the Jaw in a Research Study of
Bisphosphonate Therapy for Breast Cancer
What is osteonecrosis of the jaw?
Osteonecrosis of the jaw is another name for a specific type of damage to the jawbone.
It is a very uncommon but serious possible side effect of taking drugs called
bisphosphonates.
Why do I need to understand osteonecrosis of the jaw?
Although this possible side effect is very uncommon, recent reports suggest a possible
link between the use of bisphosphonates that are given intravenously (through a vein in
your arm), such as zoledronic acid, and osteonecrosis of the jaw.  Bisphosphonate drugs
that are given by mouth, such as clodronate and ibandronate, may also increase the risk
of osteonecrosis of the jaw.  It is possible that you are more likely to experience
osteonecrosis of the jaw if you are taking other cancer treatment drugs at the same time
you are taking a bisphosphonate drug.
How will I know if I have osteonecrosis of the jaw?
Your study doctor will help you determine if you could have osteonecrosis of the jaw.
Some of the signs may be pain in your jaw, toothaches, loose teeth, or sores on your
gums that do not heal.  This condition may happen after you have a tooth pulled or after
other dental procedures.
What can I do to prevent osteonecrosis of the jaw?
We do not know exactly what causes osteonecrosis of the jaw so it is important to
diagnose it early.  You should continue to have regular dental exams throughout your
participation in this trial.  If you have any major dental work planned, please talk to
both your dentist and your study doctor.  In addition, you should tell your study doctor
immediately if you have infections or sores in your mouth that do not go away.
Keeping your teeth and gums healthy is important to your overall health. Good oral
health begins with a well-balanced diet, the use of mouth rinses (as directed by your
health care providers), follow-up dental care, and avoidance of tobacco and alcohol.
Your study doctor can provide additional information and answer any
questions you may have.


 
 
 
 
 
 
November 15, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
October 18, 2007 
AE #2007038758 
October 23, 2007 
AE #2007038539 
November 7, 2007 
AE #2007040962 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Simone Lake - Novartis 
 
Jean Barce 
Ulf Wiegand – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
November 1, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
September 20, 2007          AE #2007034510 
September 20, 2007          AE #2007028574 
September 26, 2007          AE #2007034745 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Simone Lake - Novartis 
 
Jean Barce 
Ulf Wiegand – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
 
 
 
 
Distribution Date: 
October 15, 2007 
CTEP Submission Date: June 18, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE MEDICAL 
ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  Patient enrollments 
from institutions that are not aligned with SWOG will be conducted via the NCI 
Cancer Trials Support Unit (CTSU) and all data should be sent to the SWOG Data 
Operations unless otherwise specified in the CTSU logistical appendix (See Section 
19.1). 
 
FROM: Gilbert R. Carrizales, M.S., Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast 
Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston  
 
AMENDMENT #1 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
 
( √ )   Full board review required.  Reason: 
(    )   Initial activation (should your institution choose to participate) 
( √ )   Increased risk to patient 
(    )   Complete study redesign 
(    )   Addition of tissue banking requirements 
(    )   Study closure due to new risk information 
 
(   )  Expedited review allowed  
 
(   )   No review required  
 
 
AMENDMENT #1 
 
The protocol referenced above has been amended as follows: 
 
1. 
(Revision #3, distributed 4/1/07, item #2):  A typo in the version date incorrectly 
described the version date as 01/15/07.  The version date has been corrected to 
"01/25/07".  
 
2. 
(Fast Fact Sheet):  The following changes have been made to this page: 
• Drugs provided:  Berlex/Schering (producer of clodronate) has merged with Bayer 
and has changed its name to "Bayer Schering Pharma Oy". 
• Eligibility:  In the second row, the first sentence has been revised.  "Must receive 
standard adjuvant therapy for breast cancer" has been changed to "Must receive 
standard (systemic) adjuvant therapy for breast cancer".  Also, the following new 
statements have been added:  "Additional therapies are allowed including radiation 
therapy and biologic agents (e.g. Herceptin®, Avastin®, hematopoietic growth 
factors).  Neoadjuvant therapy is permitted, but enrollment must occur after 
completion of surgery." 
• Eligibility:  In the third row, the following new statement has been added to the end 
of the paragraph:  "Additional biological therapy or radiation therapy is allowed at 
any time before or after registration." 
• Eligibility:  In the eighth (last) row, the criterion that begins with "Must not be co-
enrolled on protocols that have bone density as an endpoint..." has been moved to 
the ineligibility criteria column.   
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 
 


 
S0307 
 
Amendment #1 (contd.) 
 
Page 2 
 
Amended 3/11/08 
 
 
 
 
 
 
 
 
 
• Ineligibility:  In the second row, the following ineligibility criteria have been added:  
"Use of biologic agents only or local radiation therapy only (without chemotherapy 
and/or hormone therapy)" and "Patients who are at such a low risk of recurrence 
that adjuvant therapy will not be prescribed.   
• Prestudy requirements:  Regarding the timing of the dental examination, "≤ 6 
months before registration" has been changed to "≤ 6 months before initiation of 
treatment".  Also, the following has been added under the prestudy requirements:  
"≤ 24 – 72 hours before initiation of treatment:  Pregnancy test (for women of 
childbearing potential)".  
 
(Reason:  The eligibility, ineligibility, and prestudy requirement sections have been 
changed to match the modifications to the eligibility criteria, Section 5.0 [see item #8 
below].) 
 
3. 
(Title page):  The following changes have been made to this page: 
• The version date has been updated (version 06/18/07).   
• The table of contents has been updated. 
• Under the participant list, the bolded statement "Non-Southwest Oncology Group 
participants must register through the CTSU" has been changed to "Patient 
enrollments from institutions that are not aligned with SWOG will be conducted via 
the NCI Cancer Trials Support Unit (CTSU) and all data should be sent to the 
SWOG Data Operations unless otherwise specified in the CTSU logistical 
appendix (See Section 19.1). 
• Under the agent list, "Berlex/Schering" has been changed to "Bayer Schering 
Pharma Oy". 
 
4. 
(Page 11, Section 2.0, Background):  Under the discussion of osteonecrosis of the jaw 
(ONJ), third paragraph, recent toxicity information regarding the incidence of ONJ with 
zoledronic acid use is presented.  Page 11a was added to prevent extensive 
repagination.   
 
5. 
(Page 13a, Section 2.0, Background):  The ethnic/racial table has been updated to 
reflect the revised accrual goal of the study.  (Reason:  See item #13 below) 
 
6. 
(Page 16, Section 3.2a, Drug Information):  "Schering Oy", the manufacturer of 
clodronate, has merged with Bayer and changed its name to "Bayer Schering Pharma 
Oy". 
 
7. 
(Page 18, Section 3.2c, Drug Information):  In the clodronate supplier information, the 
third sentence has been revised.  "However, for this study it is being supplied free-of-
charge by Berlex/Schering" has been changed to "However, for this study it is being 
supplied free-of-charge by Bayer Schering Pharma Oy". 
 
8. 
(Pages 26-27, Section 5.0, Eligibility Criteria):  The following changes have been 
made to this section: 
• Section 5.2:  "Patients must receive standard adjuvant therapy for their breast 
cancer.  Chemotherapy, hormone therapy, or combined chemo/hormone therapy is 
permitted.  Hematopoietic growth factors are allowed.  Neoadjuvant therapy is 
permitted for inclusion, but enrollment must occur post-operatively.  Patients who 
are at such a low risk of recurrence that adjuvant therapy will not be prescribed are 
excluded." 
 
The above eligibility criteria have been replaced with the following revised section:   
 
"Patients must receive standard (systemic) adjuvant therapy for their breast 
cancer.  Chemotherapy, hormone therapy, or combined chemo/hormone therapy is 
permitted.  Additional therapies are allowed including radiation therapy and biologic 
agents (e.g. Herceptin®, Avastin®, hematopoietic growth factors).  Patients who  
 


S0307 
Amendment #1 (contd.) 
Page 3 
 
 
 
 
receive biologic agents only or local radiation therapy only (without chemotherapy 
and/or hormone therapy) are not eligible.  Patients who are at such a low risk of 
recurrence that adjuvant therapy will not be prescribed are ineligible.  Neoadjuvant 
therapy is permitted, but enrollment must occur after completion of surgery. 
 
(Reason:  These changes were made in order to provide clarification on the types of 
therapies that are allowed while on study.) 
 
• Section 5.3:  The following new statement has been added at the end of this 
eligibility criterion:  "Additional biological therapy or radiation therapy is allowed at 
any time before or after registration."  (Reason:  This change was made in order to 
provide clarification on the timing of therapies that are allowed while on study.) 
• Section 5.6:  The first sentence has been revised.  "Patients may not be co-
enrolled..." has been changed to "Patients must not be co-enrolled..."  (Reason:  
This change was made for editorial purposes.) 
• Section 5.9:  "Patients must undergo a dental examination within 6 months prior to 
registration per Section 7.3" has been changed to "Patients must undergo a dental 
examination within 6 months prior to initiation of treatment per Section 7.4".  
(Reason:  This change was made in order to provide clarification on the timing of 
the dental examination prior to the initiation of treatment not prior to study 
enrollment.) 
• Section 5.12:  The third sentence has been revised.  "Women of child-bearing 
potential must have a pregnancy test within 24-48 hours..." has been changed to 
"Women of child-bearing potential must have a pregnancy test within 24-72 
hours..." (Reason:  This change was made in order to allow pregnancy tests to be 
performed on Friday so that initiation of treatment can begin the following Monday.) 
 
9. 
(Page 28, Section 7.2, Treatment Plan):  The second bolded paragraph has been 
revised.  "Women of child-bearing potential must have a pregnancy test within 24-48 
hours prior to initiation of treatment" has been changed to "Women of child-bearing 
potential must have a pregnancy test within 24-72 hours prior to initiation of 
treatment."  (Reason:  See item #8, fifth bullet, above) 
 
10. 
(Page 29, Section 7.4, Treatment Plan):  In the first paragraph, the first sentence has 
been revised.  "Patients will undergo a dental exam within 6 months prior to 
registration" has been changed to "Patients will undergo a dental exam within 6 
months prior to initiation of treatment".  The parenthetical statement regarding the 
Dental Examination Form in the second sentence has been revised.  "...(may be 
retrospectively completed if the exam was prior to registration)" has been changed to 
"...(may be retrospectively completed if the exam was prior to initiation of treatment)".  
(Reason:  See item #8, fourth bullet, above) 
 
11. 
(Page 30, Section 7.9, Treatment Plan):  The second sentence has been revised.  
"Additionally, a dental examination will also be required at the end of protocol 
treatment (within 3 months prior to or after study completion)" has been changed to 
"Additionally, a dental examination will also be required at the end of protocol 
treatment (within 6 months after study completion or removal from protocol treatment, 
see Section 7.11)".  (Reason:  This change was made in order to allow dental exams 
within 6 months for patients that complete treatment or are removed from protocol 
treatment early.) 
 
12. 
(Page 32, Section 9.0, Study Calendar):  The following changes have been made to 
this page: 
• The third sentence of the dental exam footnote (λ) has been updated.  "To keep in 
line with patient's normal dental exam schedule, exams 6 months pre-enrollment 
and 3 months pre- or post-completion of study are required" has been changed to 
"To keep in line with patient's normal dental exam schedule, exams 6 months pre-
enrollment and 6 months post-completion of study (or removal from protocol 
treatment, see Section 7.11) are required".  (Reason:  See item #10 above) 


S0307 
Amendment #1 (contd.) 
Page 4 
 
 
 
 
• The pregnancy test footnote (∆) has been updated.  "To be performed within 24-48 
hours prior to initiation of treatment" has been changed to "To be performed within 
24-72 hours prior to initiation of treatment."   (Reason:  See item #8, fifth bullet, 
above) 
 
13. 
(Pages 33-34a, Sections 11.0, Statistical Considerations):  The statistical 
considerations (Sections 11.1-11.6) have been replaced with updated sections (new 
Sections 11.1-11.8).  (Reason:  Due to a lower than anticipated accrual rate, the 
statistical design assumptions were adjusted to be more in line with the currently 
observed accrual rate. The adjusted accrual goal will be lowered from 6,000 to 4,500 
women. The accrual period would be extended from 4 years to 6 years, but the follow-
up period would be shortened by one year. The Bonferroni corrected pairwise 
comparisons will be replaced by using the Fisher’s Least Significant Difference for 
adjusting for multiple comparisons. The adjusted statistical design has been approved 
by the SWOG DSMC.)  Page 34a was added to prevent extensive repagination. 
 
14. 
(Page 49, Section 17.0, Bibliography):  The bibliography has been updated.  
References #63 - #65 have been added. 
 
15. 
(Page 50, Section 18.2, Master Forms Set):  The Southwest Oncology Group  
Registration Form Code Sheet (version 12/8/04) has been updated and replaced with 
version 10/24/06.   
 
16. 
(Page 51, Model Consent Form, Readability Statistics):  The readability statistics have 
been updated.  Flesch reading ease has been updated from 63.9 to 57.6.  Flesch-
Kincaid grade level has been changed from 8.1 to 9.3. 
 
17. 
(Page 53, Model Consent Form, How many people will take part in the study?):  
"About 6,000 people will take part in this study" has been changed to "About 4,500 
women will take part in this study."  (Reason:  See item #13 above)  
 
18. 
(Page 53, Model Consent Form, Before you begin the study...):  The seventh (last) 
bullet has been revised.  "Women of child-bearing potential must have a pregnancy 
test performed within 24-48 hours prior to initiation of treatment" has been changed to 
"Women of child-bearing potential must have a pregnancy test performed within 24-72 
hours prior to initiation of treatment."  (Reason:  See item #8, fifth bullet, above) 
 
19. 
(Page 55, Model Consent Form, Study Chart):  In the first column, fourth row, "Within 
24-48 hours prior to starting study" has been changed to "Within 24-72 hours prior to 
starting study".  (Reason:  See item #8, fifth bullet, above) 
 
20. 
(Page 55a, Model Consent Form, Study Chart):  In the second row, first column, the 
timing of the dental examination has been revised.  "Within 3 months before or after 
completing study" has been changed to "Within 6 months after completing study or 
ending the study early".  (Reason:  See item #11 above)  
 
21. 
(Page 58, Model Consent Form, What side effects or risks can I expect from being in 
the study?):  Under the rare, but serious category of risks for zoledronic acid the 
following new risk related to irregular heartbeats (atrial fibrillation) has been added as 
provided by Novartis: 
"Irregular heartbeat:  In a recent study in post-menopausal women with osteoporosis, 
a small number of patients treated with zoledronic acid experienced an irregular 
heartbeat called atrial fibrillation. More patients who received zoledronic acid 
experienced this kind of irregular heartbeat than patients who did not receive 
zoledronic acid.  So far, this symptom has not been seen in cancer patients taking 
zoledronic acid.  Atrial fibrillation is a common condition which can be treated; 
however, more research is needed before the importance of this finding becomes 
clear."   
 


S0307 
Amendment #1 (contd.) 
Page 5 
 
 
 
 
22. 
(Page 59, Model Consent Form, What side effects or risks can I expect from being in 
the study?):  The paragraph regarding osteonecrosis of the jaw (ONJ) has been 
modified to include recent toxicity information regarding the incidence of ONJ with 
zoledronic acid use. 
 
"Osteonecrosis of the jaw:  Recent reports suggest a possible association between 
the use of intravenous bisphosphonates, such as zoledronic acid, and osteonecrosis 
of the jaw (permanent damage to the jawbone), a rare, but serious potential side 
effect.  This condition may be painful and may happen after tooth extraction or other 
dental procedures such as tooth cleaning or when a patient is also getting 
chemotherapy while taking bisphosphonates.  Oral clodronate and ibandronate may 
also increase the risk of osteonecrosis of the jaw, although this link is not as well 
established.   
 
The above paragraph has been changed to:   
 
"Osteonecrosis of the jaw:  Recent reports suggest a possible association between 
the use of intravenous bisphosphonates, such as zoledronic acid, and osteonecrosis 
of the jaw (permanent damage to the jawbone), a rare, but serious potential side 
effect.  This condition may be painful and may happen after tooth extraction or other 
dental procedures such as tooth cleaning or when a patient is also getting 
chemotherapy while taking bisphosphonates.  A recent study of 3,360 patients 
receiving standard treatment with or without zoledronic acid reported seven cases of 
osteonecrosis of the jaw, all in the zoledronic acid arm, with an average of eight doses 
received at the time of the event.  This represented 0.4% of patients on the zoledronic 
acid arm.  Oral clodronate and ibandronate may also increase the risk of 
osteonecrosis of the jaw, although this link is not as well established.   
 
23. 
(Page 60, Model Consent Form, What are the costs of taking part in this study?):  In 
the third paragraph, the first sentence has been revised.  "The drug manufacturers, 
Berlex/Schering and Roche, will provide you..." has been changed to "The drug 
manufacturers, Bayer Schering Pharma Oy and Roche, will provide you..." 
 
24. 
(Page 62, Model Consent Form, Additional Research Studies):  Before the future 
contact question, "I agree to allow my study doctor...to contact me regarding future 
research involving my participation in this study", the following language has been 
added to provide rationale for the "future contact" question:   
 
"Occasionally, researchers working with the Southwest Oncology Group (SWOG) may 
have another research idea that relates to people who were on a SWOG study.  In 
some cases, to carry out the new research, we would need to contact participants in a 
particular study.  You can agree or not agree to future contact."   
 
25. 
(Page 86, Appendix 19.1, CTSU Participation Procedures):  In the drug procurement 
section, "Berlex/Schering" has been changed to "Bayer Schering Pharma Oy".   
 
Institutions must update their local consent forms to include the above information for 
future registrations.  Patients currently being treated on this study should be informed 
of these changes as directed by the local Institutional Review Board (IRB). 
 
Please attach this memorandum to the front of your copy of the protocol and insert the 
replacement pages.  
 
This memorandum serves to inform the Southwest Oncology Group Statistical Center and the 
NCI. 
 
cc: 
PROTOCOL & INFORMATION OFFICE Christine McLeod 
 William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 Danika Lew, M.A. 
Simone Lake – Novartis  
 Jean Barce 
Edward McKenna – Roche 
 Lisa Gavigan 
Megan Rossmann – CTSU 
 Jeri Jardine 
 


 
 
 
 
 
 
Distribution Date: 
March 15, 2009 
E-mailed Date: 
March 10, 2009 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE MEDICAL 
ONCOLOGISTS, SURGEONS, AND PATHOLOGISTS; CTSU.  Patient enrollments 
from institutions that are not aligned with SWOG will be conducted via the NCI 
Cancer Trials Support Unit (CTSU) and all data should be sent to the SWOG Data 
Operations as specified in the CTSU logistical appendix (See Section 19.1). 
 
FROM: 
Gilbert R. Carrizales, M.S., Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast 
Cancer."  Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
MEMORANDUM 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone:  206/288-7722 
Email:  pink@u.washington.edu 
 
IRB Review Requirements 
 
(    )    Full board review required.  Reason: 
(    )   Initial activation (should your institution choose to participate) 
(    )   Increased risk to patient 
(    )   Complete study redesign 
(    )   Addition of tissue banking requirements 
(    )   Study closure due to new risk information 
 
(    )    Expedited review allowed  
 
( √ )    No review required  
 
 
MEMORANDUM 
 
Please note that the intellectual property terms applicable to participation in this trial, as 
partially funded by an industry collaborator, are different from the terms set forth in the 
Purchase Service Agreement (PSA) signed by registering members.  Specifically, participation 
in this trial requires agreement and compliance with allowing the industry collaborator a non-
exclusive license to any intellectual property resulting from this trial, including use for 
commercial purposes. This is in contrast to the standard intellectual property terms in the PSA 
which restricts the industry collaborator to a non-exclusive license for research purposes only. 
This exception to the standard intellectual property terms has been approved by the NCI. You 
are required to inform your site’s appropriate grants and contracts office about this 
modification to the PSA. Please direct any questions related to this modification to the legal 
department at Group Headquarters Office at 734- 998-7173. 
 
Please attach this memorandum to the front of your copy of the protocol.       
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Jeri Jardine 
 William E. Barlow, Ph.D. 
Megan Rossman– CTSU 
 
 Danika Lew, M.A. 
Ulf Wiegand - Roche 
 Christine McLeoud 
Lans H. Breimer– Bayer Schering Pharma Oy  
 Lisa Gavigan 
Simone Lake - Novartis 
 Jean Barce 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
September 1, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
August 1, 2007          AE #2007027436 
August 2, 2007          AE #2007027975 
August 8, 2007          AE #2007028574 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Simone Lake - Novartis 
 
Jean Barce 
Ulf Wiegand – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
August 1, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
June 15, 2007 
AE #2006032513(4) 
June 29, 2007 
AE #2007023743 
July 9, 2007 
AE #2007024457 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Simone Lake - Novartis 
 
Jean Barce 
Edward McKenna – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
June 15, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
 Reports: 
 
May 21, 2007          AE #2006032513(3) 
May 31, 2007          AE #2007019013 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Simone Lake - Novartis 
 
Jean Barce 
Edward McKenna – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
June 1, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety report has been posted regarding an adverse event that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access this safety report via 
the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
This safety report pertains to the following study: 
 
S0307 Breast 
 Report: 
 
May 2, 2007          AE #2007014121(1) 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in this report if it is deemed necessary by your institution.  Please append this notice 
and this report to your copy of the protocol and forward a copy to your Institutional Review Board (IRB) as 
required by your local policies and procedures. Should any further information regarding this adverse 
event be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Bayer Schering Pharma Oy 
 
Danika Lew, M.A. 
Simone Lake - Novartis 
 
Jean Barce 
Edward McKenna – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Megan Rossmann – CTSU 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
May 1, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
April 4, 2007          AE #2007010897(1) 
April 12, 2007        AE #2007012082 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Berlex 
 
Danika Lew, M.A. 
April Monge - Novartis 
 
Jean Barce 
Edward McKenna – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Kendra Godfrey Barrow – CTSU 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
April 15, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
March 5, 2007          AE #2007006800 
March 12, 2007        AE #2006032513(1) 
March 15, 2007        AE #2006040116(2) 
March 21, 2007        AE #2006032513(2) 
March 29, 2007        AE #2006031029(1) 
April 2, 2007             AE #2007010897 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution. Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Berlex 
 
Danika Lew, M.A. 
April Monge – Novartis 
 
Jean Barce 
Edward McKenna – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Kendra Godfrey Barrow – CTSU 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
Revised  
June 18, 2007 
Distribution Date: 
April 1, 2007 
CTEP Submission Date: 
January 25, 2007 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE 
MEDICAL 
ONCOLOGISTS, 
SURGEONS 
AND 
PATHOLOGISTS; CTSU.   
 
FROM: 
Gilbert R. Carrizales, M.S., Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer." Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
REVISION #3 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone number:  206/288-7722 
E-mail:  206/288-2054 
 
IRB Review Requirements 
 
(   ) Full board review required.  Reason: 
 
(    ) 
Initial activation (should your institution choose to participate) 
 
(    ) 
Increased risk to patient 
 
(    ) 
Complete study redesign 
 
(    ) 
Addition of tissue banking requirements 
 
(    ) 
Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(   ) No review required 
 
 
REVISION #3 
 
The protocol referenced above has been revised as follows: 
 
1. 
(Fast Fact Sheet):  Under "prestudy requirements", serum creatinine testing has 
been changed from "≤ 14 days before registration" to "≤ 7 days before registration".  
(This change was made to be consistent with the eligibility requirement in Section 
5.7.) 
 
2. 
(Title page):  The version date has been updated (version 01/25/07).  The contact 
information for Dr. Robert Livingston has been updated. 
 
3. 
(Page 19, Section 3.2c, Drug Information):  In the first sentence of the clodronate 
handling and disposal section, "ibandronate" has been changed to "clodronate".   
 
4. 
(Page 28, Section 7.0, Treatment Plan; Page 31, Section 8.6, Dosage 
Modifications):  The phone number for Dr. Robert Livingston has been updated.  
 
5. 
(Pages 29 & 30, Sections 7.4 & 7.9, respectively; Treatment Plan):  In each section 
the phone number for the Southwest Oncology Group Operations Office has been 
changed from 210/677-8808 to 210/450-8808. 
 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
S0307 
 
Revision #3 (contd.) 
 
Page 2 
 
 
 
 
 
 
 
 
6. 
(Page 32, Section 9.0, Study Calendar):  The following changes have been made 
to this page: 
 
• 
X-rays and scans:  Chest x-rays and CT scans are NOT required every 6 
months for the assessment of disease.  The checkmarks (for Months 6, 12, 18, 
24, 30, and 36) and corresponding "**" footnote have been removed.  (We DO, 
however, want patients on protocol treatment assessed for side effects and 
disease recurrence at 3 month intervals (starting with Month 6) as noted in the 
study calendar.) 
• 
"◊" footnote:  The serum creatinine footnote has been revised.  "To be 
performed within 14 days prior to registration..." has been changed to "To be 
performed within 7 days prior to registration..." 
 
7. 
(Page 55, Model Consent Form, Study Chart):  The following changes have been 
made to this page: 
 
• 
Third row:  In the first column, "Within 14 days prior to starting study" has been 
changed to "Within 7 days prior to starting study".  In the second column, "Get 
serum creatinine and calculated creatinine clearance blood tests" has been 
changed to "Get kidney function test."  (This 'patient friendly' description was 
made at the request of several IRBs.) 
• 
Sixth row:  In the second column, "Get serum creatinine blood test" has been 
changed to "Get kidney function test." 
• 
Seventh row:  In the second column, first bullet, "Get routine blood tests 
(including serum creatinine)" has been changed to "Get routine blood tests 
(including kidney function test)." 
• 
Seventh row:  In the second column, second bullet, the sentence "X-rays and 
scans as needed for disease assessment only for Months 6, 12, 18, 24, 30, 
and 36" has been removed.   
 
8. 
(Page 62, Model Consent Form, Additional Research Studies):  The following 
changes have been made to this page; 
 
• 
First banking sentence (tissue):  "I agree to submit a tissue specimen...to see if 
the breast cancer has spread to the bones" has been changed to "I agree to 
submit a tissue specimen...to see if this predicts the risk of your breast cancer 
spreading to the bones.  This is an experimental test that may indicate a higher 
chance that breast cancer has spread to the bones.  Since the significance of 
this test is not proven, neither you nor your doctor will be given the results of 
this test." 
• 
Second banking sentence (blood):  "I agree to submit a blood sample...to see if 
high levels will predict if breast cancer will spread to the bones" has been 
changed to "I agree to submit a blood sample...to see if high levels will predict 
the risk of your breast cancer spreading to the bones.  This is an experimental 
test that may indicate a higher chance that breast cancer has spread to the 
bones.  Since the significance of this test is not proven, neither you nor your 
doctor will be given the results of this test." 
 
9. 
(Page 63, Model Consent Form, Consent Form for Use of Specimens in 
Research):  Under "Where will my specimens be kept", a typo has been corrected 
in the address.  "RT-1 South" has been changed to "RC-1 South". 
 
CTSU related changes 
 
10. 
(Page 4, CTSU Address and Contact Information; Pages 84-86a, Section 19.1, 
CTSU Participation Procedures):  These sections have been revised to incorporate 
the Cancer Trials Support Unit (CTSU) form tracking change to basic service for 
this protocol.  Page 86a was added to prevent extensive repagination. 


 
S0307 
 
Revision #3 (contd.) 
 
Page 3 
 
 
 
 
 
 
 
 
 
Institutions should update their local consent forms to include the above-noted 
changes for future registrations.  Patients currently being treated on this study 
should be informed of the changes in the manner determined by the local 
Institutional Review Board (IRB).   
 
Please attach this memorandum to the front of your copy of the protocol and insert the 
replacement pages.     
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
William E. Barlow, Ph.D. 
Danika Lew, M.A. 
Christine McLeod 
Lisa Gavigan 
Jean Barce 
Jeri Jardine 
Kendra Godfrey Barrow - CTSU 
Edward McKenna - Roche 
Lans H. Breimer - Berlex 
Gail A. Larkins - Novartis 
 
 
 


 
 
 
 
 
 
 
March 15, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
February 19, 2007        AE #2006027512(2) 
February 19, 2007        AE #2006040116(1) 
February 19, 2007        AE #2006005298 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Berlex 
 
Danika Lew, M.A. 
Gail A. Larkins - Novartis 
 
Jean Barce 
Edward McKenna – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Kendra Godfrey Barrow – CTSU 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
February 15, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety report has been posted regarding an adverse event that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access this safety report via 
the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
The safety report pertains to the following study: 
 
S0307 Breast 
Report: 
 
January 25, 2007 
AE #2006032523(1) 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in this report if it is deemed necessary by your institution.  Please append this notice 
and this report to your copy of the protocol and forward a copy to your Institutional Review Board (IRB) as 
required by your local policies and procedures.  Should any further information regarding this adverse 
event be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Berlex 
 
Danika Lew, M.A. 
Gail A. Larkins - Novartis 
 
Jean Barce 
Edward McKenna – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Kendra Godfrey Barrow – CTSU 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
February 1, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
 Reports: 
 
January 10, 2007        AE #2006040021(1) 
January 11, 2007        AE #2006032513 
January 15, 2007        AE #2007000323 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Lars H. Breimer – Berlex 
 
Danika Lew, M.A. 
Gail A. Larkins - Novartis 
 
Jean Barce 
Edward McKenna – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Kendra Godfrey Barrow – CTSU 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
January 15, 2007 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND 
AFFILIATE MEDICAL ONCOLOGISTS, SURGEONS AND 
PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
November 29, 2006        AE #2006036528 
December 13, 2006        AE #2006036528(1) 
 December 15, 2006        AE #2006027512(1) 
January 2, 2007              AE #2006040116 
January 2, 2007              AE #2006040021 
 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Suzan Lanz – Berlex 
 
Danika Lew, M.A. 
Gail A. Larkins - Novartis 
 
Jean Barce 
Edward McKenna – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Kendra Godfrey Barrow – CTSU 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
November 15, 2006 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in 
association with the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please 
access these safety reports via the safety report link in the member section of the Southwest 
Oncology Group website (https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following 
study: 
 
S0307 Breast 
Reports: 
 
October 13, 2006        AE #2006030074 
October 20, 2006 
AE #2006031029 
November 1, 2006 
AE #2006032523 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to 
include the information provided in these reports if it is deemed necessary by your institution.  
Please append this notice and these reports to your copy of the protocol and forward copies to 
your Institutional Review Board (IRB) as required by your local policies and procedures.  Should 
any further information regarding these adverse events be made available, it will be forwarded to 
you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Suzan Lanz – Berlex 
 
Danika Lew, M.A. 
Gail A. Larkins - Novartis 
 
Jean Barce 
Edward McKenna – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Kendra Godfrey Barrow – CTSU 
 
 
 
 
Operations Office 
14980 Omicron Drive • San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
November 1, 2006 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
 
MEMORANDUM 
 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
The following safety reports have been posted regarding adverse events that occurred in association with 
the drug Bonefos® (clodronate disodium tetrahydrate, IND# 71,481).  Please access these safety reports 
via the safety report link in the member section of the Southwest Oncology Group website 
(https://swog.org/SafetyReports/SafetyReports.asp).   
 
These safety reports pertain to the following study: 
 
S0307 Breast 
Reports: 
 
April 6, 2006 
AE #2006003411(1) 
July 17, 2006 
AE #2006018731 
July 28, 2006 
AE #2006015298(1) 
August 24, 2006 
AE #2006015297(1) 
August 30, 2006 
AE #2006024776 
August 31, 2006 
AE #2006018731(1) 
September 18, 2006 
AE #2006026124 
September 25, 2006  
AE #2006003780(1) 
September 29, 2006 
AE #2006027512 
 
Protocol amendments are not necessary at this time, but your consent form may be revised to include the 
information provided in these reports if it is deemed necessary by your institution.  Please append this 
notice and these reports to your copy of the protocol and forward copies to your Institutional Review 
Board (IRB) as required by your local policies and procedures.  Should any further information regarding 
these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Suzan Lanz – Berlex 
 
Danika Lew, M.A. 
Gail A. Larkins - Novartis 
 
Jean Barce 
Edward McKenna – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Kendra Godfrey Barrow – CTSU 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-677-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
Distribution Date: 
November 1, 2006 
CTEP Submission Date: 
September 25, 2006 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE 
MEDICAL 
ONCOLOGISTS, 
SURGEONS 
AND 
PATHOLOGISTS; CTSU.   
 
FROM: 
Gilbert R. Carrizales, M.S., Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer." Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
REVISION #2 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone number:  206/288-7722 
E-mail:  206/288-2054 
 
IRB Review Requirements 
 
(   ) Full board review required.  Reason: 
 
(    ) 
Initial activation (should your institution choose to participate) 
 
(    ) 
Increased risk to patient 
 
(    ) 
Complete study redesign 
 
(    ) 
Addition of tissue banking requirements 
 
(    ) 
Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(   ) No review required 
 
 
REVISION #2 
 
The protocol referenced above has been revised as follows: 
 
1. 
(Revision #1 change memo, distributed 8/15/06):  Item #28, fourth bullet incorrectly 
reported the change made to the model consent form.  "Day 1 of Months 1-6 
and..." has been changed to "Day 1 of Months 2-6 and..." 
 
2. 
(Title page):  The version date has been updated (version 09/25/06). 
 
3. 
(Page 16, Section 3.1c):  A new section entitled "Handling and disposal/Drug 
returns" has been added that discusses procedures for zoledronic acid drug 
returns and disposal.   
 
4. 
(Page 19, Section 3.2c):  A new section entitled "Handling and disposal/Drug 
returns" has been added that discusses procedures for clodronate drug returns 
and disposal.  Page 19a has been added to prevent repagination.  Page 19a was 
added to prevent extensive repagination. 
 
5. 
(Page 22, Section 3.3c):  A new section entitled "Handling and disposal/Drug 
returns" has been added that discusses procedures for ibandronate drug returns 
and disposal.  Page 22a has been added to prevent repagination. 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-450-8808 • FAX 210-677-0006 • http://swog.org 


 
S0307 
 
Revision #2 (contd.) 
 
Page 2 
 
 
 
 
 
 
 
 
 
6.   
(Page 28, Section 7.1):  Formatting changes have been made to this section, but 
the content remains unchanged. 
 
7. 
(Pages 32, Section 9.0):  The following changes have been made to this page: 
 
• 
Title:  The study calendar title has been corrected to match the title page.   
• 
X-rays/Scans:  Chest x-rays and CT scans have been checked at Months 6, 
12, 18, 24, 30, and 36 as these months were previously unchecked.  (This 
corresponds with the disease assessment interval outlined in the study.) 
• 
λ  footnote:  The sentence "Flexibility will be allowed" has been removed, as it 
is a requirement that dental exams be performed at the beginning and end of 
treatment. 
• 
** footnote:  A new "**" footnote corresponding to the disease assessment 
schedule has been added as follows:  "Disease will be assessed clinically at 
Months 6, 12, 18, 24, 30, and 36.  X-rays and scans as needed for tumor 
measurement will use the same methods used at baseline."  
 
8. 
(Page 35, Section 13.3a):  In the paragraph that begins, "For assistance...", the 
phone number for the Southwest Oncology Group Operations Office has been 
changed from 210/677-8808 to 210/450-8808. 
 
9. 
(Pages 36-37, Section 14.2-14.3):  The SWOG data submission procedures have 
been replaced with updated sections.  Page 37 (Sections 14.4-14.12) has been 
reformatted. 
 
10. 
(Page 38, Section 15.2c):  The following changes have been made to this section: 
 
• 
In the second paragraph, the last two sentences have replaced with an 
updated section. 
 
"ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE NO 
EXCEPTIONS.  For any questions or problems regarding the Specimen Tracking 
program, please send an email to technicalquestion@crab.org" 
The sentences above have been replaced with the following text: 
 
"ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE NO 
EXCEPTIONS.  
 
To report technical problems with Specimen Tracking, such as database errors or 
connectivity issues, please send an email to technicalquestion@crab.org.  For 
procedural help with logging and shipping specimens, there is an introduction to 
the 
system 
on 
the 
Specimen 
Tracking 
main 
page 
(http://dnet.crab.org/SpecTrack/Documents/SpecTPrimer-Insts.pdf); or contact the 
Data Operations Center at 206/652-2267 to be routed to the Data Coordinator for 
further assistance." 
 
• 
The paragraph that begins with "A copy of the Shipment Packing list produced 
by the Specimen Tracking system..." has been removed. 
 
11. 
(Pages 39 & 41, Sections 15.3e & 15.4d, respectively):  The SWOG Solid Tumor 
Tissue Bank has moved from the University of Cincinnati to the University of 
Colorado HSC at Fitzsimons, and the contact information has been updated.   
 
12. 
(Pages 43 & 45, Sections 16.1e & 16.1f, respectively):  In the last sentence, the 
Southwest Oncology Group Operations Office has been changed from 210/677-
8808 to 210/450-8808. 
 


 
S0307 
 
Revision #2 (contd.) 
 
Page 3 
 
 
 
 
 
 
 
 
13. 
(Page 55, Model Consent Form, Study Chart):  The following changes have been 
made to this page: 
 
• 
Sixth row, first column:  Month 24 was inadvertently left out as mentioned in the 
Revision #1 change memo.  This has been corrected. 
• 
Seventh row, second column:  "Return to your doctor's office...for your next 
physical examination (only for Months 6, 12, 18, 24, 30, and 36)" has been 
changed to "Return to your doctor's office...for your next physical examination 
(X-rays and scans as needed for disease assessment only for Months 6, 12, 
18, 24, 30, and 36)."    
 
14. 
(Page 63, Model Consent Form, Where will my specimens be kept?):  The contact 
information for the Southwest Oncology Group Solid Tumor Tissue Bank at the 
University of Colorado HSC at Fitzsimons has been added.  
 
Institutions should update their local consent forms to include the above-noted 
changes for future registrations.  Patients currently being treated on this study 
should be informed of the changes in the manner determined by the local 
Institutional Review Board (IRB).   
 
Please attach this memorandum and the attachments to the front of your copy of the 
protocol and insert the replacement pages.     
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
William E. Barlow, Ph.D. 
Danika Lew, M.A. 
Christine McLeod 
Lisa Gavigan 
Jean Barce 
Jeri Jardine 
Kendra Godfrey Barrow - CTSU 
Edward McKenna - Roche 
Susan Lanz - Berlex 
Gail A. Larkins - Novartis 
 
 
 


 
 
 
 
 
Protocol Distribution Date: August 15, 2006 
Re-revised: 
June 12, 2006 
Revised: 
April 14, 2006 
CTEP Submission Date: 
February 7, 2006 
 
TO: 
ALL 
SOUTHWEST 
ONCOLOGY 
GROUP 
MEMBER, 
CCOP 
AND 
AFFILIATE 
MEDICAL 
ONCOLOGISTS, 
SURGEONS 
AND 
PATHOLOGISTS; CTSU.   
 
FROM: 
Gilbert R. Carrizales, M.S., Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer." Study Coordinators:  Drs. J. Gralow and R. Livingston. 
 
REVISION #1 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone number:  206/288-7722 
E-mail:  206/288-2054 
 
IRB Review Requirements 
 
(   ) Full board review required.  Reason: 
 
(    ) 
Initial activation (should your institution choose to participate) 
 
(    ) 
Increased risk to patient 
 
(    ) 
Complete study redesign 
 
(    ) 
Addition of tissue banking requirements 
 
(    ) 
Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(   ) No review required 
 
 
REVISION #1 
 
The protocol referenced above has been revised as follows: 
 
1.  
The S0307 Fast Fact Sheet has been inserted before the title page. 
 
2.  
(Title page): The version date has been updated (version 06/12/06). The table of 
contents has been updated. 
 
3.  
(Page 2, PI information):  Added "Special Consultant" next to Mark Schubert, 
D.D.S, M.D.S. 
 
4.  
 (Page 3, PI information): Updated the email address for Dr. Mark J. Clemons 
(NCIC-CTG Study Coordinator). Updated the phone number for Kim Dammann, 
Research RN for S0307. 
 
5.  
(Page 5, Schema): The dose information for each bisphosphonate has been 
removed. 
 
6.  
(Page 7, Section 2.0): Added additional background information at the beginning of 
the paragraph that begins, "The intriguing but contradictory results of these three 
adjuvant bisphosphonate studies...". Three new citations were introduced and 
included in the bibliography section as #18-20. Subsequent background 
information in Section 2.0 has been reformatted. 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-677-8808 • FAX 210-677-0006 • http://swog.org 


 
S0307 
 
Revision #1 (contd.) 
 
Page 2 
 
 
 
 
 
 
 
 
 
 
7.  
(Pages 9-13a, Section 2.0): In the first paragraph on Page 9, the author references 
have been replaced with citation numbers (see bibliography Section 17.0). On 
pages 9-13, the citation numbers have been updated. Page 13a was added to 
prevent extensive repagination. 
 
8.  
(Page 16, Section 3.1c): Under zoledronic acid supplier information, the drug 
supplier name has been changed from UintaVision to "UVI, Inc.". Also, the address 
has been removed as this information is no longer current. Institutions should 
continue to use the phone and/or fax number to order study drug. 
 
9.  
(Page 18, Section 3.2c): In the first sentence, "Clodronate is not commercially 
available in the United States" has been changed to "Clodronate is investigational 
for this study." Under clodronate supplier information, the drug supplier name has 
been changed from UintaVision to "UVI, Inc.". Also, the address has been removed 
as this information is no longer current. Institutions should continue to use the 
phone and/or fax number to order study drug. 
 
10.  
(Page 22, Section 3.3c): Under ibandronate supplier information, the drug supplier 
name has been changed from UintaVision to "UVI, Inc.". Also, the address has 
been removed as this information is no longer current. Institutions should continue 
to use the phone and/or fax number to order study drug. 
 
11.  
(Page 26-27, Section 5.0): The following changes have been made to these pages: 
 
•  
New instructions have been inserted at the top of the eligibility criteria page.  
The third sentence "For each patient, this section must be photocopied, 
completed, and submitted to the Date Operations Center in Seattle (see 
Section 14.0)" has been replaced with "For each criterion requiring test results 
and dates, please complete the Prestudy Form and submit to the Data 
Operations Center in Seattle (see Section 14.0). Any potential eligibility issues 
should be addressed to the Data Operations Office in Seattle at 206/652-2267 
prior to registration." 
•  
Section 5.3: This eligibility criterion has been replaced with the following:  
"Patients may be enrolled prior to, simultaneously with, or after beginning 
adjuvant systemic therapy. Patients receiving hormonal therapy alone (no 
chemotherapy) or pre-operative chemotherapy should be enrolled within 84 
days (12 weeks) after the date of final surgical procedure. Patients receiving 
adjuvant post-operative chemotherapy may be enrolled up to 8 weeks after 
completion of chemotherapy." The final surgery blank has been removed. 
•  
Section 5.4: "Patients must be offered the opportunity to consent for tissue and 
serum specimen submission and banking as per Section 15.0" has been 
replaced with the following: "Institutions are encouraged to seek patient 
consent to submit tissue and serum for banking. Patients who wish to 
participate in the tissue and serum sample submissions for banking as outlined 
in Sections 15.3 and 15.4 must consent to the procedures. Written informed 
consent must be obtained prior to submitting samples." 
•  
Section 5.5: The performance status blank has been removed. 
•  
Section 5.7: "Patients must have a serum creatinine that is ≤ 2 times the 
institutional upper limit of normal within 7 days prior to enrollment" has been 
changed to "Patients must have a serum creatinine that is ≤ 2 times the 
institutional upper limit of normal (IULN) and a calculated creatinine clearance 
of ≥ 30 mL/min within 7 days prior to enrollment." The serum creatinine, IULN, 
and date blanks have been removed. 
•  
Section 5.8: The date of previous IV or oral bisphosphonate blank has been 
removed. 
•  
Section 5.9: The blank for date of dental examination has been removed. 


 
S0307 
 
Revision #1 (contd.) 
 
Page 3 
 
 
 
 
 
 
 
 
 
•  
Section 5.10: Blanks for bone pain and for ruling out metastatic disease have 
been removed. 
•  
Section 5.12: Added the following sentence to the end of this section: "Women 
of child-bearing potential must have a pregnancy test performed within 24 - 48 
hours prior to initiation of treatment (see Section 7.2)." 
•  
Section 5.14: "If Day 28 or 84..." has been changed to "If Day 14, 28, or 84..."  
In the bolded paragraph, the second sentence "...the Monday four weeks later 
would be considered Day 28" has been changed to "...the Monday two weeks 
later would be considered Day 14." 
 
12.  
(Page 28, Section 7.0): The following changes have been made to this page: 
 
•  
First paragraph: Updated the phone number for Kim Dammann. 
•  
Section 7.2: In the second paragraph, the bolded information has been 
replaced with the following updated section: "Investigators are encouraged to 
begin bisphosphonate therapy as soon as possible after surgery. Patients may 
be registered and begin bisphosphonate therapy prior to, simultaneously, or 
after systemic therapy. Patients receiving hormonal therapy alone (no 
chemotherapy) or pre-operative chemotherapy should be enrolled within 84 
days (12 weeks) after the date of final surgical procedure. Patients receiving 
adjuvant post-operative chemotherapy may be enrolled up to 8 weeks after 
completion of chemotherapy (see Section 5.3)." 
 
13.  
(Pages 29-31, Section 7.0): The following changes have been made to these 
pages: 
 
•  
The treatment plan table has been renumbered as Section 7.3. Subsequent 
sections have been reformatted. 
•  
Section 7.3 has been titled "treatment plan". The following text has been added 
to the first paragraph: "Every effort should be made to administer zoledronic 
acid to patients in Arm 1 every 4 weeks during the first 6 months of dosing, 
however minor deviances from these dosing intervals are acceptable.  It is 
suggested that the infusions be given within ± 2 days (2 days earlier or later). 
During the remaining period of dosing, zoledronic acid may be given within ± 7 
days (7 days earlier or later). The last dose of zoledronic acid in Arm 1 should 
be administered at Month 33. Oral bisphosphonates given in Arms 2 and 3 are 
to continue daily until the first day of Month 36 and are then discontinued." 
•  
Section 7.4: In the first sentence, the S0307 Dental Exam Form has been 
changed to "Dental Examination Form". The final form number has been 
inserted. 
•  
Section 7.7: A new section discussing pill compliance has been added.  
Subsequent sections have been reorganized. 
•  
Section 7.11: A new criteria for removal from protocol treatment has been 
added as "(c) Greater than 4 weeks in delay of protocol treatment."  
Subsequent sections have been reorganized. 
 
14.  
(Page 31, Section 8.0): The following changes have been made to this page: 
 
•  
Section 8.4: A new Section 8.4 has been added: "Bisphosphonates from any of 
the three arms may be held or delayed for up to four weeks for any reason 
without requiring removal from the study. The total duration of treatment will be 
36 months. Missed treatments will not be made up." Subsequent sections have 
been renumbered. 
•  
Section 8.5: "Osteonecrosis of the jaw: Completion of the S0307 
Osteonecrosis Jaw Lesion Form..." has been changed to "Osteonecrosis of the 
jaw: Completion of the Osteonecrosis Jaw Lesion Form..." The Osteonecrosis 
Jaw Lesion Form is no longer a study specific form. The final form number has 
been inserted. Also, the phone number for Dr. Mark Schubert has been 
corrected. 
•  
Section 8.6: The phone number for Kim Dammann has been updated. 


 
S0307 
 
Revision #1 (contd.) 
 
Page 4 
 
 
 
 
 
 
 
 
 
15.  
(Page 32, Section 9.0): The following changes have been made to this page: 
 
•  
The study calendar has been restructured to include months instead of weeks. 
Treatment: Zoledronic acid treatment has been revised to clarify that treatment 
is to be given on Day 1 every 4 weeks for 6 months and then on Day 1 every 3 
months until Month 33. 
 
•  
Laboratory: 
 
a.  
Added pregnancy test at prestudy. "Δ" footnote describes that this 
test is to be performed 24-48 hours prior to initiation of treatment. 
b.  
Clarified that serum creatinine testing should be performed monthly 
for the first 6 months (starting with Month 2) and then once every 
three months until Month 36. 
c.  
Added "creatinine clearance (calculated)" test at prestudy. 
d.  
Clarified that other laboratory tests (excluding serum creatinine and 
pregnancy test) are to be performed at Months 2, 4, and 6 and then 
once every three months until Month 36. 
e.  
Added "§" footnote next to electrolytes (to remind reader that this test 
is suggested at prestudy for Good Medical Practice). 
 
•  
Physical: 
 
a.  
Clarified that history, physical exam, weight, PS, and toxicity notation 
are to be performed at Months 2, 4, and 6 and then once every three 
months until Month 36. 
b.  
Clarified that disease assessments are to be performed every 6 
months until Month 36. 
 
•  
Footnotes: 
 
a.  
"Ω" footnote: "Zoledronic acid will be administered on Day 1 q 4 
weeks for the first 6 months and then on Day 1 q 3 months for 30 
months" has been changed to "Zoledronic acid will be administered 
by IV on Day 1 q 4 weeks for the first 6 months, however, minor 
deviations are acceptable. It is suggested that the infusions be given 
within ± 2 days (2 days earlier or later). During the remaining period 
of dosing, zoledronic acid may be given within ± 7 days (7 days 
earlier or later)." 
b. 
 "ψ" footnote: Added the following sentence "Discontinue oral 
bisphosphonate on the first day of Month 36." 
c.  
"α" footnote: Added the following sentence "Discontinue oral 
bisphosphonate on the first day of Month 36." 
d.  
"ƒ" footnote: "Patients off protocol treatment prior to recurrence 
should return at least every 6 months for disease assessment" has 
been changed to "Patients off protocol treatment prior to recurrence 
should return for disease assessment at least every 6 months for 5 
years and then annually for 5 years or until death (whichever occurs 
first)." 
e. 
 "λ" footnote: In the first sentence "Dental exam should be 
performed at the beginning and end of the study" has been changed 
to "Dental exam should be performed at the beginning and end of 
treatment". In the second sentence "Dental exam form to be 
completed" has been changed to "Complete the Dental Examination 
Form (Form# 30100)." 
f.  
"√" footnote: This footnote has been removed. 
g.  
Added "Δ" footnote (see description above). 
 
16.  
(Page 34, Section 12.0): Formatting changes have been made to this section, but 
no changes have been made to the content. 


 
S0307 
 
Revision #1 (contd.) 
 
Page 5 
 
 
 
 
 
 
 
 
 
17.  
(Pages 37-38, Section 14.0): The following changes have been made to these 
pages: 
 
•  
Section 14.4a: Removed "Breast Cancer" from the S0307 Prestudy Form title. 
•  
Section 14.4b: "A completed copy of Section 5.0 of the protocol…" has been 
removed. Subsequent sections have been reorganized. 
•  
Section 14.4: Replaced item "d" (a copy of the consent form page documenting 
answers to the specimen consent questions) with "Dental Examination Form," 
now located in Section 14.4c. 
•  
Section 14.5: "WITHIN 90 DAYS OF REGISTRATION, submit the Dental 
Examination Form" has been removed. Subsequent sections have been 
renumbered. The S0307 Treatment Summary Form has been updated. Final 
form numbers were added throughout new Section 14.5. 
•  
Section 14.8: "AFTER OFF TREATMENT – ANNUALLY UNTIL YEAR 10 OR 
DEATH..." has been changed to "AFTER OFF TREATMENT – EVERY 6 
MONTHS UNTIL YEAR 5, THEN ANNUALLY UNTIL YEAR 10 OR UNTIL 
DEATH..." 
•  
Sections 14.9 and 14.10: "Southwest Oncology Group Follow-Up Form" has 
been renamed as "Follow-Up Form". 
•  
Section 14.11: "S0307 Osteonecrosis Jaw Lesion Form" has been renamed as 
"Osteonecrosis Jaw Lesion Form." 
•  
Final form numbers were added throughout this section. 
 
18.  
(Page 38, Section 15.1): "One block of fixed tissue will be banked for the purpose 
of investigating PTHrP and other markers of preferential bone metastasis in the 
future" has been replaced with "Institutions are encouraged to seek patient consent 
to submit tissue and serum for banking (see Sections 15.3 and 15.4)." 
 
19.  
(Pages 38-39, Section 15.2c): The location of the Specimen Tracking laboratory ID 
numbers listed in the second paragraph has been updated. On page 39, the last 
paragraph that begins, "A copy of the Southwest Oncology Group Specimen 
Submission Form..." has been removed. 
 
20.  
(Pages 39-41, Sections 15.3 and 15.4): The tissue and serum submission 
instructions for banking have been updated. 
 
21.  
(Page 44, Table 16.1): Formatting changes have been made to this table, but no 
changes have been made to the content. 
 
22.  
(Page 45, Section 16.1g): In the first paragraph, first sentence, "All cases of acute 
myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphocytic 
leukemia (ALL) that occur..." has been changed to "All cases of acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS) that occur..." In the first 
bullet, "AML/MDS/ALL" has been changed to "AML/MDS". Additionally, the 
address for the Investigational Drug Branch has been removed as the AML/MDS 
report form and documentation should be only be faxed. 
 
23.  
(Pages 47-49, Section 17.0): The bibliography has been updated per item #6 
above. 
 
24.  
(Page 50, Section 18.0): The following changes have been made to this page: 
 
•  
Section 18.1: The following new instructions have replaced the original section: 
"The Model Informed Consent Form is included in this section, preceded by 
"Notes for Local Institution Consent Form Authors" and "Notes for Local 
Investigators." The study – as well as the local consent form meeting the 
guidelines noted in these documents – must be reviewed and approved by the 
Institutional Review Board prior to registration and treatment of patients on this 
study." 
 


 
S0307 
 
Revision #1 (contd.) 
 
Page 6 
 
Revised 9/25/06 
 
 
 
 
 
 
 
 
 
 
 
• 
Section 18.2a: Added "Southwest Oncology Group Registration Form Code 
Sheet" 
• 
Section 18.2b: Removed "Breast Cancer" from the S0307 Prestudy Form title. 
• 
Section 18.2c: The S0307 Treatment Summary Form has been updated. 
• 
Section 18.2e: Removed "Southwest Oncology Group" from Follow-Up Form. 
• 
Section 18.2k: Removed "S0307" from Osteonecrosis Jaw Lesion Form. 
• 
Added final form numbers and version dates throughout. 
 
25.  
(Pages 51-52, Model Consent Form): Formatting changes have been made to 
these pages, but no changes have been made to the content. 
 
26.  
(Page 54, Model Consent Form): Under During the study, fourth bullet, "If you are 
assigned to Arm 1 you will need to have your kidney function tested..." has been 
changed to "You will need to have your kidney function tested..." ("If you are 
assigned to Arm 1" has been removed from the sentence). Routine laboratory tests 
will be performed for all patients in all three arms of the study. 
 
27. 
 (Page 55, Model Consent Form, During the study…) After the first paragraph, the 
following was added: "If you are assigned to either Group 2 or 3, it is strongly 
encouraged that you record the number of pills you take each day on a calendar.  
During visits with your doctor (at Months 6, 12, 24, and 36) you will be asked how 
many pills were missed during the last month of protocol treatment. This will be 
done in order to determine if you are having any problems taking the drug and to 
confirm you are taking it as directed." 
 
28.  
(Pages 55-55a, Model Consent Form, Study Chart): The following changes have 
been made to these pages (page 55a was added to prevent extensive 
repagination): 
 
• 
Second row: In the second column, fourth bullet, "Get tumor biopsy for 
research studies..." has been changed to "Tissue from the original tumor 
biopsy will be submitted for research studies..." 
• 
Third row: In the first column, "Within 7 days prior to starting study" has been 
changed to "Within 14 days prior to starting study." In the second column, "Get 
serum creatinine blood test" has been changed to "Get serum creatinine and 
calculated creatinine clearance blood tests." 
• 
Fifth row: "Week 1" has been changed to "Day 1 of Month 1". 
• 
Sixth row: "Weeks 5, 13, 21, 37, 61, 85, 108, 132" has been changed to "Day 1 
of Months 2-6 and Months 9, 12, 15, 18, 21, 24, 27, 30, 33, and 36." 
• 
Seventh row: "Week 9, 17, 25, 49, 73, 97, 120, & 144" have been changed to 
"Day 1 of Months 2, 4, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, and 36". "Return to 
your doctor's office...for your next physical examination (only for Weeks 25- 
144)" has been changed to "Return to your doctor's office...for your next 
physical examination (only for Months 6, 12, 18, 24, 30, and 36). 
• 
Last row: "Annually after completing study" has been changed to "After 
completing study, every 6 months for 5 years, then annually until Year 10 or 
until death." 
 
29.  
(Page 56, Model Consent Form, Schema): The dose information for each 
bisphosphonate has been removed. 
 
30.  
(Page 58, Model Consent Form, Risks): "Osteonecrosis of the jaw" has been 
added under the 'rare, but serious' category of risks for clodronate. 


 
S0307 
 
Revision #1 (contd.) 
 
Page 7 
 
 
 
 
 
 
 
 
 
 
 
 
31.  
(Page 59, Model Consent Form, Risks): The following changes have been made to 
this page: 
 
• 
"Osteonecrosis of the jaw" has been added under the 'rare, but serious' 
category of risks for ibandronate. 
• 
The "Osteonecrosis of the jaw" paragraph has been replaced with the following 
updated text (This change was made at the recommendation of the CIRB): 
 
"Osteonecrosis of the jaw: Recent reports suggest an association between the 
use of intravenous bisphosphonates, such as zoledronic acid, and 
osteonecrosis of the jaw (permanent damage to the jawbone), a rare, but 
serious potential side effect. This condition may be painful and may happen 
after tooth extraction or other dental procedures such as tooth cleaning or 
when a patient is also getting chemotherapy while taking bisphosphonates. 
Oral clodronate and ibandronate may also increase the risk of osteonecrosis of 
the jaw, although this link is not as well established." 
 
32.  
(Page 62, Model Consent Form): In the additional research studies section a new 
question has been added that states the following: "I agree to allow my study 
doctor, or someone approved by my study doctor, to contact me regarding future 
research involving my participation in this study." 
 
33.  
(Page 63, Model Consent Form): The following changes have been made to this 
page: 
 
• 
Where will my specimens be kept: The contact information for the Southwest 
Oncology Group Serum Bank at the CLASS Laboratory, University of 
Michigan, has been removed. Also, the telephone and fax number for the 
Southwest Oncology Group Tissue Bank has been updated. 
• 
About using specimens for research: The first paragraph that begins, "You 
have had a biopsy (or surgery) to see if you have cancer..." has been removed.  
In the paragraph that begins, "We would like to keep some of the specimens 
that are left over for future research..." the first sentence has been changed to 
"We would like to keep leftover tissue and serum for future research..." 
 
34.  
(Page 64, Model Consent Form): The following changes have been made to this 
page: 
 
• 
In the consent form for use of specimens for research, third question of 
"Making your choice", the sentence "Someone may contact me in the future to 
ask me to take part in more research" has been revised to "Someone may 
contact me in the future for my permission to allow other uses of my 
specimens". 
• 
In the last paragraph of "Making your choice", the sentence that begins, 
"Please designate in the written withdrawal whether you would prefer to have 
the specimens destroyed or returned to the treating physician" has been 
changed to "If you decide to withdraw your permission from the banking part of 
the study, your tissue will be returned to the treating institution, and any blood 
specimens will be destroyed." (This change was made at the recommendation 
of the CIRB.) 
 
35.  
(Page 65, Model Consent Form): Formatting changes have been made to this 
page, but no changes have been made to the content. 
 
36.  
(Master Forms Set): The following forms have been updated. 
 
• 
S0307 Registration Form 
• 
S0307 Prestudy Form 
• 
S0307 Treatment Summary Form 
• 
Due to the inclusion of new forms, repagination was required for pages 83-88, 
Section 19.0. 


 
S0307 
 
Revision #1 (contd.) 
 
Page 8 
 
 
 
 
 
 
 
 
37.  
(Page 84, Section 19.1): Under CTSU requirements for patient enrollment on 
S0307, fourth bullet, "Specimen materials submitted per Section 15.0" has been 
replaced with "Patients who wish to participate in the tissue and serum sample 
submissions for banking as outlined in Sections 15.3 and 15.4 must consent to the 
procedures. Written informed consent must be obtained prior to submitting 
samples." 
 
38.  
(Page 85, Section 19.1): Under specimen collection for serum banking, the second 
sentence, "prior to patient registration, contact the CLASS lab to order serum 
collection kits" has been removed. 
 
39.  
(Page 86, Section 19.1, Drug Procurement): In the second paragraph, the name of 
"ibandronic acid" was misspelled and has been corrected. Also, "UintaVision" has 
been changed to "UVI, Inc." throughout this section. 
 
Institutions should update their local consent forms to include the above-noted 
changes for future registrations.  Patients currently being treated on this study 
should be informed of the changes in the manner determined by the local 
Institutional Review Board (IRB).   
 
Please attach this memorandum and the attachments to the front of your copy of the 
protocol and insert the replacement pages.     
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
William E. Barlow, Ph.D. 
Danika Lew, M.A. 
Christine McLeod 
Lisa Gavigan 
Amy Edwards 
Jeri Jardine 
Kendra Godfrey Barrow - CTSU 
Edward McKenna, Pharm.D. - Roche 
Hartwig H. Hennekes, Ph.D. - Berlex 
Gail A. Larkins - Novartis 
 
 
 


 
 
 
 
 
August 1, 2006 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
We have recently received two safety reports via the National Surgical Adjuvant Breast and 
Bowel Project (NSABP) from Schering Oy, the manufacturer of Bonefos® (clodronate 
disodium tetrahydrate, IND# 71,481).  These safety reports describes events of renal failure 
as discussed in the reports dated June 20, 2006.   
 
The safety reports can be accessed via the S0307 abstract page or the safety report link on 
the Southwest Oncology Group website (https://swog.org/safetyreports/safetyreports.asp). 
 
The safety reports pertain to the following study: 
 
S0307 Breast 
 Report: 
 
 June 20, 2006         AE #2006015297 
 June 20, 2006         AE #2006015298 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised 
to include the information provided in this report if it is deemed necessary by your institution.  
Please append this notice and this report to your copy of the protocol and forward a copy to 
your Institutional Review Board (IRB) as required by your local policies and procedures.  
Should any further information regarding this adverse event be made available, it will be 
forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical 
Center.   
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Hartwig H. Hennekes, Ph.D. – Berlex 
 
Danika Lew, M.A. 
Gail A. Larkins - Novartis 
 
Jean Barce 
Edward McKenna, Pharm.D. – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Kendra Godfrey Barrow – CTSU 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-677-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
July 1, 2006 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
We have recently received a safety report via the National Surgical Adjuvant Breast and 
Bowel Project (NSABP) from Schering Oy, the manufacturer of Bonefos® (clodronate 
disodium tetrahydrate, IND# 71,481).  This safety report describes osteonecrosis of the jaw 
on a patient from the Czech Republic as discussed in the report dated May 29, 2006.   
 
The safety report can be accessed via the S0307 abstract page or the safety report link on 
the Southwest Oncology Group website (https://swog.org/safetyreports/safetyreports.asp). 
 
This safety report pertains to the following study: 
 
S0307 Breast 
 Report: 
 
 May 29, 2006         AE #2006-007626 
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised 
to include the information provided in this report if it is deemed necessary by your institution.  
Please append this notice and this report to your copy of the protocol and forward a copy to 
your Institutional Review Board (IRB) as required by FDA regulation.  Should any further 
information regarding this adverse event be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical 
Center.   
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Hartwig H. Hennekes, Ph.D. – Berlex 
 
Danika Lew, M.A. 
Gail A. Larkins - Novartis 
 
Amy Edwards 
Edward McKenna, Pharm.D. – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Kendra Godfrey Barrow – CTSU 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-677-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
May 15, 2006 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
( √ ) Expedited review allowed 
 
(    ) No review required 
 
 
MEMORANDUM 
 
We have recently received a follow-up safety report via the National Surgical and Bowel 
Safety Project (NSABP) from Schering Oy, the manufacturer of Bonefos® (clodronate 
disodium tetrahydrate, IND# 71,481).  This follow-up safety report describes a non-healing 
ulceration of the upper palate with a small area of exposed bone on a patient described in 
the report dated March 8, 2006.   
 
The safety report can be accessed via the S0307 abstract page or the safety report link on 
the Southwest Oncology Group website (https://swog.org/safetyreports/safetyreports.asp). 
 
These safety report pertain to the following study:
 
S0307 Breast 
 Reports: 
 
 April 21, 2006         AE #2006003410(1)
 
 
Protocol amendments are not necessary at this time, but your consent form may be revised 
to include the information provided in this report if it is deemed necessary by your institution.  
Please append this notice and this report to your copy of the protocol and forward a copy to 
your Institutional Review Board (IRB) as required by FDA regulation.  Should any further 
information regarding this adverse event be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and the Southwest Oncology Group Statistical 
Center.   
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Hartwig H. Hennekes, Ph.D. – Berlex 
 
Danika Lew, M.A. 
Gail A. Larkins - Novartis 
 
Amy Edwards 
Edward McKenna, Pharm.D. – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Kendra Godfrey Barrow – CTSU 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-677-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
April 1, 2006 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
 (    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
 (  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
We have recently received several safety reports via the National Surgical Adjuvant 
Breast and Bowel Project (NSABP) from Schering Oy, the manufacturer of Bonefos® 
(clodronate disodium tetrahydrate, IND# 71,481).  Three of these safety reports detail 
osteonecrosis of the jaw appearing in patients (one with metastatic renal cell carcinoma, one 
with myeloma, and one details unknown) who received oral clodronate after previous 
treatment with IV zoledronate or IV pamidronate.  We have now received a fourth report 
(AE#2006003780) of a probable case  from one of NSABP's sites of a patient enrolled on 
NSABP B-34 who has received two years of treatment with clodronate (the patient's study 
medication was unblinded following the diagnosis) with no previous exposure to other 
bisphosphonates.   
 
This B-34 patient has had a small, non-healing area of bone exposure on the left palatal 
torus (a bony prominence on the anterior palatal bone).  The lesion is currently painless and 
there is no history of recent dental extraction.  Clodronate therapy has been stopped.  The 
toxicity has been described as Grade 2.   
 
This B-34 case suggests that osteonecrosis of the jaw and maxilla might be seen with all 
classes of bisphosphonates, although we continue to believe that the incidence with 
clodronate will be much lower than that seen with the more potent agents currently 
available.  We have been informed that it is the practice in some countries for patients on 
potent bisphosphonates who develop osteonecrosis of the jaw or maxilla, or symptoms 
suggesting that this toxicity may be occurring, to be switched to oral clodronate.  Therefore, 
we expect that there may be further reports of this potentially serious toxicity in patients 
receiving clodronate.   
 
 
The Southwest Oncology Group, in accordance with the NSABP medical staff, agrees that 
this recent information does not require any change to the protocol or reconsent of the 
patients, but we do suggest continued vigilance in the routine clinical examination of the 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-677-8808 • FAX 210-677-0006 • http://swog.org 


 
Memorandum (cont.) 
 
Page 2 
 
 
 
 
 
 
 
 
patients (which should include examination of the oropharynx).  We should also re-
emphasize the importance of good dental hygiene and, where possible, the avoidance of 
dental extractions while patients are on bisphosphonates.  Patients on S0307 who develop 
any exposed area of bone in the mandible or maxilla should have study medication 
discontinued.  Patients who have symptoms of jaw or maxillary pain should be investigated 
with this toxicity in mind although, of course, there are other possible diagnoses.  
 
The safety reports can be accessed via the S0307 abstract page or the safety report link on 
the Southwest Oncology Group website (https://swog.org/safetyreports/safetyreports.asp). 
 
These safety reports pertain to the following 
study: 
 
S0307 Breast 
 Reports: 
 
 February 27, 2006 AE #2006001006(1)
 March 1, 2006 
AE #2006003411 
 March 8, 2006 
AE #2006003410 
 March 9, 2006 
AE #2006003780 
  
 
Please append this notice and the reports to your copy of the protocol and forward copies to 
your Institutional Review Board (IRB) as required by FDA regulation.  Should any further 
information regarding these adverse events be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Hartwig H. Hennekes, Ph.D. – Berlex 
 
Danika Lew, M.A. 
Gail A. Larkins – Novartis 
 
Amy Edwards 
Edward McKenna, Pharm.D. – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Kendra Godfrey Barrow – CTSU 


 
 
 
 
 
March 1, 2006 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS AND PATHOLOGISTS; CTSU 
 
FROM: 
Southwest Oncology Group Operations Office 
 
RE: 
IND Safety Reports for Clodronate (IND-71,481) 
 
MEMORANDUM 
 
IRB Review Requirements 
 
(    ) Full board review required.  Reason: 
(   ) Initial activation (should your institution choose to participate) 
(   ) Increased risk to patient 
(   ) Complete study redesign 
(   ) Addition of tissue banking requirements 
(   ) Study closure due to new risk information 
 
(  √ ) Expedited review allowed 
 
(     ) No review required 
 
 
MEMORANDUM 
 
A safety report was submitted to our office via the National Surgical and Bowel Safety 
Project (NSABP) from Schering Oy, the manufacturer of Bonefos® (clodronate disodium 
tetrahydrate, IND# 71,481).  The report, from French health authorities, describes a recent 
serious adverse event detailing the first confirmed case report of osteonecrosis of the jaw in 
a male patient receiving clodronate.  Osteonecrosis of the jaw has been previously reported 
with more potent bisphosphonate drugs, but not in association with clodronate.   
 
A description of osteonecrosis of the jaw is already included as a potential side-effect of all 
bisphosphonates in the S0307 model informed consent. Additionally, because it appears 
that this particular serious adverse event was due to a pre-existing condition unlikely to be 
related to clodronate, we will not require modification of the protocol or consent form.  
 
The safety report can be accessed via the S0307 abstract page or the safety report link on 
the Southwest Oncology Group website (https://swog.org/safetyreports/safetyreports.asp). 
 
This safety report pertains to the following study:
 
S0307 Breast 
 Report: 
 
 February 1, 2006 
AE #2006001006 
 
Please append this notice and the report to your copy of the protocol and forward a copy to 
your Institutional Review Board (IRB) as required by FDA regulation.  Should any further 
information regarding this adverse event be made available, it will be forwarded to you. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
Christine McLeod 
 
William E. Barlow, Ph.D. 
Hartwig H. Hennekes, Ph.D. – Berlex 
 
Danika Lew, M.A. 
Gail A. Larkins - Novartis 
 
Amy Edwards 
Edward McKenna, Pharm.D. – Roche 
 
Lisa Gavigan 
Joyce Mull – NSABP 
 
Jeri Jardine 
Kendra Godfrey Barrow – CTSU 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-677-8808 • FAX 210-677-0006 • http://swog.org 


 
 
 
 
 
 
 
November 15, 2005 
 
 
TO: 
ALL SOUTHWEST ONCOLOGY GROUP MEMBER, CCOP AND AFFILIATE 
MEDICAL ONCOLOGISTS, SURGEONS AND PATHOLOGISTS; CTSU.   
 
FROM: 
Gilbert R. Carrizales, M.S., Protocol Coordinator 
 
RE: 
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary 
Breast Cancer." Study Coordinators:  J. Gralow, R. Livingston, W.E. Barlow. 
 
STATUS NOTICE 
 
Study Coordinator:  Julie Gralow, M.D. 
Phone number:  206/288-7722 
E-mail:  206/288-2054 
 
IRB Review Requirements 
 
( √ ) Full board review required.  Reason: 
 
( √ ) 
Initial activation (should your institution choose to participate) 
 
(    ) 
Increased risk to patient 
 
(    ) 
Complete study redesign 
 
(    ) 
Addition of tissue banking requirements 
 
(    ) 
Study closure due to new risk information 
 
(   ) Expedited review allowed 
 
(   ) No review required 
 
 
ACTIVATION 
 
The study referenced above is now open for participation.  Entire copies of the protocol are 
enclosed for your use. 
 
This memorandum serves to notify the NCI and Southwest Oncology Group Statistical 
Center. 
 
 
cc: 
PROTOCOL & INFORMATION OFFICE 
William E. Barlow, Ph.D. 
Danika Lew, M.A. 
Christine McLeod 
Lisa Gavigan 
Amy Edwards 
Kendra Godfrey Barrow - CTSU 
Edward McKenna, Pharm.D. - Roche 
Hartwid H. Hennekes, Ph.D. - Berlex 
Gail A. Larkins - Novartis 
 
 
 
 
 
Operations Office 
14980 Omicron Drive•San Antonio, TX 78245-3217 • Telephone 210-677-8808 • FAX 210-677-0006 • http://swog.org 


Appended 6/12/06 
Revised 1/25/07 
Amended 6/18/07 
Amended 3/11/08 
 
 
 
 
SOUTHWEST ONCOLOGY GROUP 
PROTOCOL FAST FACT SHEET 
 
THIS FORM HAS BEEN DESIGNED AS A RESOURCE ONLY AND IS NOT INTENDED FOR USE IN THE FULFILLMENT OF 
PATIENT REGISTRATION AND TREATMENT REQUIREMENTS  
 
S0307  
 
PHASE III TRIAL OF BISPHOSPHONATES AS ADJUVANT THERAPY FOR PRIMARY BREAST CANCER 
 
Treatment initiation: Within 5 working days 
Drugs provided:  Zoledronic acid (Novartis), Clodronate (Bayer Schering Pharma Oy), Ibandronate (Roche) 
 
Arm 1: 
 
Zolendronic Acid 
 
IV over 15 minutes on 
Day 1 
→ 
q monthly for 6 months then q 3 
months for 2.5 years. 
 
 
 
 
Arm 2: 
 
Clodronate 
PO, start on Day 1 
 
→ 
q day for 3 years 
 
 
Arm 3: 
Ibandronate 
PO, start on Day 1 
→ 
q day for 3 years 
 
 
Eligibility 
Ineligibility 
Histologically confirmed primary invasive adenocarcinoma of the 
breast, Stage I, II, III, with no evidence of metastatic disease. 
Pregnant or nursing women may not participate. 
Must receive standard (systemic) adjuvant therapy for breast 
cancer. Chemotherapy, hormone therapy, or combined therapy 
permitted.  Additional therapies are allowed including radiation 
therapy and biologic agents (e.g. Herceptin®, Avastin®, 
hematopoietic growth factors).  Neoadjuvant therapy is permitted, 
but enrollment must occur after completion of surgery. 
Use of biologic agents only or local radiation therapy only 
(without chemotherapy and/or hormone therapy).   
 
Patients who are at such a low risk of recurrence that 
adjuvant therapy will not be prescribed.   
Patients may be enrolled prior to, simultaneously with, or after 
beginning adjuvant systemic therapy.  Patients receiving hormonal 
therapy alone (no chemotherapy) or pre-operative chemotherapy 
should be enrolled within 84 days (12 weeks) after the date of final 
surgical procedure.  Patients receiving adjuvant post-operative 
chemotherapy may be enrolled up to 8 weeks after completion of 
chemotherapy.  Additional biological therapy or radiation therapy is 
allowed at any time before or after registration. 
Esophageal stricture or motility disorder. Patients with a 
history of gastroesophageal reflux disorder (GERD) are 
eligible, but caution should be used when giving oral 
bisphosphonates. 
Patients who wish to participate in the tissue and serum sample 
submissions for banking must consent to the procedures.   
No other prior malignancy is allowed except treated basal 
cell or squamous cell skin cancer, in situ cervical cancer, 
adequately treated stage I or II cancer from which patient is 
currently in complete remission. 
Zubrod performance status of 0-2. 
No other use of bisphosphonates.  Previous use OK as long 
as bisphosphonates are discontinued at registration. 
Serum creatinine that is ≤ 2 X IULN and measured creatinine 
clearance of ≥ 30 ml/min within 7 days of registration. 
 
Patients with skeletal pain if a bone scan and/or 
roentgenological exam shows metastatic disease. 
Must undergo a dental examination within 6 months prior to 
registration.  
Must not be co-enrolled on protocols that have bone density 
as an endpoint.  If allowed by the protocol, can be enrolled 
on other locoregional or systemic therapy breast cancer 
study, including cooperative group studies. 
 
PRESTUDY REQUIREMENTS: 
≤ 6 months before initiation of treatment:  Dental examination 
≤ 7 days before registration:  Serum creatinine and measured creatinine clearance 
≤ 28 days before registration:  History and physical exam, weight and height, performance status, and chest x-rays unless done 
for the original diagnostic workup.  Bone Scan if patient has bone pain. 
≤ 72 hours before initiation of treatment:  Pregnancy test (for women of childbearing potential)  
 
Suggested for Good Medical Practice 
CBC/Diff/PLTS, bilirubin, SGOT/SGPT, alk phosph, calcium, phosphate, magnesium *albumin (only if serum calcium is 
drawn, not needed for ionized calcium), electrolytes including sodium, potassium, chloride and bicarbonate  
*This form has been developed with the support of the SWOG Nurse Oncologists’ Committee. 
R 
A 
N 
D 
O 
M 
I 
Z 
E 


 
 
 
 
PRIVILEGED COMMUNICATION 
Revised 1/25/07 
S0307 
FOR INVESTIGATIONAL USE ONLY 
Amended 6/18/07 
Activated November 15, 2005 
Revised 6/12/06 
Amended 3/11/08 
Revised 10/11/11 
 
 
Revised 12/19/14 
 
SWOG 
 
PHASE III TRIAL OF BISPHOSPHONATES AS ADJUVANT THERAPY FOR  
PRIMARY BREAST CANCER 
 
 
Page 
  
SCHEMA…………………………………………………………………………………………..5 
   1.0 
OBJECTIVES……………………………………………………………………………………..6 
   2.0 
BACKGROUND…………………………………………………………………………………. 6 
   3.0 
DRUG INFORMATION………………………………………………………………………...14 
   4.0 
STAGING CRITERIA ...................................................................................................... .22 
   5.0 
ELIGIBILITY CRITERIA .................................................................................................. .26 
   6.0 
STRATIFICATION FACTORS  ....................................................................................... .28 
   7.0 
TREATMENT PLAN ........................................................................................................ .28 
   8.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS .......................... .31 
   9.0 
STUDY CALENDAR ....................................................................................................... .32 
 10.0  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS .................................. .33 
 11.0 
STATISTICAL CONSIDERATIONS  ............................................................................... .33 
 12.0 
DISCIPLINE REVIEW ..................................................................................................... .34a 
 13.0 
REGISTRATION GUIDELINES ...................................................................................... .34a 
 14.0 
DATA SUBMISSION SCHEDULE .................................................................................. .36 
 15.0 
SPECIAL INSTRUCTIONS ............................................................................................. .38 
 16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ..................................................... .41 
 17.0 
BIBLIOGRAPHY ............................................................................................................. .46 
 18.0 
MASTER FORMS SET ................................................................................................... .50 
 19.0 
APPENDIX……………………………………………………………………………………….83 
 
 
SWOG STUDY COORDINATORS: 
AGENTS: 
Julie Gralow, M.D. (Medical Oncologist) 
Clodronate (NSC-713466) (IND-71,481) 
University of Washington School of Medicine 
 
 Supplied by Bayer Schering Pharma Oy 
Seattle Cancer Care Alliance 
Ibandronate (NSC-722623) (IND-71,481) 
825 Eastlake Ave East, MS G4-830 
  
Supplied by Roche 
Seattle, WA 98109-1023 
Zoledronic Acid (CGP 42446) (NSC-721517) 
Phone:  206/288-7722 
  
Supplied by Novartis 
FAX:  206/288-2054 
 
E-mail:  pink@u.washington.edu  
BIOSTATISTICIANS 
 
William E. Barlow, Ph.D. (Biostatistics) 
 
Cancer Research and Biostatistics 
 
1730 Minor Avenue, Suite 1900 
 
Seattle, WA  98101-1468 
 
Phone:  206/652-2267 
 
Fax:  206/652-4612 
 
E-mail:  williamb@crab.org 
 
Robert B. Livingston, M.D. (Medical Oncologist) 
Danika Lew, M.A. (Biostatistics) 
Arizona Cancer Center 
Southwest Oncology Group Statistical Center 
1515 N. Campbell Avenue 
Fred Hutchinson Cancer Research Center 
P.O. Box 245024, Hem/Onc Section 
1100 Fairview Avenue North, M3-C102 
Tucson, AZ  85724-5024 
P.O. Box 19024 
Phone:  520/626-2816 
Seattle, WA  98109-1024 
FAX:  520/626-3754 
Phone:  206/667-4623 
E-mail:  rlivingston@azcc.arizona.edu 
FAX:  206/667-4408 
 
E-mail:  dlew@fhcrc.org  
 
 
mb 
(Version Date 12/19/14) 


Revised 6/12/06 
S0307 
Revised 7/13/09 
Page 2 
 
 
 
 
 
NCCTG STUDY COORDINATOR 
BIOLOGIC CORRELATES 
 
James N. Ingle, M.D.  
Daniel F. Hayes, M.D. 
Professor of Oncology 
Clinical Director, Breast Oncology Program 
Mayo Clinic 
University of Michigan Comprehensive Cancer Center 
200 First Street SW 
6312 Cancer Center 
Rochester, MN  55905 
1500 E. Medical Center Drive 
Phone:  507/284-8432 
Ann Arbor MI  48109-0942 
FAX:  507/284-1803 
Phone:  734/615-6725 
E-mail:  Ingle.james@mayo.edu 
FAX:  734/615-3947 
 
E-mail:  hayesdf@umich.edu 
 
ECOG STUDY COORDINATOR 
CO-COORDINATOR BONE HEALTH 
 
Carla Falkson, M.D. 
Dawn Hershman, M.D., M.S. 
 
Professor, Dept of Medicine 
Assistant Professor of Medicine  
Division of Hematology/Oncology 
Columbia University College of Physicians & Surgeons 
University of Alabama at Birmingham 
Herbert Irving Cancer Center 
 
WTI 275 J1 
 
161 Ft Washington, Room 1068  
1824 6th Ave South  
New York, NY 10032  
Birmingham, AL 35294 
Phone:  212/305-1945 
Phone:  205/975-2691 
FAX:  212/05-0178 
FAX:  205/975-0805  
E-mail:  Dlh23@columbia.edu 
E-mail:  cfalkson@uab.edu 
 
 
NSABP STUDY COORDINATOR 
CO-COORDINATOR JAW/DENTAL HEALTH 
 
Alexander Paterson, M.D. 
Mark Schubert, D.D.S., M.D.S. (Special Consultant) 
Tom Baker Cancer Center 
University of Washington School of Dentistry 
Dept. of Medicine 
Director and Professor of Oral Medicine 
1331 29th Street NW 
Seattle Cancer Care Alliance 
Calgary, AB T2N 4N2, Canada 
825 Eastlake Ave East, Mailstop G6900 
Phone:  403/944-1707 
Seattle, WA 98109 
FAX:  403/283-1651 
Phone:  206/288-1331 
E-mail:  alexpate@cancerboard.ab.ca 
FAX:  206/288-1332   
 
E-mail:  mschuber@seattlecca.org 
 
CALGB STUDY COORDINATOR 
CO-COORDINATOR STATINS 
 
 
E. Claire Dees, M.D. 
Alison T. Stopeck, M.D.  
Assistant Professor of Medicine  
Medical Oncologist 
Division of Hematology and Oncology  
Arizona Cancer Center 
University of North Carolina at Chapel Hill 
1515 N. Campbell Ave 
CB 7305, 3009 Old Clinic Bldg 
P.O. Box 245024 
Chapel Hill, NC 27514 
Tucson, AZ 85724-0001 
Phone:  919/843-7714 
Phone:  520/626-2816 
FAX:  919/966-6735 
FAX:  520/626-3754 
E-mail:  claire_dees@med.unc.edu 
E-mail:  astopeck@azcc.arizona.edu 
 
 
 
CO-COORDINATOR PHARMOCOGENOMICS 
 
Catherine H. Van Poznak, M.D. 
Department of Internal Medicine 
Division of Hem/Onc 
1500 E Medical Center Drive 
C346 MIB/Box 0848 
Ann Arbor, MI 48109-0848 
Phone:  734/936-9209 
FAX:  734/615-2109 
E-mail:  cvanpoz@umich.edu 
 


 
S0307 
 
Page 3 
 
Revised 6/12/06 
 
Revised 1/21/10 
 
Revised 12/19/14 
 
 
 
 
NCIC-CTG STUDY COORDINATOR: 
 
 
Mark J. Clemons, M.D. 
 
Medical Oncologist 
 
Division of Medical Oncology 
 
The Ottawa Hospital Cancer Centre  
 
501 Smyth Road  
 
Ottawa, ON  K1H 8L6 
 
Phone:  613/737-7700 
FAX:  613/247-3511 
E-mail:  mclemons@toh.on.ca 
 
 
 
 
 
 
 
For questions relating to treatment please contact the Southwest Oncology Group Coordinator 
(Dr. Gralow) or: 
Kim Dammann,  
Research RN 
Seattle Cancer Care Alliance 
Phone:  206/288-6900 
Email:  ADJBISJG@u.washington.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PARTICIPANTS 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
 
NCIC-CTG/NCIC Clinical Trials Group 
 
NRG/NRG Oncology 
 
SWOG/SWOG 
 


Revised 1/25/07 
S0307 
Amended 3/11/08 
Page 4 
 
 
 
 
 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Institutions not aligned with SWOG will participate through the CTSU  
mechanism as outlined below and detailed in the CTSU logistical appendix. 
 
• 
The study protocol and all related forms and documents must be downloaded from the protocol-
specific Web page of the CTSU Member Web site located at https://members.ctsu.org 
 
• 
Send completed site registration documents to the CTSU Regulatory Office. Refer to the CTSU 
logistical appendix for specific instructions and documents to be submitted.  
 
• 
Patient enrollments will be conducted by the CTSU. Refer to the CTSU logistical appendix for specific 
instructions and forms to be submitted. 
 
• 
Data management will be performed by the Southwest Oncology Group. Case report forms (with the 
exception of patient enrollment forms), clinical reports, and transmittals must be sent to the 
Southwest Oncology Group Data Operations Center unless otherwise directed by the protocol. Do not 
send study data or case report forms to the CTSU Data Operations.  
 
• 
Data query and delinquency reports will be sent directly to the enrolling site by the Southwest 
Oncology Group. Please send query responses and delinquent data to the Southwest Oncology Group 
Data Operations Center and do not copy the CTSU Data Operations. 
  
• 
Each site should have a designated CTSU Administrator and Data Administrator and must keep their 
CTEP AMS account contact information current. This will ensure timely communication between the 
clinical site and the SWOG data center. 
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data directly to 
the Lead Cooperative Group 
unless otherwise specified in 
the protocol: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone:  1-888/823-5923 
Fax:  215/569-0206 
CTSU Patient Registration 
Voice Mail:  1-888/462-3009 
Fax:  1-888/691-8039  
Hours: 9:00 am – 5:30 pm EST, 
Monday – Friday (excluding holidays) 
 
[Registrations received after 5:00 PM 
ET will be handled the next business 
day. For CTSU patient enrollments that 
must be completed within 
approximately one hour, or other 
extenuating circumstances, call 
301/704-2376 between 9:00 am and 
5:30 pm.] 
Southwest Oncology Group Data 
Operations Center 
Fax:  1-800/892-4007 
[Please do not use a cover sheet 
for faxed data.] 
 
Do not submit study data or forms 
to CTSU Data Operations. Do not 
copy the CTSU on data 
submissions.   
For treatment- or toxicity-related questions contact the Study PI of the Coordinating Group.  
For eligibility questions contact the Southwest Oncology Group Data Operations Center by phone or email:  
Phone:  206/652-2267; Email:  breastquestion@crab.org 
For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help Desk 
by phone or e-mail:  CTSU General Information Line:  1-888/823-5923, or ctsucontact@westat.com. All calls 
and correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Public Web site is located at: www.ctsu.org  
The CTSU Registered Member Web site is located at https://members.ctsu.org 
CTSU logistical information is located in Appendix 19.1  
 


 
S0307 
 
Page 5 
 
Revised 6/12/06 
 
 
 
 
 
SCHEMA 
 
Randomization 
 
 
 
 
 
 
 
Arm 1  
Arm 2 
Arm 3 
Zoledronic Acid (IV) 
Clodronate (PO) 
Ibandronate (PO) 
monthly X 6 months, then  
daily x 3 years 
daily x 3 years 
q3 months x 2.5 years 
 
 
Patients will be followed for disease-free and overall survival, as well as sites of first recurrence. 
 
 
 
 


 
S0307 
 
Page 6 
 
Revised 7/13/09 
 
 
 
 
1.0 
OBJECTIVES 
 
1.1 
To compare disease-free survival in patients receiving clodronate versus ibandronate 
versus zoledronic acid as adjuvant therapy for breast cancer.   
 
1.2 
To compare overall survival in patients receiving clodronate versus ibandronate versus 
zoledronic acid as adjuvant therapy for breast cancer.   
 
1.3 
To compare the distributions of sites of first recurrence on the three arms. 
 
1.4 
To assess the adverse events of clodronate compared to ibandronate compared to 
zoledronic acid in this cohort of patients. 
 
1.5    
To assess the association of PTHrP status and serum N-telopeptide levels at baseline 
with disease-free survival and sites of first recurrence. 
 
1.6 
To test treatment-PTHrP and serum N-telopeptide levels interactions with respect to 
disease-free survival and sites of first recurrence. 
 
1.7 
To investigate whether there is an association between  inherited germ-line single 
nucleotide polymorphisms (SNP, rs2297480) in farnesyl diphosphate sythase (FDPS) 
and the adverse event of acute phase reactions in this cohort of patients (see Appendix 
19.3). 
 
 
2.0 
BACKGROUND 
 
Bone metastases are very common in patients with breast cancer.  The skeleton is the initial site 
of recurrence in 35 - 40% of patients.  (1)  Up to 60 - 80% of patients with metastatic breast 
cancer eventually develop signs and symptoms related to bone involvement.  (2)  Bone 
metastases are a major cause of morbidity in breast cancer, with complications including pain, 
pathologic fractures, hypercalcemia, bone marrow suppression, and spinal cord compression.   
 
There is increasingly persuasive evidence that overactivation of osteoclasts is the primary 
process of neoplastic damage in bone.  Breast cancer cells present in bone marrow appear to 
release factors that activate osteoclasts to resorb bone.  (3)  Stimulators of osteoclastic activity 
include tumor-derived factors such as parathyroid hormone related peptide (PTHrP) and 
transforming growth factor beta (TGF-β).  Recent work has suggested that PTHrP may be the 
major mediator of osteoclastic hyperactivity in patients with lytic bone metastases.  (4, 5) 
 
Bisphosphonates are a diverse group of compounds, which have profound effects on bone 
mineralization and resorption.  As a group, they are poorly absorbed from the gastrointestinal 
tract and when given orally are associated with reduced compliance due to gastrointestinal 
intolerance.  They bind avidly to bone, altering the properties of hydroxyapatite crystals and 
rendering them resistant to hydrolysis by endogenous phosphates.  (4)  Bisphosphonates are a 
class of drugs capable of inhibition of osteoclast function.  They are effective in treating 
conditions in which there is excessive bone resorption and osteoclast activity, including 
osteoporosis and Paget’s disease of bone.  Several randomized clinical trials in breast cancer 
patients with bone metastases have demonstrated the ability of bisphosphonates to reduce 
skeletal-related events and symptoms, including pathologic fractures, requirement for surgery or 
radiation, spinal cord compression, hypercalcemia, and pain.  (5-8)  Bisphosphonates have not 
shown improved survival in these patients. Clodronate (Bonefos®) and pamidronate (Aredia®) 
have been extensively evaluated in patients with metastatic cancer and are widely used in 
oncology.  (5-7)  Zoledronic acid (Zometa®) and ibandronate (Bondronat®) represent highly 
potent, newer generation bisphosphonates with recently demonstrated benefit in reducing 
skeletal-related events.  (9-13) 
 
Three randomized clinical trials of the oral bisphosphonate clodronate as adjuvant therapy in 
breast cancer have been reported, yielding conflicting results with respect to development of 
bone metastases and survival.  A German trial of 302 breast cancer patients with 
immunocytochemical evidence of cancer cells in a bone marrow aspirate but no other evidence 
of metastatic disease showed a reduction in bone recurrence and an increase in overall survival 
with two years of clodronate.  (14, 15)  With almost 5 years of follow-up, bone metastases were 


 
S0307 
 
Page 7 
 
Revised 6/12/06 
 
 
 
 
reduced in the clodronate group compared to a control group (14% versus 24%, p=0.044) and 
visceral metastases showed a trend toward reduction (17% versus 26%, p=0.091).  Overall 
survival was higher in the clodronate arm (91% versus 77%, p=0.002).  The effect of adjuvant 
clodronate appeared weakened with longer follow-up.  
 
A Finnish trial involving 299 women with lymph node-positive breast cancer randomized to 3 
years of adjuvant clodronate showed virtually the opposite result, with no effect on the rate of 
bone metastasis and a deleterious effect on relapse rates of non-bone metastasis as well as 
survival.  (16)  After 5 years of follow-up, bone metastases were detected equally in the 
clodronate group and placebo groups (21% versus 17%, p=0.27), and non-skeletal metastases 
were significantly more common in the clodronate group (43% versus 25%, p=0.0007).  Overall 
survival was worse in the clodronate group (79% versus 83%, p=0.009). 
 
Most recently, a randomized, multicenter trial involving 1,079 primary breast cancer patients 
evaluating 2 years of adjuvant clodronate reported a benefit in overall survival.  (17)  Within the 
two years of clodronate treatment, bone metastases were significantly lower in the group 
receiving clodronate compared to placebo (2.3% versus 5.2%, p=0.016); however, at 5 years of 
follow-up, bone metastasis were no longer significantly different between the two treatment arms 
(12% versus 15%, p=0.107).  No effect was observed on visceral sites of metastasis (17% versus 
20%, p>0.05), although reassuringly there was no trend toward an increase.  Overall survival was 
significantly improved in the clodronate arm (82% versus 76%, p=0.047). 
 
All three adjuvant clodronate trials were recently updated at the American Society of Clinical 
Oncology meeting in 2004.  (18-20)  The German trial continues to show a survival benefit for the 
clodronate arm (80% vs. 60%) overall survival at 103 months, p=0.04).  (18)  The final analysis of 
the larger UK-led trial shows a statistically significant survival benefit for the clodronate arm, with 
a hazard ratio for survival of 0.768 (p=0.048) that persists at 10 years of follow-up.  (19)  The 
Finnish study no longer shows a significant survival detriment at 10 years of follow-up.  (20)  The 
intriguing but contradictory results of these three adjuvant bisphosphonate studies highlight the 
need for further investigation to determine whether bisphosphonates can influence the 
development of bone metastases and improve survival in early stage breast cancer.  The 
National Surgical Adjuvant Breast and Bowel Project (NSABP) has recently completed accrual on 
a multicenter confirmatory trial.  NSABP B34 is evaluating oral clodronate for 3 years versus 
placebo in addition to standard treatment in 3,200 patients with Stage I or II breast cancer.  The 
North American Intergroup trial S0307 will compare newer, more potent bisphosphonate agents 
to clodronate.  It is noteworthy that this trial design will still be valid even if the B-34 study results 
are not able to show a benefit for clodronate.  As long as the clodronate arm is not inferior to 
placebo in B-34 (which is fairly unlikely provided the weight of the available evidence), the 
clodronate arm of the proposed trial would serve as a "reference control" against which one could 
still study the two newer, more potent bisphosphonates. 
 
Ibandronate is a highly potent aminobisphosphonate that is currently approved in Europe in 
intravenous (6 mg) and oral (50 mg) form in breast cancer patients with bone metastases. 
Placebo-controlled trials of both oral and intravenous ibandronate in metastatic breast cancer 
show significant activity in reducing skeletal related events.  (9, 10) 
 
A phase III placebo-controlled trial of 466 breast cancer patients with bone metastases compared 
either 2 mg or 6 mg ibandronate as a 1- or 2-hour infusion or placebo injections every 3 - 4 
weeks for up to two years in addition to their antineoplastic therapy.  (9)  The primary study 
endpoint, skeletal morbidity period rate, was lower in both ibandronate groups compared to 
placebo (p=0.004 for ibandronate 6 mg versus placebo).  Ibandronate 6 mg reduced the number 
for new bone metastases by 38% and increased time to first new bone event.  Additionally, 
patients on ibandronate 6 mg experienced decreased bone pain cores and analgesic use.  
 


 
S0307 
 
Page 8 
 
Revised 6/12/06 
 
 
 
 
An oral formulation of ibandronate has also been developed and Phase III clinical trials of oral 
ibandronate versus placebo in breast cancer patients with bone metastases have recently been 
reported.  (10)  Two pivotal studies were performed in which two doses of ibandronate (20 mg 
and 50 mg) were compared to placebo.  Both oral ibandronate doses demonstrated significant 
treatment effects in breast cancer patients with metastatic bone disease compared to placebo.  In 
a pooled analysis, oral ibandronate 50 mg significantly reduced the mean skeletal morbidity 
period rate, the primary study endpoint, compared to placebo (0.95 versus 1.18, p=0.004).  Both 
the 20 and 50 mg ibandronate doses also demonstrated significant treatment effects on the 
secondary efficacy parameters, WHO performance status, bone pain and markers of bone 
resorption.   
 
Zoledronic acid, another third-generation aminobisphosphonate, has been shown to be superior 
to pamidronate in treating hypercalcemia of malignancy, and is at least as effective as 
pamidronate in the prevention of SREs in breast cancer and multiple myeloma patients.  (11,12)  
A major advantage of zoledronic acid is that it can be given safely over short infusion durations. A 
randomized Phase III non-inferiority trial comparing 4 mg and 8 mg of zoledronic acid versus 
pamidronate in breast cancer and multiple myeloma patients with documented bone metastases 
was conducted.  (12,13)  Partway through the trial, the 8 mg arm was eliminated and the infusion 
volume and time for the 4 mg arm was lengthened due to concerns about renal toxicity.  For the 
primary study endpoint, the proportion of patients with at least one skeletal-related event, results 
were similar in patients treated with zoledronic acid and pamidronate.  With a fifteen-minute 
infusion rate, zoledronic acid was more convenient to administer than pamidronate (90 mg), 
which requires a 2-hour infusion.  Zoledronic acid has been approved by the FDA at a dose of 4 
mg over 15 minutes every 3 - 4 weeks for reduction of skeletal complications in cancer patients 
with bone metastases. 
 
Some patients may prefer oral formulations to IV formulations for reasons of comfort and 
convenience.  Zoledronic acid is available only as an intravenous infusion, whereas ibandronate 
may be given either intravenously or as an oral tablet. While oral bioavailability of 
bisphosphonates is overall very low (≤ 0.5-4%), it has been shown that oral dosing of ibandronate 
resulting in comparable drug exposure to effective intravenous doses can be achieved, and that 
this dose is tolerable and efficacious in inhibiting skeletal-related events. 
 
This study proposes to determine whether two newer, potentially more potent bisphosphonates, 
zoledronic acid and ibandronate, can delay or prevent the occurrence of metastases compared 
with the control arm containing oral clodronate.  Breast cancer patients receiving standard 
adjuvant systemic therapy will be eligible.  At registration, patients would be randomized to either 
zoledronic acid 4 mg IV to be given over 15 minutes every 4 weeks for the first six months, and 
then every 3 months for the following 2.5 years, clodronate 1,600 mg/day orally, or ibandronate 
50 mg/day orally for three years.  The proposed duration of bisphosphonate therapy is 3 years. 
 
Bisphosphonates in Pre-Menopausal Women 
 
All 3 bisphosphonates used in S0307 are approved worldwide for treatment of bone metastases 
without restriction regarding menopausal status, and there is no data to support excluding 
premenopausal women from enrollment in S0307.  Potential impact on fetal development is a 
concern in this population should the patient become pregnant, but with proper patient 
awareness and education regarding adequate contraception this should not be a reason to 
restrict studying the use of a potentially life-saving anti-cancer agent in premenopausal women.  
 
It is possible that long-term effects on bone quality and bone health may differ in premenopausal 
versus postmenopausal women.  None of the adjuvant bisphosphonate trials to date, all of which 
included large percentages of premenopausal women, have shown any trend toward increased 
long-term bone or other toxicities when compared to placebo.  We plan on performing a substudy 
addressing bone health, including serial bone biopsies in a small number of patients enrolled on 
S0307, to further address this issue (we have submitted a grant to the NIH to fund this substudy). 
We will also be collecting detailed bone fracture follow-up data on all patients.  
 


 
S0307 
 
Page 9 
 
Revised 6/12/06 
 
 
 
 
Clodronate is approved in Canada, Europe and Asia at the 1,600 mg per day dose for treatment 
of bone metastases and has been widely used for greater than a decade.  It is on fast-track 
approval with the FDA in the U.S.  The label does not restrict usage based on menopausal 
status. The three adjuvant European trials evaluating clodronate versus placebo were recently 
updated with 10-year follow-up data at ASCO 2004.  (18-20)  All three of these trials enrolled both 
pre- and post-menopausal early stage (non-metastatic) breast cancer patients.  Thirty-seven 
percent of the women in the German trial were premenopausal (113 of 302 patients).  (19)  In the 
Finnish trial, 52% of the enrollees were pre-menopausal (148 of 282).  (18)  In the larger UK-led 
trial, 50 % of trial participants were pre-menopausal (520 out of 1069 patients).  (20)  None of 
these trials reported toxicity rates based on menopausal status, but none of the trials reported 
any major significant difference in toxicities between the clodronate and placebo arms. 
 
A recent publication of the extended safety profile of oral clodronate in the UK adjuvant 
clodronate study concluded that clodronate was well-tolerated with no serious long-term 
sequelae.  (21)  The precursor trial to S0307, the 3,200 patient NSABP B-34 study, met accrual in 
March of 2004.  B-34 randomized early stage breast cancer patients to 3 years of clodronate 
versus placebo.  The study has not yet reached a sufficient number of events to allow analysis 
based on the statistical plan.  The Data Safety and Monitoring board has not identified any 
adverse events worthy of reporting.  B-34 did not restrict enrollment based on menopausal status.  
 
Ibandronate has recently been approved in Europe, Central America and Asia for the treatment of 
bone metastases in both intravenous form (6 mg dose monthly) and oral form (50 mg daily). 
There is no restriction based on menopausal status in the labeling in any country, and the trials 
leading to the approval of this drug included breast cancer patients of all ages.  It is approved, but 
not yet available, in the U.S. for an osteoporosis indication at a substantially lower dose than that 
used in bone metastases (and in S0307).  Again, no restriction has been placed based on 
menopausal status.  The breast cancer studies of intravenous and oral ibandronate performed to 
date collected patient age but not menopausal status, and therefore such a breakdown is 
impossible. Of the 435 patients with metastatic breast cancer treated on the pivotal oral 
ibandronate studies, the median age was 57, and the age range was 29 - 92.  (22)  Some of the 
younger women who would normally have been within a pre-menopausal age range were likely 
post-menopausal secondary to their anti-cancer therapies, but based on the age range at least 
some pre-menopausal women were undoubtedly treated on this study.  The median age and age 
range are similar in the intravenous ibandronate trials. The metastatic ibandronate trials included 
follow-up reporting of up to 2 years of treatment, and have shown a statistical decrease in 
skeletal-related events and improvement in quality of life. 
 
Zoledronic acid is approved in the United States at the dose to be used in S0307 for the 
treatment of bone metastasis in multiple myeloma and all solid tumors.  There is no restriction 
based on menopausal status.  The S0307 protocol background, drug information and toxicity 
sections do not limit discussion to post-menopausal women.  There were 3 pivotal trials leading 
to approval of zoledronic acid for the bone metastasis indication: 1 in breast cancer and multiple 
myeloma, one in prostate cancer, and one in all other sold tumors.  The breast and myeloma trial 
randomized between pamidronate and zoledronic acid. The other 2 trials randomized between 
placebo and zoledronic acid.  Pre-menopausal status was not an exclusion criterion.  In the 
breast cancer and myeloma study, 12.8% of patients were < 45 years of age, 11.8% were 
between ages 45-49, and 75.3% were > 49 years.  In the solid tumor study, 7.4% of patients 
were less than 45, 6.3% were 45-49, and 86.3% were > 49 years (and at least half were male).  
All three studies showed a decrease in skeletal-related events with up to 24 months of treatment, 
and an improvement in quality of life scores.  


 
S0307 
 
Page 9a 
 
Revised 7/25/08 
 
 
 
 
Adjuvant Bisphosphonate Therapy 
 
A recent study investigating the adjuvant use of zoledronic acid reported an improvement in 
disease-free survival, in addition to favorable effects on bone mineral density. The Austrian 
Breast and Colorectal Cancer Study Group (ABCSG) trial, ABCSG-12, enrolled 1,800 pre-
menopausal women with ER-positive breast cancer. (66) All patients received ovarian 
suppression for three years with a leutinizing hormone releasing hormone (LHRH) analogue, 
goserelin.  Patients were randomized in a 2 x 2 design to receive tamoxifen versus anastrozole, 
and zoledronic acid (4 mg q 6 months) or not.  At the first efficacy analysis, reported after 137 
events (70 distant relapses) with approximately 60 months of follow-up, there was no difference 
in outcome with respect to the endocrine therapy randomization.  There was, however, a 
statistically significant improvement in disease-free survival for the patients who received 
zoledronic acid (HR 0.64; p = 0.01), with a similar trend towards improved overall survival (HR 
0.60, p = 0.10).  While ABCSG-12 clearly provides additional support for the metastasis-
suppressing potential of adjuvant bisphosphonates, this study enrolled only a narrow subset of 
breast cancer patients:  pre-menopausal women with estrogen receptor-positive tumors who did 
not receive adjuvant chemotherapy.  While promising, caution must be taken not to over-
extrapolate these findings, or this dose schedule, to all breast cancer patients. 
 
The Zometa-Femara Adjuvant Synergy Trials (Z-FAST and ZO-FAST) enrolled ER-positive, 
postmenopausal women receiving letrozole and randomized them to "upfront" versus "delayed" 
zoledronic acid therapy (every 6 months for 5 years) in an attempt to reduce bone loss-related 
morbidity. Time to recurrence was a secondary endpoint. A recent combined analysis of these 
trials showed lower recurrence rates in the group receiving upfront zoledronic acid therapy (1.1% 
versus 2.3%, p = 0.04). (67) 
 
The results of ongoing and recently closed studies will aid in defining the optimal patient and 
tumor populations for the addition of adjuvant bisphosphonates, as well as optimal doses and 
schedules of administration, and long-term toxicities. Whether doses used in metastatic disease 
are required for prevention or whether lower doses will suffice is unknown. It is unclear whether 
adjuvant bisphosphonates should be given continuously and orally, whether intravenous therapy 
is preferable, and whether "less intensive" intravenous regimens will turn out to be as effective as 
"more intensive" regimens.  The optimal duration of adjuvant bisphosphonate therapy is also 
unknown. 
 
 


 
S0307 
 
Page 10 
 
Revised 6/12/06 
 
 
 
Bone density and bone quality 
 
Bisphosphonates increase bone density and have been shown to reduce fracture rates in women 
with osteopenia and osteoporosis.  (23)  It may be that patients enrolled in S0307 will have a 
fracture rate that is less than age and race matched controls.  Osteoporotic fractures, an 
important cause of chronic disability and disfigurement in the elderly, result when stresses placed 
on the bone exceed the strength of the bone.  (24)  Bone density is one important determinant of 
the strength of bone.  However, bone strength depends on both the quantity and the quality of 
bone.  One factor that influences the bone quality is the mineralization density.  (25)  
Bisphosphonates inhibit bone turnover, interfere with bone remodeling, and increase 
mineralization density, which could potentially make the bone more brittle.  
 
Studies in beagles have shown increased bone density but also markedly decreased bone 
formation rates and development of fatigue damage after one year of high dose alendronate or 
risedronate.  (26)  Biomechanical testing showed increased bone strength, but decreased 
toughness.  A case report was recently published of a boy who developed osteopetrosis (marble 
bone disease) after several years of treatment with high doses of pamidronate. Osteopetrosis is 
the result of defective remodeling and is characterized by dense, poorly-formed and brittle 
skeletal tissue. Although the bones in this patient became extremely dense, he fractured his 
radius with only minimal trauma, suggesting decreased bone strength.  (27,28) 
 
In this study, bisphosphonates will be used in much higher doses than currently recommended 
for treatment of postmenopausal osteoporosis, and the long-term effects of such high doses of 
bisphosphonates on the skeleton are not known.  In order to determine if the effects of 
bisphosphonates are beneficial or detrimental to the skeleton, we will collect prospective data on 
traumatic and non-traumatic fractures. In addition, a separate companion study to S0307 will 
evaluate bone density and turnover in a subset of patients, and a small, limited-institution 
companion study of bone quality on S0307 will include bone biopsies and experimental measures 
of bone strength and elasticity. 
 
Renal toxicity 
 
As there are limited data on the long-term renal safety of high-dose bisphosphonates in healthy 
patients, S0307 will be collecting data on renal function.  Oral and short-term intravenous 
administration of bisphosphonates, when given according to recommended infusion doses, times, 
and intervals, are associated with a low risk of renal dysfunction. In a randomized comparison of 
monthly pamidronate (90 mg as a 2-hour infusion) versus zoledronic acid (4 mg as a 15-minute 
infusion), 6% to 8% of patients with breast cancer experienced deterioration of renal function 
during the first 12 months of bisphosphonate therapy.  (12)  Renal dysfunction was defined as a 
change in baseline serum creatinine ≥ 0.5 mg/dL or ≥ 2 times baseline value in patients with 
baseline normal creatinine (< 1.4 mg/dL), or a change from baseline serum creatinine ≥ 1.0 
mg/dL or ≥ 2 times baseline value in patients with abnormal baseline creatinine. Rare case 
reports of more serious renal toxicity have been reported with long-term and/or high-dose use of 
pamidronate.  (29-31)  
 
The American Society of Clinical Oncology 2003 update on the role of bisphosphonates in 
women with breast cancer recommends that serum creatinine be monitored prior to each dose of 
zoledronic acid, in accordance with FDA-approved labeling.  (32) In order to be able to compare 
renal toxicity between all three arms of the study, S0307 will require a monthly serum creatinine 
in all patients for the first 6 months, increasing the creatinine assessment interval to q3 monthly at 
6 months as the zoledronic acid arm moves to quarterly infusion intervals. Patients with baseline 
abnormal creatinine levels will be excluded from S0307.  Patients who develop renal dysfunction 
on S0307 will have their bisphosphonate held.  Reassessment of renal function will occur every 
3-4 weeks, and the bisphosphonate should be reinstituted cautiously when renal function returns 
to baseline. 


Revised 6/12/06 
S0307 
Amended 6/18/07 
Page 11 
 
 
 
 
 
The ASCO guidelines also recommend that serum calcium, electrolytes, phosphate, magnesium, 
and hematocrit/hemoglobin also be monitored regularly, although the time interval is not 
specified. In S0307, these laboratory values will be monitored on a q6 monthly basis. 
 
Osteonecrosis of the jaw 
 
Case reports of osteonecrosis of the jaw in cancer patients on high-dose bisphosphonates have 
been recently published.  (33,34)  In one series, 36 patients receiving pamidronate or zoledronate 
for bone metastases (evenly split between multiple myeloma and breast cancer) presented with 
painful bone exposure in the mandible, maxilla or both that was unresponsive to surgical or 
medical treatment.  (33)  Approximately two-thirds of these patients were also receiving steroids, 
and two-thirds were receiving chemotherapy. Seventy-eight percent of the patients in this series 
had a dental extraction preceding the diagnosis of osteonecrosis, while the remainder developed 
exposed bone spontaneously.  
 
Although a cause and effect relationship has yet been definitively established, subsequent to the 
publication of these two case report series Novartis Pharmaceuticals has received over 80 
adverse event reports of osteonecrosis of the jaw in cancer patients receiving pamidronate or 
zoledronate (personal communication, Novartis).  Additionally, two large oral surgery practices in 
Florida and New York have each collected series of approximately 75-80 cancer patients with 
osteonecrosis of the jaw while on high dose bisphosphonates (personal communication, R. Marx 
and S. Ruggiero).  Although the number of reported jaw osteonecrosis cases has steadily 
increased since this phenomenon was initially recognized and reported in 2003 and may at this 
point approach a few hundred patients, this is in the setting of over 2.5 million cancer patients 
worldwide having been treated with pamidronate or zoledronic acid in the past decade. 
Additionally, clinical trials of pamidronate and zoledronic acid in more than 3,000 cancer patients 
dating back to the early 1990s did not detect this complication. Osteonecrosis of the jaw appears 
to be a very rare complication of high-dose bisphosphonate use, and is not likely limited to 
intravenous bisphosphonate administration alone.  
 
Toxicity data for the AZURE study (an adjuvant trial of control versus zoledronic acid) was 
recently presented. (63)  In this study of 3,360 patients receiving standard adjuvant systemic 
therapy, patients were randomized to receive either no additional treatment or zoledronic acid 
monthly x 6, then every 3 months for 8 doses, followed by every 6 months for 5 doses to 
complete 5 years.  Patients were enrolled between September 2003 and January 2006.  There 
was no significant difference in SAEs or AEs reported.  There was a small numerical difference in 
vomiting (1.1% vs 2.5%) and pyrexia (1.1% vs 2.3%), higher in the zoledronic acid arm.  Seven 
cases of osteonecrosis of the jaw have been reported, all in the zoledronic acid arm, with a 
median of 8 doses received at the time of ONJ (range 1-12 doses).  This represents 0.4% of 
patients on the zoledronic acid arm.  Efficacy data for this trial are expected in 2008. 
 
S0307 will attempt to further define the magnitude of the problem of osteonecrosis of the jaw 
related to bisphosphonate use, and identify risk factors for the development of this complication.  
Therefore, all patients enrolling on S0307 will be asked to undergo a dental exam at baseline and 
completion of the study, to evaluate for periodontal disease and exposed bone.  Any patient who 
develops dental complications while on study will be evaluated for risk factors and clinical course. 
Since q 6-12 monthly dental exams and cleaning are considered to be part of good oral hygiene 
practice, these exams will not be considered to be study-specific with respect to reimbursement 
purposes.  A small pool of money will be available for financially-limited patients without dental 
insurance who would not have access to dental care by any other means.  
 
It is worth noting that there are no reports in the literature of osteonecrosis of bone in any other 
site (other than the jaw) related to bisphosphonate use.  This may be because the jaws are the 
only bones in the skeleton exposed to the external environment, via the teeth, which frequently 
have periodontal inflammation, dental abscesses, root canal treatments, and other pathologies 
that increase the demand for and rate of bone turnover.  
 


 
S0307 
 
Page 11a 
 
Amended 6/18/07 
 
 
 
 
Statins 
 
There is increasing evidence that statin drugs, through interactions that are indirect of lipid 
controlling activity, may mediate suppression of a number of molecular pathways that may confer 
benefit in cancer.  (35)  At pharmacologic doses, statins inhibit prenylation of several isoforms of 
the small GTPase protein family including Ras, Rac, Rho, and cdc42 in a number of cell types 
including endothelial and epithelial cells, resulting in an abrogation of angiogenic factors VEGF, 
FGF, and hyperglycemia-stimulated angiogenesis.  (36-46)  Statins have also been associated 
with a reduction in PAI-I activity and phosphorylation of AKT by IP-3 kinase; as well as down-
regulation of MMPs; key mediators of tumor invasion and spread.  (39,4245,46) 


 
S0307 
 
Page 12 
 
Revised 6/12/06 
 
 
 
 
In two large retrospective studies of over 60,000 patients, statin use was associated with a 
statistically significant decrease in newly diagnosed cancers.  Graaf and colleagues in the 
Netherlands reported a 20% decrease in relative risk for all cancers among statin users.  (47)  In 
another study that included over 68,000 women over the age of 35 enrolled in a Health Care Plan 
from Virginia, Mortimer et al demonstrated lower breast cancer risk in those women concurrently 
taking statins.  (48)  Statins, while designed to target liver cholesterol biosynthesis, can also have 
bone and brain effects.  Simvastatin (Zocor), in particular, has been demonstrated to accumulate 
in bone and has been associated with increased bone mineral density, positive changes in serum 
and urine bone formation and resorption factors and with a controversial decrease in risk of 
osteopenic fractures. In a randomized clinical trial comparing simvastatin 40 and 80 mg/day to 
atorvastatin (Lipitor) 20 and 40 mg/day, serum levels of bone specific alkaline phosphatase were 
significantly reduced by simvastatin in a dose-dependent fashion.  (49) 
 
Because of anti-tumor activity demonstrated in several preclinical models, statins are currently 
under investigation as anti-cancer agents in early phase clinical trials.  No studies to date have 
evaluated the efficacy of long-term statin use for preventing or diminishing liver, bone or other 
organ specific metastasis when administered in low, chronic, and safe doses in patients with 
curable or early stage disease.  (50) 
 
Overall the epidemiologic, cell culture and animal studies, and early human clinical trial data 
suggest that statin agents, particularly those that are more systemically bioavailable (i.e., 
atorvastatin, simvastatin), may demonstrate anti-tumor activity at the sites of highest accumulated 
doses (liver, bone, brain).  Therefore a strong rationale exists to collect data on statin use in the 
adjuvant Southwest Oncology Group trial S0307 to test our hypothesis that statin use may 
decrease the risk of recurrence to liver, bone and brain and may act synergistically with 
bisphosphonate therapy to decrease the risk of recurrence to the bone. 
 
Biologic Correlates 
 
Tumor PTHrP and Bone Recurrence 
 
Metastases involving the skeleton are the first site of recurrence in 25-40% of metastatic breast 
cancer patients.  It would be useful to determine which patients were at particular risk for 
developing osseous metastasis and who therefore might be expected to benefit most by receiving 
a bisphosphonate agent.  Although several classes of adhesion molecules and cell-cell 
interaction molecules have been suggested to play a role in determining sites of metastasis, the 
one factor for which there is the most practical (but still preliminary) evidence in breast cancer is 
parathyroid hormone related protein (PTHrP).  (51)  Work done by Powell et al. showed that 
PTHrP expression could be detected by immunohistochemistry (IHC) in 92% of breast cancer 
bone metastasis, but only 17% of metastasis at other sites.  (52)  Work using IHC by Rivkin et al, 
has shown that for patients whose tumors were low expressers of PTHrP, 33% of patients 
developed bone metastasis while for patients who were high expressers of PTHrP, 65% 
developed bone metastasis.  (53)  This study has been supported by nearly identical results 
obtained by IHC of PTHrP in study of breast cancer patients in Japan.  (54)  Taken together 
these studies suggest that PTHrP may help identify breast cancer patients at high and low risk for 
developing osseous metastasis.  
 
These observations are consistent with work on PTHrP measured by other methods. For 
example, Bundred et al, found that approximately 60% of breast cancers overexpressed PTHrP 
as measured in breast tumor cytosols, and preliminary results suggested that patients with 
tumors overexpressing PTHrP had twice the risk of developing bone marrow metastases.  (55)  
Expression of PTHrP in primary breast tumor has been reported to correlate with the subsequent 
incidence of bone metastases.  (56)  Overexpression of PTHrP mRNA detected by PCR also has 
been associated with an elevated risk of developing bone metastasis.  (56)  Measurement of 
PTHrP levels may also have other implications, as it has been suggested in model systems that 
PTHrP may serve as an autocrine growth factor.  (57, 58) 
 


 
S0307 
 
Page 13 
 
Revised 6/12/06 
 
Revised 7/13/09 
 
 
 
 
The above studies are preliminary, but suggest that expression of PTHrP in primary tumors 
correlate with subsequent incidence of bone metastases.  We propose to test the hypothesis that 
patients with PTHrP expressing tumors will have a higher rate of bone recurrence.  We will 
prospectively evaluate for presence of PTHrP in the tumor by IHC and correlate with the 
occurrence of bone relapse. 
 
Serum NTx and Bone Recurrence 
 
The development of bone metastases involves complex interactions between cancer cells and 
the bone microenvironment.  Circulating breast cancer cells 13have affinity for bone and exhibit 
chemotactic responses to areas of bone undergoing resorption.  (59)  The majority of 
disseminated tumor cells die, but a few are capable of proliferation or can remain dormant, with 
bone serving as a reservoir.  In the early establishment of metastases, bone is destroyed by the 
osteoclast, which is activated by a variety of cytokines produced directly or indirectly by the tumor 
cell.  (60)  As bone matrix is broken down, a rich supply of mitogenic factors is released, which 
can in turn lead to increased proliferation of the breast cancer cells.  (61)   
 
We propose to test the hypothesis that elevated levels of biochemical markers of bone 
remodeling, such as the bone collage breakdown product N-telopeptide (NTx), will predict for 
future development of bone metastases.  (62)  We will collect baseline serum on patients enrolled 
on S0307 for NTx evaluation and correlate with the occurrence of bone relapse. 
 
We realize that since all patients on this study will receive a bisphosphonate, this could influence 
the site of future metastases and impact our ability to study both tumor PTHrP expression and 
serum NTx levels as predictors of bone recurrence.  We hope that the large potency differences 
between the three bisphosphonates will allow us to still detect differences in the first site of 
recurrence between the most potent (zoledronic acid) and the least potent (clodronate), and to 
evaluate our proposed biologic correlates across treatment groups. 
 
Pharmacogenomic Studies 
 
Pharmacogenomics investigates the inherited variation in genes that dictate drug response and 
explores ways that these variations can be used to predict whether a patient will have a good 
response to a drug, a bad response to a drug, or perhaps, no response at all. In the practice of 
medical oncology, it is common to treat many patients, when only a few actually derive distinct 
benefit from a specific drug therapy. The admixing of pharmacology, genetics and oncology offers 
the opportunity to practice individualized medicine.  
 
The objectives of the pharmacogenomic studies include to investigate whether there is an 
association between single nucleotide polymorphisms (SNPs) and the adverse event of acute 
phase reactions in patients with early stage breast cancer who have been randomly assigned to 
one of three adjuvant bisphosphonates on clinical trial S0307. This study will investigate SNPs 
within FDPS, CYP2C8, and the VEGF pathway as they associate with the efficacy and toxicity of 
the 3 adjuvant bisphosphonate therapies administered in S0307. The resource developed here 
will provide materials for present and future research as related to bisphosphonate and breast 
cancer therapies, as well as serve as a DNA repository for future investigations 
 
It is strongly recommended that all S0307 participants, new and existing patients already 
registered to the protocol at the time of Revision #5, be given the opportunity to consent to 
submission of whole blood specimen prior to the their next blood draw for routine laboratory 
testing. The S0307 whole blood specimen may be drawn at any point of clinical care or planned 
study phlebotomy and at any time of study participation or follow up. Patients need not be in 
active therapy to donate the whole blood specimen for DNA.  
 
 


 
S0307 
 
Page 13a 
 
Revised 6/12/06 
 
Amended 6/18/07 
 
Revised 7/13/09 
 
 
 
 
Rationale for Banking of Tissue Specimens 
 
An analysis of tumor markers in stored paraffin blocks from this study has the potential to allow 
the testing of proposed prognostic and predictive factors for bone recurrence.  Additionally, 
evaluation of these markers may allow us to predict which patients are particularly likely to benefit 
from bisphosphonate therapy.   
 
Rationale for Banking of Serum/Whole Blood Samples 
 
Several studies have shown that a variety of circulating markers can provide insight into bone 
turnover.  We propose to collect samples from this clinical trial and store them in the  Southwest 
Oncology Group Solid Tumor Bank. We propose to test the hypothesis that elevated levels of 
markers of bone turnover (specifically serum NTx) at baseline will predict for future development 
of bone metastases.  These specimens will also serve as a valuable resource for future studies of 
tumor/bone interaction and pharmacogenomics. 
 
Inclusion of Women and Minorities: 
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
270 
0 
270 
Not Hispanic or Latino 
5,130 
0 
5,130 
Total Ethnic 
 
5,400 
0 
5,400 
Racial Category 
American Indian or Alaskan Native 
14 
0 
14 
Asian 
134 
0 
134 
Black or African American 
444 
0 
444 
Native Hawaiian or other Pacific Islander 
7 
0 
 
7 
White 
4,801 
0 
4,801 
Racial Category: Total of all  
Subjects* 
5,400 
0 
5,400 
 
Differences among treatment arms are not expected to be a function of race or ethnicity.  Thus 
the study is not designed to detect differences within race or ethnicity subsets.  This will be 
explored as part of the final analysis. 
 
 


 
S0307 
 
Page 14 
 
Revised 10/11/11 
 
 
 
 
3.0 
DRUG INFORMATION 
 
3.1 
Zoledronic Acid (Zometa®) (NSC-721517) 
 
a. 
Description 
 
1. 
Zoledronic acid is a third generation bisphosphonate which is a highly 
potent inhibitor of bone resorption and will decrease hypercalcemia of 
malignancy. 
 
2. 
Molecular Formula C5H10N2O7P2 · H2O 
 
3. 
Molecular Weight 290.1 g/Mol 
 
b. 
Pharmacology 
 
Zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. 
Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and 
cartilage through its binding to bone. Zoledronic acid inhibits the increased 
osteoclastic activity and skeletal calcium release induced by various stimulatory 
factor released by tumors.  
 
c. 
Pharmacokinetics 
 
1. 
Distribution: Decline of zoledronic acid concentrations in plasma is 
consistent with a triphasic process showing a rapid decrease from peak 
concentrations at end of infusion to less than 1% of Cmax 24 hours post 
infusion with population half-lives of t1/2α 0.24 hours and t1/2β 1.87 
hours for the early disposition phases of the drug. The terminal 
elimination phase of zoledronic acid was prolonged, with very low 
concentrations in plasma between Days 2 and 28 post infusion, and a 
terminal elimination half-life t 1/2γ of 146 hours. The area under the 
plasma concentration versus time curve (AUC0-24h) of zoledronic acid 
was dose proportional from 2-16 mg. The accumulation of zoledronic 
acid measured over three cycles was low, with mean AUC0-24h ratios 
for cycles 2 and 3 versus 1 of 1.13 ± 0.30 and 1.16 ± 0.36, respectively. 
In-vitro and ex-vivo studies showed low affinity of zoledronic acid for the 
cellular components of human blood. In vitro, mean zoledronic acid 
protein binding in human plasma ranged from 28% at 200 ng/mL to 53% 
at 50 ng/mL.  
 
2. 
Metabolism: Zoledronic acid does not inhibit human P450 enzymes in 
vitro. Zoledronic acid does not undergo biotransformation in vivo. In 
animal studies, less than 3% of the administered intravenous dose was 
found in the feces, with the balance either recovered in the urine or taken 
up by bone, indicating that the drug is eliminated intact via the kidney. In 
animal studies, less than 3% of the administered intravenous dose was 
found in the feces, with the balance either recovered in the urine or taken 
up by bone, indicating that the drug is eliminated intact via the kidney. 
 
3. 
Elimination: In 64 patients with cancer and bone metastases, on average 
(± s.d.) 39 ± 16% of the administered zoledronic acid dose was 
recovered in the urine within 24 hours, with only trace amounts of drug  
 


Amended 3/11/08 
S0307 
Revised 4/21/11 
Page 15 
 
Revised 10/11/11 
 
 
 
 
found in urine post-Day 2. The cumulative percent of drug excreted in 
the urine over 0-24 hours was independent of dose. The balance of drug 
not recovered in urine over 0-24 hours, representing drug presumably 
bound to bone, is slowly released back into the systemic circulation, 
giving rise to the observed prolonged low plasma concentrations. The 0-
24 hour renal clearance of zoledronic acid was 3.7 ± 2.0 L/h. 
 
d. 
Adverse Effects  
 
1. 
The most common adverse events (≥ 25%) are nausea, fatigue, anemia, 
bone pain, constipation, fever, vomiting, and dyspnea. In less than 10% 
of patients treated with zoledronic acid, the following adverse events 
were reported: asthenia, chest pain, leg edema, mucositis, dysphagia, 
granulocytopenia, 
thrombocytopenia, 
pancytopenia, 
nonspecific 
infection, 
dehydration, 
arthralgias, 
headache 
and 
somnolence. 
Electrolyte 
abnormalities, 
most 
commonly 
hypocalcemia, 
hypophosphatemia 
and 
hypomagnesemia, 
can 
occur 
with 
bisphosphonate use.  
 
Injection Site Reactions: Local reactions at the infusion site, such as 
redness or swelling, were observed infrequently. In most cases, no 
specific treatment is required and the symptoms subside after 24-48 
hours.  
 
Renal Toxicity: Administration of zoledronic acid 4 mg given as a 5-
minute intravenous infusion has been shown to result in an increased 
risk of renal toxicity, as measured by increases in serum creatinine, 
which can progress to renal failure. Preexisting renal insufficiency and 
multiple cycles of zoledronic acid and other bisphosphonates are risk 
factors for subsequent renal deterioration with zoledronic acid. Factors 
predisposing to renal deterioration, such as dehydration or the use of 
other nephrotoxic drugs, should be identified and managed, if possible.   
 
Musculoskeletal Pain: Severe an occasionally incapacitating bone, joint, 
and/or muscle pain has been reported. The time of onset of symptoms 
varied from one day to several months after starting the drug.  
 
Osteonecrosis of the Jaw: Cases of osteonecrosis (primarily involving 
the jaws) have been reported predominantly in cancer patients. The 
majority of the reported cases are following invasive dental procedures, 
such as tooth extraction.   
 
Ocular Adverse Events: Cases of uveitis, scleritis, epislceritis, 
conjunctivitis, iritis, and orbital inflammation including orbital edema have 
been reported during postmarketing use. In some cases, symptoms 
resolved with topical steroids.  
 
Hypersensitivity Reactions: There have been rare reports of allergic 
reaction with intravenous zoledronic acid including angioedema, and 
bronchoconstriction. Very rare cases of anaphylactic reaction/shock 
have also been reported.  
 
2. 
Pregnancy and Lactation: Pregnancy Category D. ZOLEDRONIC ACID 
SHOULD NOT BE USED IN PREGNANCY. If a patient becomes 
pregnant while taking this drug, the patient should be apprised of the 
potential harm to the fetus. Women of childbearing potential should be  
 
 


Revised 6/12/06 
Revised 1/21/10 
S0307 
Revised 9/25/06 
Revised 4/21/11 
Page 16 
Amended 6/18/07 
Revised 10/11/11 
 
 
 
 
advised to avoid becoming pregnant. It is not known whether zoledronic 
acid is excreted in human milk. Because many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions 
in nursing infants from zoledronic acid, a decision should be made to 
discontinue nursing or to discontinue the drug, taking in to account the 
importance of the drug to the mother. Zoledronic acid binds to bone long 
term and may be released over weeks.  
 
3. 
Drug interactions: In-vitro studies indicate that zoledronic acid is 
approximately 22% bound to plasma proteins. In-vitro studies also 
indicate that zoledronic acid does not inhibit microsomal CYP450 
enzymes. In-vivo studies showed that zoledronic acid is not metabolized, 
and is excreted into the urine as the intact drug. 
 
Aminoglycosides 
Caution is advised as these agents may have 
an additive effect to lower serum calcium levels 
for prolonged periods. This effect has not been 
reported in clinical trials.  
Loop diuretics 
Caution is advised due to an increased risk of 
hypocalcemia. 
Nephrotoxic drugs 
Caution is advised with other potentially 
nephrotoxic drugs.  
Thalidomide 
No dose adjustment of zoledronic acid is 
needed when co-administered with thalidomide. 
 
e. 
Administration & Dosing 
 
1. 
See Treatment Plan Section 7.0 
 
2. 
Vials of zoledronic acid concentrate for infusion contain overfill allowing 
for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic 
acid). This concentrate should immediately be diluted in 100 mL of sterile 
0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following 
proper aseptic technique, and administered to the patient by infusion. Do 
not store undiluted concentrate in a syringe, to avoid inadvertent 
injection.  
 
f. 
Storage/Stability 
 
1. 
Zoledronic acid must not be mixed with calcium or other divalent cation-
containing infusion solutions, such as Lactated Ringer’s solution, and 
should be administered as a single intravenous solution in a line 
separate from all other drugs.  
 
2. 
Cartons of zoledronic acid vials should be stored at 25°C (77°F); 
excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room 
Temperature]. If not used immediately after dilution with infusion media, 
for microbiological integrity, the solution should be refrigerated at 2-8°C 
(36-46°F). The refrigerated solution should then be equilibrated to room 
temperature prior to administration. The total time between dilution, 
storage in the refrigerator, and end of administration must not exceed 24 
hours.  
 
  


Revised 4/21/11 
 
S0307 
Revised 10/11/11 
Page 16a 
 
Revised 5/29/12 
 
 
 
 
g. 
How Supplied  
 
1. 
Zoledronic acid is available in a 4 mg / 5 mL single-use vial of concentrate. 
Each 5 mL vial contains 4.264 mg of zoledronic acid monohydrate, 
corresponding to 4 mg zoledronic acid on an anhydrous basis, 220 mg of 
mannitol, USP, water for injection, and 24 mg of sodium citrate, USP.  
 
2. 
Zoledronic acid is being supplied free-of-charge by Novartis. To obtain a 
supply of zoledronic acid, contact UVI, Inc at:  
 
UVI, Inc 
Phone: 800-370-2508 
Fax: 650-745-3877 
 
UVI, Inc. office hours are 8:00 a.m. to 1:00 p.m. PST; a phone message 
may be left at other times. Orders received by 12:00 p.m. PST Monday 
through Thursday will be shipped for next day delivery. Orders received by 
3:00 p.m. PST on Friday will be shipped the following Monday for receipt 
Tuesday, unless institutions specifically request Saturday delivery and can 
guarantee their institution will accept delivery. Patients must be registered 
to the study before study drug can be obtained. 
 
3. 
Drug handling and Accountability 
 
a. 
Drug Accountability: The principal investigator, or authorized 
designee, must maintain careful record of the receipt, disposition, 
and return of all zoledronic acid using the NCI Investigational Drug 
Accountability Record Form available on the CTEP forms page 
http://ctep.cancer.gov/forms/. Institution specific electronic logs 
allowable if approved by NCI. 
 
b. 
Drug Returns: All unused drug supplies should be returned to 
Novartis Pharmaceutical for destruction. Returned drug must be 
sent with the zoledronic acid return form, which can be requested 
by contacting Novartis Pharmaceuticals.  The Novartis contact 
information can be found on the S0307 abstract page of the 
SWOG website (www.swog.org).  
 
3.2 
Clodronate (Bonefos®) (NSC-713466) (IND-71,481) 
 
a. 
DESCRIPTION 
 
Clodronate (Bonefos®) is not FDA-approved for use in the U.S. 
 
Manufacturer:  Bayer Schering Pharma Oy, Pansiontie 47, FIN-20210 Turku, 
Finland. 
 
Active Ingredient:  One clodronate 800 mg tablet contains 800 mg disodium 
clodronate. 
 
Inactive Ingredients:  Clodronate 800 mg tablets:  Silicified microcrystalline 
cellulose (consisting of microcrystalline cellulose and colloidal anhydrous silica), 
croscarmellose sodium, stearic acid, magnesium stearate, hypromellose, 
polyethylene glycol 400, titanium dioxide (E171). 
 


 
 
S0307 
 
Page 16b 
 
Revised 10/11/11 
 
 
 
 
Clodronate is intended for the treatment of bone diseases and for reduction of 
occurrence of bone metastases in primary breast cancer.  Clodronate contains 
disodium clodronate as an active ingredient.  Clodronate is chemically defined as 
bisphosphonate and is an analogue of the natural pyrophosphate.  Clodronate 
has a strong affinity for mineralized tissues such as bone, where it inhibits bone 
resorption, which may be abnormally increased due to malignancy.  
Consequently, reduction in elevated serum calcium concentrations and a 
decrease in fracture risk have been observed in patients during clodronate 


 
S0307 
 
Page 17 
 
 
 
treatment.  In patients with primary breast cancer clodronate treatment has been 
shown to reduce occurrence of bone metastases, and to be associated with 
reduced mortality. 
 
Clodronate is indicated for the treatment of osteolysis and hypercalcemia due to 
malignancy and for reduction of occurrence of bone metastases in primary breast 
cancer. 
 
Clodronate shall not be used concomitantly with other bisphosphonates or for 
patients with known hypersensitivity to bisphosphonates. 
 
b. 
TOXICOLOGY 
 
Adequate fluid intake shall be maintained during clodronate treatment.  This is 
particularly important when clodronate is used in connection with hypercalcemia 
or renal failure.  
 
Clodronate is eliminated mainly via the kidneys.  Clodronate should therefore be 
used with caution in connection with renal failure; daily doses exceeding 1,600 
mg should not be used continuously. 
 
The following interactions with clodronate have been reported:  Clodronate forms 
poorly soluble complexes with divalent cations.  Therefore, if clodronate is taken 
simultaneously with food, liquids or drugs containing divalent cations, e.g. 
antacids or iron preparations, the bioavailability of clodronate is reduced 
significantly.  This may in turn reduce the efficacy of clodronate.  An interval of 
one hour is recommended after drug intake before eating or drinking other than 
plain water.  In some cases when clodronate has been used simultaneously with 
anti-inflammatory analgesics (NSAIDs) renal dysfunction has been reported. 
 
Due to increased risk of hypocalcemia, caution should be taken when using 
clodronate together with aminoglycoside antibiotics.  Concomitant use of 
estramustine phosphate with clodronate has been reported to increase the 
serum concentration of estramustine phosphate. 
 
The most frequently reported adverse reactions attributable to clodronate are 
gastrointestinal effects such as nausea, vomiting and diarrhea.  These may occur 
in up to 10% of patients.  However, such effects are usually mild and occur more 
commonly with high doses.  Occasionally, clodronate treatment may elevate 
serum concentrations of parathyroid hormone and aminotransferases.  These 
usually transient changes rarely exceed twice the laboratory reference range.  
Changes in serum concentrations of alkaline phosphatase have also been 
reported, as well as usually asymptomatic hypocalcemia.  In addition, individual 
cases of impairment of respiratory function resembling hypersensitivity reaction 
or in patients with aspirin-sensitive asthma, as well as skin reactions have been 
reported.  Reversible proteinuria, serum creatinine elevation, and renal 
dysfunction have been reported.  However, most patients have been terminally ill 
and the causal role of clodronate treatment in the renal dysfunction has not been 
confirmed. 
 
Pregnancy and lactation:  It is not known if clodronate can cause damage to the 
fetus, or affect reproduction, or if it is secreted in human milk.  Therefore, 
clodronate should not be used for pregnant or lactating women, unless the 
therapeutic advantages clearly outweigh any risks. 
 


 
S0307 
 
Page 18 
 
Revised 6/12/06 
 
Amended 6/18/07 
 
 
 
 
c. 
PHARMACOLOGY 
 
Formulation:  Clodronate 800 mg tablets:  White, oval, scored, film-coated 
tablets, marked L134 on one side.  Size of tablet 9 mm x 20 mm. 
 
Storage and Stability:  Clodronate 800 mg tablets shelf life:  Three years.  Do not 
store above 30°C (86°F).  Keep the medicine out of the reach of children. 
 
Expiration date:  Check the expiration date on the package.  Do not use the 
medicine after the expiration date or if there are any visible changes in the 
preparation. 
 
Administration:  Oral.  A clodronate 800 mg tablet may be divided into two to 
ease swallowing, but the halves have to be taken at the same time of 
administration.  Clodronate tablets should not be crushed or dissolved before 
intake. 
 
When clodronate is taken as a single daily dose, it should preferably be taken in 
the morning on an empty stomach together with a glass of water.  Thereafter, the 
patient should refrain from eating, drinking (other than plain water), and taking 
any other oral drugs for one hour. 
 
If the daily dose of clodronate is taken as divided doses, the first dose should be 
taken as recommended above.  The second dose should be taken between 
meals, more than two hours after and 30 minutes before eating, drinking (other 
than plain water), or taking any other oral drugs. 
 
Clodronate should in no case be taken with milk, food or drugs containing 
calcium or other divalent cations, because they impair the absorption of 
clodronate. 
 
Children:  Safety and efficacy in pediatric patients have not been established. 
 
Elderly:  There are no special dosage recommendations for the elderly. 
 
Adult patients with normal renal function:  The dose is individual and depends on 
the indication clodronate is used for.  The recommended starting dose is 1,600 
mg/day taken as a single dose.  If clinically necessary, the dose may be 
increased, but is not recommended to exceed 1,600 mg daily.  For reduction of 
occurrence of bone metastases in primary breast cancer, the recommended 
dose is 1,600 mg daily. 
 
Patients with renal failure:  Clodronate is eliminated mainly via the kidneys.  
Therefore clodronate should be used with caution for patients with renal failure; 
daily doses exceeding 1,600 mg should not be used continuously. 
 
Supplier:  Clodronate is investigational for this study.  This drug will not be 
supplied by the NCI.  However, for this study it is being supplied free-of-charge 
by Bayer Schering Pharma Oy.  To obtain a supply of clodronate (Bonefos®), 
contact UVI, Inc.: 
 
UVI, Inc. 
Phone:  800/370-2508 
FAX:  650/745-3877 
 
UVI, Inc. office hours are 8:00 a.m. to 1:00 p.m. PST; a phone message may be 
left at other times. 


Revised 9/25/06 
S0307 
Revised 1/25/07 
Page 19 
Revised 7/13/09 
Revised 4/21/11 
 
 
 
 
Orders received by 12:00 p.m. PST Monday through Thursday will be shipped for 
next day delivery.  Orders received by 3:00 p.m. PST on Friday will be shipped 
the following Monday for receipt Tuesday, unless institutions specifically request 
Saturday delivery and can guarantee their institution will accept delivery.  
Clodronate (Bonefos®) orders from USA sites only will be accepted.  Patients 
must be registered to the study before study drug can be obtained. 
 
Drug Returns:  Unused drug supplies should NOT be returned.  Unused drug 
should be disposed of per local institutional guidelines. 
 
Drug Accountability:  The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return 
or disposal of all drugs received from the supplier using the NCI Drug 
Accountability Record Form (DARF) available at http://ctep.cancer.gov. 
 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to UVI at 800/370/2508. 
 
3.3 
Ibandronate (Ibandronic acid, Bondronat®) (NSC-722623) (IND-71,481)  
 
a. 
DESCRIPTION 
 
Manufacturer:  Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland. 
 
Ibandronic acid, monosodium salt, monohydrate (Bondronat™) is a nitrogen-
containing bisphosphonate that inhibits osteoclast-mediated bone resorption.  
The 
chemical 
name 
for 
ibandronate 
is 
3-(N-methyl-N-pentyl)amino-1-
hydroxypropane-1,1-diphosphonic acid, monosodium salt, monohydrate with the 
molecular formula C9H22NO7P2Na·H2O and a molecular weight of 359.24. 
 
Active Ingredient:  Ibandronate is available as a white to off-white in colour, 
engraved L2/IT, 50 mg film-coated tablet for oral administration.  One tablet 
contains 50 mg of ibandronic acid (as ibandronic sodium monohydrate). 
 
Inactive Ingredients:  lactose monohydrate, povidone, microcrystalline cellulose, 
crospovidone, purified stearic acid, colloidal silicon dioxide, and purified water.  
The tablet film coating contains hypromellose, titanium dioxide, talc, polyethylene 
glycol 6000, and purified water.   
 
Metabolism:  There is no evidence that ibandronate is metabolized in animals or 
humans. 
 
Elimination:  The absorbed fraction of ibandronate is removed from the 
circulation via bone absorption (estimated to be 40-50%) and the remainder is 
eliminated unchanged by the kidney.  The unabsorbed fraction of ibandronate is 
eliminated unchanged in the faeces.  The range of observed apparent half-lives 
is broad and dependent on dose and assay sensitivity, but the apparent terminal 
half-life is generally in the range of 10-60 hours.  However, early plasma levels 
fall quickly, reaching 10% of peak values within 3 and 8 hours after intravenous 
or oral administration respectively.  Total clearance of ibandronate is low with 
average values in the range 84-160 ml/min. Renal clearance (about 60 ml/min in 
healthy postmenopausal females) accounts for 50-60% of total clearance and is 
related to creatinine clearance.  The difference between the apparent total and 
renal clearances is considered to reflect the uptake by bone. 
 


 
S0307 
 
Page 19a 
 
Revised 9/25/06 
 
 
 
 
b. 
TOXICOLOGY 
 
Oral ibandronate has been studied in over 3,900 patients in postmenopausal 
osteoporosis trials of up to 3 years duration.  The overall adverse event profile of 
ibandronic acid in these studies was similar to that of placebo.  Most adverse 
events were mild or moderate and did not lead to discontinuation.  The incidence 
of serious adverse events was 20% in the placebo group and 23% in the 
ibandronic acid group.  The percentage of patients who withdrew from treatment 
due to adverse events was approximately 17% in both the ibandronate group 
and the placebo group.  Overall, and according to body system, there was no 
difference between ibandronate and placebo, with adverse events of the 
digestive system being the most common reason for withdrawal.  Caution should 
be used when administering oral bisphosphonates in patients with a medical 
history of gastroesophageal reflux disease (GERD).  Patients should be 


 
S0307 
 
Page 20 
 
 
 
instructed to discontinue ibandronate therapy and seek medical attention if they 
develop symptoms of esophageal irritation such as worsening dysphagia, pain 
on swallowing, retrosternal pain, or heartburn.  Since NSAIDS and oral 
bisphosphanates are both associated with gastrointestinal irritation, caution 
should be taken during concomitant medication with ibandronate. 
 
c. 
PHARMACOLOGY 
 
Formulation:  Ibandronate is a white- to off-white powder.  It is freely soluble in 
water and practically insoluble in organic solvents.   
 
Mechanism of Action:  The action of ibandronate on bone tissue is based on its 
affinity for hydroxyapatite, which is part of the mineral matrix of bone.  
Ibandronate inhibits osteoclast activity and reduces bone resorption and 
turnover.  In post-menopausal women, it reduces the elevated rate of bone 
turnover, leading to, on average, a gain in bone mass. 
 
Drug Interactions:  When co-administered with melphalan/prednisolone in 
patients with multiple myeloma, no interaction was observed.  Other interaction 
studies in postmenopausal women have demonstrated the absence of any 
interaction potential with tamoxifen or hormone replacement therapy (oestrogen).  
In healthy male volunteers and postmenopausal women, IV ranitidine caused an 
increase in ibandronate bioavailability of about 20% (which is within the normal 
variability of the bioavailability of ibandronate), probably as a result of reduced 
gastric acidity.  However, no dosage adjustment is required when Bondronat is 
administered with H2-antagonists or other drugs that increase gastric pH.  In 
relation to disposition, no drug interactions of clinical significance are likely. 
Ibandronate is eliminated by renal secretion only and does not undergo any 
biotransformation. The secretory pathway does not appear to include known 
acidic or basic transport systems involved in the excretion of other active 
substances. In addition, ibandronate does not inhibit the major human hepatic 
P450 isoenzymes and does not induce the hepatic cytochrome P450 system in 
rats.  Plasma protein binding is low at therapeutic concentrations and 
ibandronate acid is therefore unlikely to displace other active substances.  
Caution 
is 
advised 
when 
bisphosphonates 
are 
administered 
with 
aminoglycosides, since both agents can lower serum calcium levels for 
prolonged periods. Attention should also be paid to the possible existence of 
simultaneous hypomagnesaemia.  In clinical studies, Bondronat has been 
administered concomitantly with commonly used anticancer agents, diuretics, 
antibiotics and analgesics without clinically apparent interactions occurring. 
 
Calcium Supplements/Antacids:  Products containing calcium and other 
multivalent cations (such as aluminum, magnesium, iron), including milk, food, 
and antacids are likely to interfere with absorption of ibandronate, which is 
consistent with findings in animal studies.  Ibandronate should be taken at least 1 
hour before any oral medications containing multivalent cations (including 
antacids, supplements, or vitamins).   
 
Hormone Replacement Therapy:  Oral bioavailability studies were used to 
demonstrate the lack of hormone replacement therapy (HRT) on ibandronate 
kinetics.  However, the identity and dose of the HRT could not be identified.  
Mean serum ibandronate concentrations and pharmacokinetic parameters after 
IV and oral administration were essentially the same in postmenopausal women 
taking HRT as in those not on HRT.  Hence, HRT did not alter the ibandronate 
pharmacokinetics after either IV or oral administration.  However, HRT and 
ibandronate might have synergistic effects on bone turnover suppression, which 
has been observed in studies involving alendronate when co-administered with 
estrogen ± progestin.   


 
S0307 
 
Page 21 
 
 
 
Aspirin/Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):  In the large, placebo-
controlled osteoporosis Treatment Study, aspirin and nonsteroidal anti-
inflammatory drugs were taken by 62% of the 2,946 patients.  Among aspirin or 
NSAID users, the incidence of upper gastrointestinal adverse events in patients 
treated with ibandronate daily was similar to that in placebo-treated patients.  
However, since aspirin, NSAIDs, and bisphosphonates are all associated with 
gastrointestinal irritation, caution should be exercised in the concomitant use of 
aspirin or NSAIDs with ibandronate.   
 
H2 Blockers and Proton Pump Inhibitors (PPIs):  Of over 3,500 patients enrolled 
in the ibandronate osteoporosis Treatment and Prevention Studies, 15% used 
anti-peptic agents (primarily H2 blockers and PPIs).  Among these patients, the 
incidence of upper gastrointestinal adverse experiences in the patients treated 
with ibandronate was similar to that in placebo-treated patients.   
 
Absorption:  The absorption of ibandronate in the upper gastrointestinal tract is 
rapid after oral administration.  Maximum observed plasma concentrations were 
reached within 0.5 to 2 hours (median 1 hour) in the fasted state and absolute 
bioavailability was about 0.6%.  The extent of absorption is impaired when taken 
together with food or beverages (other than plain water).  Bioavailability is 
reduced by about 90% when ibandronic acid is administered with a standard 
breakfast in comparison with bioavailability seen in fasted subjects.  When taken 
30 minutes before a meal, the reduction in bioavailability is approximately 30%.  
There is no meaningful reduction in bioavailability provided ibandronic acid is 
taken 60 minutes before a meal.  Bioavailability was reduced by approximately 
75% when Bondronat tablets were administered 2 hours after a standard meal.  
Therefore, it is recommended that the tablets should be taken after an overnight 
fast (minimum 6 hours) and fasting should continue for at least 30 minutes after 
the dose has been taken. 
 
Distribution:  After initial systemic exposure, ibandronate rapidly binds to bone or 
is excreted into urine.  In humans, the apparent terminal volume of distribution is 
at least 90 l and the amount of dose reaching the bone is estimated to be 40 - 
50% of the circulating dose.  Protein binding in human plasma is approximately 
87% at therapeutic concentrations, and thus drug-drug interaction due to 
displacement is unlikely. 
 
Animal Pharmacology and/or Toxicology:  Animal studies have shown that 
ibandronate is an inhibitor of osteoclast-mediated bone resorption.  In the 
Schenk assay in growing rats, ibandronate inhibited bone resorption and 
increased bone volume, based on histologic examination of the tibial 
metaphyses.  There was no evidence of impaired mineralization at the highest 
dose of 5 mg/kg/day (subcutaneously), which is 1,000 times the lowest 
antiresorptive dose of 0.005 mg/kg/day in this model, and 5,000 times the optimal 
antiresorptive dose of 0.001 mg/kg/day in the aged ovariectomized rat.  This 
indicates that ibandronate administered at the therapeutic doses is unlikely to 
induce osteomalacia.   
 
Administration:  Oral.  Ibandronate should be taken at least 30 minutes before 
the first food or drink (other than water) of the day or any oral medication or 
supplementation, including calcium, antacids, or vitamins.  To facilitate delivery to 
the stomach, ibandronic acid should be swallowed whole while the patient is in 
an upright position and with a full glass of plain water (6 to 8 oz).  Patients should 
not lie down for 30 minutes after taking the medication. 
 
Patients should receive supplemental calcium and vitamin D if dietary intake is 
inadequate.  Calcium supplements and calcium-, aluminum-, and magnesium- 
containing medications may interfere with the absorption of ibandronate and 
should be taken at a different time of the day.  Ibandronate is not recommended 


Revised 6/12/06 
S0307 
Revised 9/25/06 
Page 22 
Revised 7/13/09 
Revised 4/21/11 
 
 
 
 
for use in patients with severe renal impairment (creatinine clearance < 30 
mL/min).  No dosage adjustments are necessary in patients with a creatinine 
clearance ≥ 30 mL/min or in the elderly. 
 
Storage and Stability:  Store at controlled room temperature 20o-25o C (68o-77o 
F) 
 
Supplier:  Ibandronate is investigational for this study.  This drug will not be 
supplied by the NCI.  However, for this study it is being supplied free-of-charge 
by Roche.  To obtain a supply of ibandronate, contact UVI, Inc.: 
 
UVI, Inc. 
Phone:  800/370-2508 
FAX:  650/745-3877 
 
UVI, Inc. office hours are 8:00 a.m. to 1:00 p.m. PST; a phone message may be 
left at other times. 
 
Orders received by 12:00 p.m. PST Monday through Thursday will be shipped for 
next day delivery.  Orders received by 3:00 p.m. PST on Friday will be shipped 
the following Monday for receipt Tuesday, unless institutions specifically request 
Saturday delivery and can guarantee their institution will accept delivery.  
Ibandronate orders from USA sites only will be accepted.  Patients must be 
registered to the study before study drug can be obtained. 
 
Drug Returns:  Unused drug supplies should NOT be returned.  Unused drug 
should be disposed of per local institutional guidelines. 
 
Drug Accountability:  The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return 
or disposal of all drugs received from the supplier using the NCI Drug 
Accountability Record Form (DARF) available at http://ctep.cancer.gov. 
 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to UVI at 800/370/2508. 
 
 
4.0  
STAGING CRITERIA, AJCC 6th Edition, 2002 
 
DEFINITION OF TNM 
 
Primary Tumor (T) 
 
Definitions for classifying the primary tumor (T) are the same for clinical and for pathologic 
classification.  If the measurement is made by physical examination, the examiner will use the 
major headings (T1, T2 or T3).  If other measurements, such as mammographic or pathologic 
measurements are used, the subsets of T1 can be used.  Tumors should be measured to the 
nearest 0.1 cm increment. 
 


 
S0307 
 
Page 22a 
 
Revised 9/25/06 
 
Revised 4/21/11 
 
 
 
 
 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
Tis (DCIS) 
Ductal carcinoma in situ 
Tis (LCIS) 
Lobular carcinoma in situ 
Tis (Paget's) 
Paget's disease of the nipple with no tumor 
 
NOTE:  Paget's disease associated with a tumor is classified according to the size of the tumor. 
 
T1 
Tumor 2 cm or less in greatest dimension 
T1mic 
Microinvasion 0.1 cm or less in greatest dimension 
T1a 
Tumor more than 0.1 cm but no more than 0.5 cm in greatest dimension 
T1b 
Tumor more than 0.5 cm but not more than 1 cm in greatest dimension 
T1c 
Tumor more than 1 cm but not more than 2 cm in greatest dimension 
T2 
Tumor more than 2 cm but not more than 5 cm in greatest dimension 
T3 
Tumor more than 5 cm in greatest dimension 


 
S0307 
 
Page 23 
 
 
 
T4 
Tumor of any size with direct extension to (a) chest wall or (b) skin, only as 
described below: 
T4a 
Extension to chest wall, not including pectoralis muscle 
T4b 
Edema (including peau d'orange) or ulceration of the skin of the breast, or 
satellite skin nodules confined to the same breast 
T4c 
Both T4a and T4b 
T4d 
Inflammatory carcinoma  
 
Regional Lymph Nodes (N) 
 
Clinical  
 
N0 
No regional lymph node metastasis 
N1 
Metastasis to movable ipsilateral axillary lymph node(s) 
N2 
Metastasis in ipsilateral axillary lymph nodes fixed or matted, or in clinically 
apparent* ipsilateral internal mammary nodes in the absence of clinically evident 
axillary lymph node metastasis  
N2a 
Metastasis in ipsilateral axillary lymph nodes fixed to one another (matted) or to 
other structures 
N2b 
Metastasis only in clinically apparent* ipsilateral internal mammary nodes and in 
the absence of clinically evident axillary lymph node metastasis 
 
N3 
Metastasis in ipsilateral infraclavicular lymph node(s) with or without axillary 
lymph node involvement, or in clinically apparent* ipsilateral internal mammary 
lymph node(s) and in the presence of clinically evident axillary lymph node 
metastasis; or metastasis in ipsilateral supraclavicular lymph node(s) with or 
without axillary or internal mammary lymph node involvement 
N3a 
Metastasis in ipsilateral infraclavicular lymph node(s) 
N3b 
Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph 
node(s) 
N3c 
Metastasis in ipsilateral supraclavicular lymph node(s) 
 
*Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or 
by clinical examination or grossly visible pathologically. 
 
Pathologic (pN)a 
 
pN0 
No regional lymph node metastasis histologically, no additional examination for 
isolated tumor cells (ITC) 
 
NOTE:  Isolated tumor cells (ITC) are defined as single tumor cells or small cell clusters not 
greater than 0.2 mm, usually detected only by immunohistochemical (IHC) or molecular methods 
but which may be verified on H&E stains.  ITCs do not usually show evidence of malignant 
activity e.g., proliferation or stromal reaction. 
 
pN0 (i-) 
No regional lymph node metastasis histologically, negative IHC 
pN0 (i+) 
No regional lymph node metastasis histologically, positive IHC, no IHC cluster 
greater than 0.2 mm 
pN0(mol-) 
No regional lymph node metastasis histologically, negative molecular findings 
(RT-PCR)b 
pN0(mol+) 
No regional lymph node metastasis histologically, positive molecular findings 
(RT-PCR)b 


 
S0307 
 
Page 24 
 
 
 
aClassification is based on axillary lymph node dissection with or without sentinel lymph node 
dissection.  Classification based solely on sentinel lymph node dissection without subsequent 
axillary lymph node dissection is designated (sn) for "sentinel node," e.g., pN0 (i+) (sn). 
 
bRT-PCR:  reverse transcriptase/polymerase chain reaction. 
 
pN1 
Metastasis in 1 to 3 axillary lymph nodes, and/or in internal mammary nodes with 
microscopic disease detected by sentinel lymph node dissection but not clinically 
apparent** 
pN1mi 
Micrometastasis (greater than 0.2 mm, none greater than 2.0 mm) 
pN1a 
Metastasis in 1 to 3 axillary lymph nodes 
pN1b 
Metastasis in internal mammary nodes with microscopic disease detected by 
sentinel lymph node dissection but not clinically apparent.** 
pN1c 
Metastasis in 1 to 3 axillary lymph nodes and in internal mammary lymph nodes 
with microscopic disease detected by sentinel lymph node dissection but not 
clinically apparent.**  (If associated with greater than 3 positive axillary lymph 
nodes, the internal mammary nodes are classified as pN3b to reflect increased 
tumor burden) 
 
pN2 
Metastasis in 4 to 9 axillary lymph nodes or in clinically apparent* internal 
mammary lymph nodes in the absence of axillary lymph node metastasis 
pN2a 
Metastasis in 4 to 9 axillary lymph nodes (at least one tumor deposit greater than 
2.0 mm) 
pN2b 
Metastasis in clinically apparent* internal mammary lymph nodes in the absence 
of axillary lymph node metastasis 
 
pN3 
Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, 
or in clinically apparent* ipsilateral internal mammary lymph nodes in the 
presence of 1 or more positive axillary lymph nodes; or in more than 3 axillary 
lymph nodes with clinically negative microscopic metastasis in internal mammary 
lymph nodes; or in ipsilateral supraclavicular lymph nodes 
pN3a 
Metastasis in 10 or more axillary lymph nodes (at least one tumor deposit greater 
than 2.0 mm), or metastasis to the infraclavicular lymph nodes 
pN3b 
Metastasis in clinically apparent* ipsilateral internal mammary lymph nodes in the 
presence of 1 or more positive axillary lymph nodes; or in more than 3 axillary 
lymph nodes and in internal mammary lymph nodes with microscopic disease 
detected by sentinel lymph node dissection but not clinically apparent**  
pN3c 
Metastasis in ipsilateral supraclavicular lymph nodes 
 
*Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or 
by clinical examination. 
 
**Not clinically apparent is defined as not detected by imaging studies (excluding lympho-
seintiography) or by clinical examination. 
 
Distant Metastasis (M) 
 
M0 
No distant metastasis 
 


 
S0307 
 
Page 25 
 
 
 
STAGE GROUPING 
 
Stage I 
T1* 
N0 
M0 
 
Stage IIA 
T0 
N1 
M0 
 
T1* 
N1 
M0 
 
T2 
N0 
M0 
 
Stage IIB 
T2 
N1 
M0 
 
T3 
N0 
M0 
 
Stage IIIA 
T0 
N2 
M0 
 
T1* 
N2 
M0 
 
T2 
N2 
M0 
 
T3 
N1 
M0 
 
T3 
N2 
M0 
 
Stage IIIB 
T4 
N0 
M0 
 
T4 
N1 
M0 
 
T4 
N2 
M0 
 
Stage IIIC 
Any T 
N3 
M0 
 
*T1 includes T1mic 
 
NOTE:  Stage designation may be changed if post-surgical imaging studies reveal the presence 
of distant metastases, provided the studies are carried out within 4 months of diagnosis in the 
absence of disease progression and provided that the patient has not received neoadjuvant 
therapy. 


Revised 6/12/06 
S0307 
Amended 6/18/07 
Page 26 
Revised 7/25/08 
Revised 7/13/09 
 
 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  Use the spaces provided to confirm a patient's eligibility.  For each criterion requiring test 
results and dates, please complete the Prestudy Form and submit to the Data Operations Center in 
Seattle (see Section 14.0).  Any potential eligibility issues should be addressed to the Data Operations 
Center in Seattle at 206/652-2267 prior to registration. 
 
SWOG Patient No.   
 
 
 
 
Patient's Initials (L, F, M)   
 
 
5.1 
Patients must be women with histologically confirmed primary invasive adenocarcinoma 
of the breast (Stage I, II, III) with no evidence of metastatic disease.  Primary disease 
within the breast must be resected, either with mastectomy or breast sparing surgery.  An 
axillary node evaluation should be performed per the standard of care specified at each 
institution. 
 
5.2 
Patients must receive standard (systemic) adjuvant therapy for their breast cancer.  
Chemotherapy, hormone therapy, or combined chemo/hormone therapy is permitted.  
Additional therapies are allowed including radiation therapy and biologic agents (e.g. 
Herceptin®, Avastin®, hematopoietic growth factors).  Patients who receive biologic 
agents only or local radiation therapy only (without chemotherapy and/or hormone 
therapy) are not eligible.  Patients who are at such a low risk of recurrence that adjuvant 
therapy will not be prescribed are ineligible.  Neoadjuvant therapy is permitted, but 
enrollment must occur after completion of surgery. 
 
 
5.3 
Patients may be enrolled prior to, simultaneously with, or after beginning adjuvant 
systemic therapy.  Patients receiving hormonal therapy alone (no chemotherapy) or pre-
operative chemotherapy should be enrolled within 84 days (12 weeks) after the date of 
final surgical procedure for the cancer.  Patients receiving adjuvant post-operative 
chemotherapy may be enrolled up to 8 weeks after the last administration of 
chemotherapy.  Additional biological therapy or radiation therapy is allowed at any time 
before or after registration. 
 
5.4 
Institutions are encouraged to seek patient consent to submit tissue, whole blood and 
serum for banking.  Patients who wish to participate in the tissue, whole blood and serum 
submissions for banking as outlined in Section 15.3 and 15.4 must consent to the 
procedures.  Written informed consent must be obtained prior to submitting samples.   
 
 
5.5 
Patients must have a Zubrod performance status of 0 - 2 (see Section 10.5). 
 
5.6 
Patients must not be co-enrolled on protocols that have bone density as an endpoint.  
Patients may be registered to any other locoregional or systemic therapy breast cancer 
study, including cooperative group studies, as long as the protocol does not specifically 
exclude co-enrollment. 
 
5.7 
Patients must have a serum creatinine that is ≤ 2 times the institutional upper limit of 
normal and a calculated creatinine clearance of ≥ 30 ml/min within 7 days prior to 
enrollment.  Patients with renal failure are ineligible for this study. 
 
 
5.8 
Patients who have previously been or are currently being treated with a bisphosphonate 
for bone density are eligible, as long as the bisphosphonate is discontinued at 
registration.  No other forms of bisphosphonates, other than those prescribed in this 
study, may be used or planned during protocol treatment, either as an adjuvant or for the 
treatment of osteoporosis.    (Note:  This study has no placebo arm, so all patients will be 
receiving a bisphosphonate.)  
 


 
S0307 
 
Page 27 
 
Revised 6/12/06 
 
Amended 6/18/07 
 
Amended 3/11/08 
 
 
 
 
SWOG Patient No.   
 
 
 
 
Patient's Initials (L, F, M)   
 
 
5.9 
Patients must undergo a dental examination within 6 months prior to initiation of 
treatment per Section 7.4. 
 
5.10 
A patient with skeletal pain is eligible for inclusion in the study if bone scan and/or 
roentgenological examination fails to disclose metastatic disease.  Suspicious finding 
must be confirmed as benign by x-ray, MRI, or biopsy. 
 
5.11 
Patients must not have a medical history of esophageal stricture or motility disorders.  
Patients with a history of gastroesophageal reflux disorder (GERD) are eligible, but 
caution should be used when administering oral bisphosphonates. 
 
5.12 
Pregnant or nursing women may not participate due to the possibility of fetal harm or 
harm to nursing infants from this treatment regimen (see Section 3.0).  Women of 
reproductive potential may not participate unless they have agreed to use an effective 
contraceptive method while on this trial.  Women of child-bearing potential must have a 
pregnancy test performed within 72 hours prior to initiation of treatment (see Section 7.2). 
 
5.13 
No other prior malignancy is allowed except for the following:  adequately treated basal 
cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II 
cancer from which the patient is currently in complete remission, or any other cancer 
from which the patient has been disease-free for 5 years. 
 
5.14 
If Day 14, 28, or 84 falls on a weekend or holiday, the limit may be extended to the next 
working day. 
 
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0.  Therefore, if a test is done on a Monday, the Monday 
two weeks later would be considered Day 14.  This allows for efficient patient 
scheduling without exceeding the guidelines. 
 
5.15 
All patients must be informed of the investigational nature of this study and give written 
informed consent in accordance with institutional and federal guidelines.  At the time of 
registration, the date of informed consent must be provided. 
 
5.16 
At the time of patient registration, the treating institution's name and ID number must be 
provided to the Data Operations Center in Seattle in order to ensure that the current 
(within 365 days) date of institutional review board approval for this study has been 
entered into the data base.    


Revised 6/12/06 
Revised 1/25/07 
S0307 
Revised 9/25/06 
Amended 6/18/07 
Page 28 
 
 
Amended 3/11/08 
 
 
 
 
6.0 
STRATIFICATION FACTORS 
 
Balancing on patient characteristics will not be necessary due to the large sample size.  Thus, 
stratification factors are not applicable to this study.   
 
 
7.0 
TREATMENT PLAN   
 
For treatment or dose modification related questions, please contact Dr. Julie Gralow at 206/288-
7722 or Dr. Robert Livingston at 520/626-2816 or Kim Damman, BSN at 206/288-6900 (e-mail:  
ADJBISJG@u.washington.edu). 
 
7.1 
Good Medical Practice 
 
The following pre-study tests should be obtained within 28 days prior to registration in 
accordance with good medical practice.  Results of these tests do not determine eligibility 
and minor deviations would be acceptable if they do not impact on patient safety in the 
clinical judgment of the treating physician.  The Study Coordinator must be contacted if 
there are significant deviations in the values of these tests. 
 
a. 
Chest x-ray that is negative for metastatic disease.  If a chest x-ray was done as 
part of the original diagnostic and/or preoperative workup and was negative, it 
does not need to be repeated. 
 
b. 
CBC (WBC ≥ 3,000/µl, ANC ≥ 1,000/µl, platelets ≥ 100,000/µl). 
 
c. 
Total bilirubin that is ≤ 2 x the institutional upper limit of normal and SGOT or 
SGPT that is ≤ 3 x the institutional upper limit of normal. 
 
d. 
Calcium, albumin, magnesium and phosphate within institutional normal limits. 
 
e. 
Electrolytes (sodium, potassium, chloride, bicarbonate) 
 
f. 
Alkaline phosphatase within institutional normal limits. 
 
g. 
Ultrasound or CT scan of the abdomen if liver function tests (alkaline 
phosphatase, bilirubin, SGOT or SGPT) are elevated without a clear cause. 
 
h. 
CT scan of the chest and abdomen and a bone scan are recommended in 
patients at high risk for harboring metastatic disease, such as patients with Stage 
III disease or those with 10 or more lymph nodes involved by malignancy.  The 
combination of chest x-ray, liver ultrasound and bone scan (with CTs only for 
abnormal chest x-ray or ultrasound) will also be considered acceptable in these 
high risk patients. 
 
7.2 
Pre-Treatment Guidelines 
 
Patients will be randomized to zoledronic acid (Arm 1) or to clodronate (Arm 2) or to 
ibandronate (Arm 3).  The duration of bisphosphonate therapy is 3 years.  After three 
years, patients may receive non-protocol therapy at the physician's discretion. 
 
Investigators are encouraged to begin bisphosphonate therapy as soon as 
possible after surgery.  Patients may be registered and begin bisphosphonate 
therapy prior to, simultaneously, or after systemic therapy.  Patients receiving 
hormonal therapy alone (no chemotherapy) or pre-operative chemotherapy should 
be enrolled within 84 days (12 weeks) after the date of final surgical procedure.  
Patients receiving adjuvant post-operative chemotherapy may be enrolled up to 8 
weeks after completion of chemotherapy (see Section 5.3). 
 
Women of child-bearing potential must have a pregnancy test performed within 72 
hours prior to initiation of treatment. 
 


Revised 6/12/06 
Amended 3/11/08 
S0307 
Revised 1/25/07 
Revised 7/13/09 
Page 29 
Amended 6/18/07 
Revised 1/21/10 
Revised 4/21/11 
 
 
 
 
7.3 
Treatment Schedule 
 
For patients receiving zoledronic acid, peripheral or central intravenous access may be 
used.  During the first 6 months of dosing, zoledronic acid should be administered to 
patients in Arm 1 monthly (i.e. if treatment begins on the 1st of the month, then the 
subsequent doses are given on the 1st of each month thereafter), however minor 
deviances from this dosing interval are acceptable.  It is suggested that the infusions be 
given within ± 2 days (2 days earlier or later).  During the remaining period of dosing, 
zoledronic acid may be given within ± 1 week (7 days earlier or later).  The last dose of 
zoledronic acid in Arm 1 should be administered at Month 33.  Oral bisphosphonates 
given in Arms 2 and 3 are to continue daily until the first day of Month 36 and are then 
discontinued. 
 
NOTE:  For Arm 1, monthly dosing of zoledronic acid is given for 6 doses, q 3 monthly 
dosing is given for 9 doses. 
 
 
 
RX 
DRUG 
DOSE 
ROUTE 
DAY 
INTERVAL 
Arm 1 
Zoledronic acid 
*4 mg 
IV over 
1 
q monthly x 6 months then q  
 
 
15 minutes 
 
3 months for 2.5 years 
 
Arm 2 
Clodronate 
1,600 mg 
PO 
1 
q day x 35 months 
 
Arm 3 
Ibandronate 
50 mg    
PO 
1 
q day x 35 months 
* Upon treatment initiation, the recommended zoledronic acid doses for patients with 
reduced renal function (mild and moderate renal impairment) are listed below.  These 
doses are calculated to achieve the same AUC as that achieved in patients with 
creatinine clearance of 75 ml/min.  Creatinine clearance (CrCl) is calculated using the 
Cockcroft-Gault formula: 
 
 (140-age) x wt (kg x 0.85 (if female) 
 
72 x creatinine (mg/dL) 
 
Baseline Creatinine Clearance (ml/min) 
Zoledronic Acid recommended dose. 
 
(Calculated assuming AUC of 0.66 mg/hr/L) 
 
(CrCl = 75 ml/min) 
 
> 60 
4 mg 
 
50 - 60 
3.5 mg 
 
40 - 49 
3.3 mg 
 
30 - 39 
3 mg 
 
 
7.4 
Dental Examination 
 
Patients will undergo a dental exam within 6 months prior to initiation of treatment.  The 
Dental Examination Form (Form #30100) should be completed by a dental health 
professional (may be retrospectively completed if the exam was prior to initiation of 
treatment).  The exam should include visual inspection and periodontal probing.  
Specifically, evaluation of risk factors for osteonecrosis of the jaw should be evaluated.  
X-rays are not required, but should be performed, if indicated to assess degree of 
periodontal involvement and endodontic (root canal) problems.   
 
Patients on chemotherapy, who have the potential to develop neutropenia, should avoid 
undergoing teeth cleaning or elective restorative procedures due to possible increased 
risk of infection.  Patients are expected to undergo standard dental examinations and 
care while on study.  Financial assistance will be available for baseline dental exams for 
patients with severe financial need and without dental insurance who would not have 
access to dental care by any other means.  Contact the Southwest Oncology Group 
Operations Office at 210/614-8808 for further information.  X-rays are not required by this 
study and will not be covered unless significant baseline problems are identified.   


Revised 6/12/06 
Amended 3/11/08 
S0307 
Revised 1/25/07 
Revised 7/25/08 
Page 30 
Amended 6/18/07 
Revised 7/13/09 
Revised 1/21/10 
 
 
 
 
7.5 
Patients may receive radiation therapy to breast/chest wall/lymph node groups while on 
protocol treatment at the treating physician's discretion. 
 
7.6 
Patients should have supplemental administration of oral calcium and vitamin D.  
Recommended dose of calcium for premenopausal women is 1,000 mg PO daily, and 
range for postmenopausal women is 1,200-1,500 mg PO daily.  The recommended daily 
dose of vitamin D is 400-800 units/day.  These supplements should not be taken within 
30 minutes of oral bisphosphonates. 
 
7.7 
Oral bisphosphonates should be taken at least one hour before the first food or drink of 
the day other than water.  To facilitate delivery to the stomach, oral bisphosphonates 
should be swallowed while the patient is in an upright position and with a full glass of 
plain water (6 to 8 oz).  Patients should not lie down for 30 minutes after taking the 
medication. 
 
Calcium supplements and calcium-, aluminum-, and magnesium-containing medications 
may interfere with the absorption of oral bisphosphonates and should be taken at a 
different time of the day.   
 
7.8 
Pill Compliance:  Patients are encouraged to keep their own pill diary and should bring 
the diary with them to each follow-up visit.  Diaries will not be collected, but any missed 
pills during the last month of treatment should be reported on the S0307 Treatment 
Summary Form (Form #31453). 
 
7.9 
Treatment Evaluations 
 
Physical exams and labs (including CBC, electrolytes, calcium, phosphate, magnesium, 
albumin, and LFTs) should be performed prior to dosing (ideally Day 1) of Month 2, 4, 6, 
then q 3 months until Month 36. 
 
For Arm 1, serum creatinine testing must be performed within 7 days prior to 
administering subsequent zoledronic acid dosing q monthly for Months 2-6, then q 3 
months until Month 36. 
 
For Arms 2 & 3, serum creatinine testing should be performed ± 7 days (7 days earlier or 
later) q monthly for Months 2-6, then q 3 months until Month 36. 
 
7.10 
End of Treatment Evaluation 
 
An end of treatment physical examination and a bone scan will be obtained in all patients 
at the end of protocol treatment, on Day 1 of Month 36 or up to 14 days after Day 1 of 
Month 36.  Patients who have had a bone scan within 6 months prior to ending treatment 
will not be required to have the scan repeated.  Additionally, a dental examination will 
also be required at the end of protocol treatment (within 6 months after study completion 
or removal from protocol treatment, see Section 7.11). The end of treatment dental 
examination must be performed regardless of how long the patient was on treatment 
(including one month or less).  For patients without insurance to cover these 
examinations, financial assistance will be available.  Contact the Southwest Oncology 
Group Operations Office at 210/614-8808 for further information.   
 
7.11 
Evaluation at the time of recurrence 
 
a. 
Recurrence of disease must be adequately demonstrated.  Suspected 
recurrence should be biopsied or otherwise confirmed if at all possible.  Good 
medical practice requires biopsy proof of recurrent disease, as such 
documentation helps avoid the occasional mistake of misidentification of a 
benign lesion as recurrence or of second primary cancers as recurrence.  If 
biopsy proof of recurrence cannot be obtained, radiologic diagnosis will be 
allowed at the discretion of the treating physician. 
 


 
S0307 
 
Page 30a 
 
Amended 3/11/08 
 
 
 
 
b. 
Patients must be restaged at the time of recurrence.  All patients with recurrence 
must have the following studies within 30 days of diagnosis and/or biopsy 
documentation of recurrence. 
 
1. 
Nucleotide bone scan, CT of chest and abdomen (MRl, CAT or 
ultrasound of the liver may be substituted for abdomen CT if desired). 
 
2. 
For patients experiencing bone pain with other sites of recurrence, plain 
films will be obtained on the painful sites if the bone scan is negative. 
 
3. 
For patients with other possibly tumor related symptoms, appropriate 
radiologic or other studies should be obtained to document the sites of 
disease. 
 


Revised 6/12/06 
Revised 7/13/09 
S0307 
Revised 1/25/07 
Revised 8/30/10 
Page 31 
Amended 3/11/08 
Revised 4/21/11 
 
 
 
 
7.12 
Criteria for Removal from Protocol Treatment:   
 
a. 
Invasive recurrence of disease or diagnosis of new invasive breast primary.  A 
new diagnosis of ipsilateral or contralateral DCIS without an invasive component 
is not considered to be a recurrence or a second primary. 
 
b. 
Unacceptable toxicity (see Section 8.0). 
 
c. 
Greater than 3 months in delay of protocol treatment. 
 
d. 
Completion of three years of protocol treatment. 
 
e. 
The patient may withdraw from the study at any time for any reason. 
 
7.13 
All reasons for discontinuation of treatment must be documented on the Off-Treatment 
Notice. 
 
7.14 
All patients will be followed until death or for 10 years, whichever is first. 
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSAGE DELAY AND MODIFICATIONS 
 
8.1 
Two different versions of the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be used on this study. 
 
a. 
Serious Adverse Event (SAE) reporting 
 
The CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0 
will be utilized for SAE reporting only.  The CTCAE Version 4.0 is identified and 
located at the CTEP website at  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  All 
appropriate treatment areas should have access to a copy of the CTCAE Version 
4.0. 
 
b. 
Routine toxicity reporting 
 
This study will utilize the CTCAE Version 3.0 for routine toxicity reporting.  A copy 
of the CTCAE Version 3.0 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov).  All appropriate treatment areas should have access to a 
copy of the CTCAE Version 3.0. 
 
8.2 
Bisphosphonate therapy must be held for any Grade 3 or greater toxicity (that is 
attributed to the bisphosphonate by the treating physician).  If toxicity has not resolved 
within 3 months, then the patient must be removed from protocol treatment.  If toxicity 
resolves (Grade 0-1) within 3 months, the protocol treatment should be restarted.  If 
Grade 3 or greater toxicity reoccurs, then the patient must be removed from protocol 
treatment. 
 
8.3 
Renal Toxicity:  For any increase of 0.5 mg/dL from normal baseline creatinine that is > 
IULN, or any increase of ≥ 1 mg/dL from an abnormal baseline creatinine that is > IULN, 
bisphosphonate therapy should be held, and serum creatinine must be monitored until it 
returns to within 10% of baseline.  Once creatinine returns to within 10% of baseline, 
bisphosphonate therapy can be reinitiated at the same dose prior to treatment 
interruption. 
 
 


 
S0307 
 
Page 31a 
 
Revised 7/13/09 
 
Revised 8/30/10 
 
Revised 4/21/11 
 
Revised 3/28/14 
 
 
 
 
For patients in the zoledronic acid arm with an increased creatinine, consider increasing 
the infusion duration to 30 minutes in subsequent cycles. 
 
Grade 3 or higher creatinine elevations (> 3 x the institutional upper limit of normal) that 
is attributed to the bisphosphonate by the treating physician will require removal of the 
patient from protocol treatment. 
 
8.4 
Bisphosphonates from any of the 3 arms may be held or delayed for up to 3 months for 
any reason without requiring removal from protocol treatment. The total duration of 
treatment will be 35 months (through Day 1 of Month 36) for the clodronate and 
ibandronate arms regardless of how many doses may have been missed during this 
period.  The last dose on the zoledronic acid arm should be administered at Month 33, 
but no later than 36 months after registration due to treatment delays.  If treatment is 
delayed for more than one week during the first 6 months of treatment on zoledronic acid, 
the schedule should be adjusted so that there is at least 3 weeks between successive 
doses, until all 6 monthly doses have been given, after which every 3 months dosing can 
begin.  Otherwise, the original schedule on the zoledronic acid arm should be adhered to 
following treatment delays. 
 
8.5 
Osteonecrosis of the jaw:  Completion of the Osteonecrosis Jaw Lesion Form (Form 
#52641) will be required for any patient diagnosed with osteonecrosis of the jaw.  
Because of the long half-life of bisphosphonates in bone, it is not clear that stopping the 
bisphosphonate therapy will aid in healing.  Consultation with the S0307 Jaw/Dental 
Health Coordinator, Dr. Mark Schubert (206/288-1331), is recommended in this situation.   
 
8.6 
For treatment or dose modification related questions, please contact Dr. Julie Gralow at 
206/288-7722 or Dr. Robert Livingston at 520/626-2816 or Kim Dammann, BSN at 
206/288-6900 (e-mail:  ADJBISJG@u.washington.edu).  
 
8.7 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Coordinator and the NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
   
 


                                                                                                                                                                                                                                                          
9.0    STUDY CALENDAR
S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast Cancer"
€
End of
Treatment
ƒ
REQUIRED STUDIES
PRE
Month Month Month Month Month Month Month Month Month Month Month Month Month Month Month
Month
Follow
STUDY
1
2
3
4
5
6
9
12
15
18
21
24
27
30
33
36
Up
PHYSICAL
History and Physical Exam  @
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and Performance Status  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Disease Assessment  
X
X
X
X
X
X
X
X
Toxicity Notation   
X
X
X
X
X
X
X
X
X
X
X
X
X
Dental Exam λ
X
X
LABORATORY 
CBC/Differential/Platelets  §
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Calcium, phosphate, magnesium, albumin  § *
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrolytes (Na+, K+, Cl-, HCO3
-)  §
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver function tests  § π
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Creatinine   ◊
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine clearance (calculated)
X
Preganancy test Δ
X 
X-RAYS AND SCANS 
Chest X-ray  §
X
Bone Scan or roentgenological 
exam £
X†
Xδ
CT Scan Chest and Abdomen 
X†
SPECIMENS
Tumor block for PTHrP & banking
X
Serum for N-telopeptide & banking
X
Whole Blood for Pharmacogenomics 
and  Banking  β 
X
TREATMENT
Arm 1:  Zoledronic Acid Ω
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Arm 2:  Clodronate ψ
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Arm 3:  Ibandronate α
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NOTE:  Forms are found in Section 18.0.  Forms submission guidelines may be found in Section 14.0.
@ Patient height should also be assessed at prestudy.
§   Results of these tests do not determine eligibility but are suggested at prestudy for Good Medical Practice (see Section 7.1).  These tests are required during treatment as scheduled to assess toxicity.
*   Albumin is needed only if a serum calcium is drawn.  It is not needed for an ionized calcium.
π   Liver function tests:  SGOT or SGPT, Bilirubin, and Alkaline Phosphatase
Ω   Arm 1:  Zoledronic Acid will be administered by IV on Day 1 q monthly for the first 6 months, however minor deviations are acceptable.  It is suggested that the infusions be given within
      ±   2 days.  During the remaining period of dosing, zoledronic acid may be given within ±  1 week (7 days earlier or later).  NOTE:  Monthly dosing of zoledronic acid is given for 6 doses, q 3 
      monthly dosing is given for 9 doses (see Section 7.3 for definition of monthly).
ψ   Arm 2:  Clodronate will be given PO q day .  Discontinue on the first day of Month 36.
α   Arm 3:  Ibandronate will be given PO q day.  Discontinue on the first day of Month 36.
£   Bone scan should be done at baseline if the patient has bone pain (see Section 5.10), after 3 years of study drug treatment, or when the patient goes off study if it is prior to 3 years.  Patients who 
     have had a bone scan within six months of ending treatment will not be required to have the scan repeated.
β  It is strongly recommended that patients already registered to the protocol at the time of Amendment #3 be given the oppportunity to consent to submission of whole blood specimen prior to
      their next blood draw for routine laboratory testing.  The whole blood specimen may be drawn at any time during the patient's clinical care or planned phlebotomy and at any time during study
      particpation or follow-up.  Patients need not be on protocol treatment at the time of this draw.
†   CT scan of the chest and abdomen and bone scan are recommended for some patients at prestudy according to Good Medical Practice as outlined in Section 7.1f,g.
ƒ  All patients including patients off protocol treatment prior to recurrence should return for disease assessments at least every 6 months for 5 years and then annually for 5 years or until death (whichever  
    occurs first).  See Section 7.11 for restaging at recurrence. 
λ  Dental exam should be performed at the beginning and end of the treatment (regardless of how long the patient was on protocol treatment, see Section 7.10).  Complete the Dental Examination Form 
    (Form# 30100).  To keep in line with patient's normal dental exam schedule, exams 6 months pre-enrollment and 6 months post-completion of study (or removal from protocol treatment, see
     Section 7.12) are required.
◊  Arm 1:  To be performed within 7 days prior to registration, and within 7 days prior to administering all subsequent doses.
    Arm 2/Arm 3:  To be performed within 7 days prior to registration and within ± 7 days (7 days earlier or later) of q monthly for Months 2-6 and q 3 month patient visits.
Δ  To be performed within 72 hours prior to initiation of treatment.
€   All end of treatment-evaluations occur on Day 1 of Month 36, or up to 14 days after Day 1 of Month 36.
δ  Only a bone scan is acceptable at End of Treatment (see Section 7.10)  
S0307
Page 32
Revised 6/12/06
Revised 9/25/06
Revised 1/25/07
Amended 6/18/07
Amended 3/11/08
Revised 7/25/08
Revised 7/13/09
Revised 1/21/10
Revised 4/21/11
Revised 10/11/11


Amended 6/18/07 
S0307 
Revised 7/13/09 
Page 33 
 
Revised 1/21/10 
 
 
 
 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
10.1 
Invasive Recurrence:  Appearance of any new invasive lesions during or after protocol 
treatment.  Whenever possible recurrences should be documented histologically.  A new 
diagnosis of ipsilateral or contralateral DCIS without an invasive component is not 
considered to be a recurrence. 
 
10.2 
Sites of first invasive recurrence:  All sites of invasive disease documented within 30 
days of first documentation of invasive recurrence. 
 
10.3 
Disease-Free Survival:  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.   
 
10.4 
Overall Survival:  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. 
 
10.5 
Performance Status:  Patients will be graded according to the Zubrod performance 
status scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, office 
work.   
 
2 
Ambulatory and capable of self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours.   
 
3 
Capable of limited self-care, confined to bed or chair more than 50% of 
waking hours.   
 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1  
At registration, patients will be randomized to receive zoledronic acid (Z), clodronate (C) 
or ibandronate (I) for three years.  Simple randomization will be used with equal 
allocation to the treatment groups due to the large sample size planned.   
 
11.2  
The final target accrual is 5,400 patients distributed as follows: 2,000 zoledronic acid, 
2000 clodronate, and 1,400 ibandronate. After the trial began, plans to market 
ibandronate in North America were abandoned so we have concentrated remaining 
accrual in the other two arms. Nonetheless, ibandronate remains of interest since it is a 
highly active oral agent and may provide an effective treatment where IV administration 
would be difficult. The expected accrual rate currently is 286 per month.  The former 
accrual target was 4,500 patients equally allocated to the three groups with an assumed 
accrual rate of 63 per month. That accrual goal was established in 2007 under CTEP 
guidelines for reassessing accrual at one year.  Accrual increased dramatically after that 
reassessment which then shortened the trial duration and lowered power.  Consequently, 
the accrual was increased to 5,400 to restore power to desired levels. The original 
sample size goal was 6,000 patients over a four year accrual period or 125 per month.  
The final sample size is 5,400 accrued over an approximate four year period.  At the end 
of the accrual period, there will be an additional 5 years of follow-up before the scheduled 
final analysis.  However, all patients will be followed for 10 years from randomization to 
assess long-term outcomes. 
 


Revised 6/12/06 
S0307 
Amended 6/18/07 
Page 34 
Revised 7/13/09 
Revised 1/21/10 
 
 
 
 
 
11.3 
The primary outcome is disease-free survival (see Section 10.3).  The complete 
Statistical Analysis Plan may be found in Appendix 19.4 as a separate document.  Only a 
summary is provided here.  The primary analysis is a log-rank survival comparison of the 
three groups followed by three pairwise comparisons if the overall omnibus test is 
statistically significant at the designated level.  The analysis will be stratified by time 
period of randomization (3 Arms versus 2 Arms) as described in the S0307 Statistical 
Analysis Plan (see Appendix 19.4).  Each pairwise comparison is performed at the same 
α level as the overall comparison.  Given that the overall comparison is significant, this 
preserves the experiment-wise error rate at the designated level. (64)  Since three active 
treatments are being compared, we assume that clodronate is the "standard" treatment 
that the newer agents are being compared against.  Clodronate and placebo are being 
directly compared in NSABP trial B-34.  A secondary analysis of overall survival (see 
Section 10.4) will also be performed.  Stratified Cox regression will be used to estimate 
the hazard ratios and confidence intervals for the treatment comparisons, both 
unadjusted and adjusted for tumor and patient characteristics related to prognosis. 
 
11.4 
The sample size targets assumes a cumulative α=0.05 for the omnibus comparison of 
the three groups. The least effective treatment is assumed to have disease-free survival 
of 80% at 5 years. The least effective treatment compared to the most effective treatment 
is assumed to have a hazard ratio of 1.25. The third treatment is varied from 1.00 to 1.25. 
Power is computed by simulation assuming exponential distributions, 4.17 years of 
accrual, and an additional 5 years of follow-up. Power of the omnibus test depends on 
the distribution of the three hazard ratios with power lowest if the middle group is midway 
between the high and low groups (i.e. HR=1.125). Given a significant omnibus test, 
pairwise comparisons will be performed.. 
 
HR = 1.0, 1.25, 1.25 (zoledronic acid (Z) = ibandronate (I) > clodronate (C)) 
 
Power 
Power 
Power 
Power 
 
Omnibus 
Z vs C 
I vs C 
Z vs I 
Equal allocation (n=1500, 1500, 
1500) 
86% 
78% 
78% 
NA 
Equal allocation (n=1800, 1800, 
1800)  
91% 
86% 
86% 
NA 
Unequal allocation (n=2000, 
1400, 2000) 
93% 
89% 
84% 
NA 
 
HR = 1.0, 1.0, 1.25 (zoledronic acid > ibandronate = clodronate) 
 
Power 
Power 
Power 
Power 
 
Omnibus 
Z vs C 
I vs C 
Z vs I 
Equal allocation (n=1500, 1500, 
1500) 
85% 
78% 
NA 
78% 
Equal allocation (n=1800, 1800, 
1800)  
91% 
86% 
NA 
86% 
Unequal allocation (n=2000, 
1400, 2000) 
92% 
89% 
NA 
84% 
 
HR = 1.0, 1.125, 1.25 (zoledronic acid > ibandronate > clodronate) 
 
Power 
Power 
Power 
Power 
 
Omnibus 
Z vs C 
I vs C 
Z vs I 
Equal allocation (n=1500, 1500, 
1500) 
73% 
72% 
32% 
27% 
Equal allocation (n=1800, 1800, 
1800)  
81% 
80% 
39% 
29% 
Unequal allocation (n=2000, 
1400, 2000) 
86% 
85% 
36% 
28% 


Amended 6/18/07 
S0307 
 
Page 34a 
 
Revised 7/13/09 
 
 
 
 
 
HR = 1.0, 1.25, 1.125 (ibandronate > zoledronic acid > clodronate) 
 
Power 
Power 
Power 
Power 
 
Omnibus 
Z vs C 
I vs C 
Z vs I 
Equal allocation (n=1500, 1500, 
1500) 
74% 
33% 
72% 
25% 
Equal allocation (n=1800, 1800, 
1800)  
81% 
39% 
80% 
30% 
Unequal allocation (n=2000, 
1400, 2000) 
78% 
42% 
77% 
27% 
 
These examples show that omnibus power under unequal allocation ranges from 78% to 
93%, but that a comparison of zoledronic acid to clodronate would be enhanced in the 
unequal allocation scheme. It further demonstrates that restoration to an increased 
sample size is necessary due to faster than expected accrual than at the time of the 
previous sample size amendment. 
 
11.5  
Under the null hypothesis, a total of 1,314 events would be expected by the end of the 
trial.  We propose to have annual interim analyses beginning when about 31% of the 
failures have been observed which should occur shortly after the close of accrual.  P-
values for each analysis are determined using the Lan-DeMets spending function with 
bounds such that the minimal p-value is 0.001. (65)  The table below shows the expected 
percentage of events and the p-value at each analysis. 
 
If the omnibus analysis is statistically significant at an interim analysis, then pairwise 
comparisons will be performed using the same alpha level.  If one treatment group is 
clearly superior to the other two, consideration will be given to stopping the trial.  If one 
treatment group is clearly inferior to the other two, consideration will be given to stopping 
accrual to that arm (if accrual is incomplete) or having patients change to other 
treatments (if treatment is ongoing).  The exact decision will depend on the full 
information available including adverse events and efficacy.  It is also possible that the 
interim analysis will show that it is unlikely the trial will find a statistically significant 
difference among the three groups.  Conditional power will be conducted at each interim 
analysis to determine the probability of finding a significant difference at the end of the 
trial.  Additionally, the hazard ratio of the worst treatment versus the best treatment will 
be computed with a 99% confidence interval.  If the upper limit of the confidence interval 
is lower than the alternative hypothesis of HR=1.25, consideration will be given to 
stopping the trial due to futility.  If it is determined that there are justifiable reasons for 
early termination, a recommendation will be made to the Data and Safety Monitoring 
Committee. 
 
 
 
 
 
 
 
 
 
 
Year 
Analysis 
Percent of Events 
(n=1,314) 
Alpha Level for Test 
Cumulative 
probability 
4 
Interim 1 
31% 
0.0010 
0.0010 
5 
Interim 2 
46% 
0.0012 
0.0022 
6 
Interim 3 
60% 
0.0068 
0.0077 
7 
Interim 4 
74% 
.0158 
0.0158 
8 
Interim 5 
87% 
.0265 
0.0265 
9 
Final 
100% 
.0391 
0.0500 


 
S0307 
 
Page 34b 
 
Revised 7/13/09 
 
 
 
 
 
11.6 
A sample of 2,000 patients on an arm is sufficient to estimate the probability of specific 
toxicities to within at least ± 0.022.  A difference in toxicities of 0.05 between two arms 
can be detected with 90% power (2-sided α=0.05) if the mean prevalence of the adverse 
event is 20%. 
 
11.7 
Percent of patients with bone as a site of first recurrence will be compared.  
Approximately 4% of all randomized patients are expected to have bone as the site of 
first recurrence.  Bone is the site of first metastases in 40% of the patients who become 
metastatic.  If two-thirds of the patients have measured markers (e.g. PTHrP, serum N-
teleopeptide levels) and the markers are dichotomized at the median, then a difference of 
0.024 (0.052 vs. 0.028) in bone recurrence rates in all patients could be detected with 
90% power (2-sided α=0.05). 
 
11.8 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of the Southwest Oncology Group, 
three Southwest Oncology Group members, three non-voting representatives from the 
National Cancer Institute (NCI), and the Group Statistician (non-voting).  The members of 
this Committee will receive confidential reports every six months from the Southwest 
Oncology Group Statistical Center, and will meet at the Group's bi-annual meetings as 
necessary.  The Committee will be responsible for decisions regarding possible 
termination and/or early reporting of the study 
  
12.0 
DISCIPLINE REVIEW 
 
There will be no discipline review for this study. 
  
13.0 
REGISTRATION GUIDELINES 
 
13.1  
Patients must be registered prior to initiation of treatment (no more than five working 
days prior to planned start of treatment). 
 
13.2  
For either phone or web registration, the individual registering the patient must have 
completed the appropriate Southwest Oncology Group Registration Form. The completed 
form must be referred to during the registration but should not be submitted as part of the 
patient data. 
 
The individual registering the patient must also be prepared to provide the treating 
institution's name and ID number in order to ensure that the current (within 365 days) 
date of institutional review board approval for this study has been entered into the data 
base.  Patients will not be registered if the IRB approval date has not been provided or is 
> 365 days prior to the date of registration. 
 


 
S0307 
 
Page 35 
 
Revised 9/25/06 
 
Revised 1/21/10 
 
 
 
 
13.3  
Registration procedures 
 
a. 
You may register patients from Member, CCOP and approved Affiliate institutions 
to a therapeutics study using the SWOG Registration program. To access the 
Registration program go to the SWOG Web site (http://swog.org) and click on the 
Logon 
link 
to 
go 
to 
the 
SWOG 
Members 
Area 
logon 
page 
(https://swog.org/visitors/logon.asp).  This Web program is available at any time 
except for periods listed under Down Times.  Log on as an Individual User 
using your SWOG Roster ID Number and individual web user password.  Help 
for the logon process may be found at https://swog.org/visitors/logonhelp.asp. 
After you have logged on, click on the Clinical Trials link and then the Patient 
Reg link to go to the Entry Page for the Patient Registration program. If you are a 
Registrar at an institution with Internet access you are encouraged to register this 
way.  For new users, the link to a "Starter Kit" of help files may be found by 
clicking on Starter Kit link at the logon page. 
 
To register a patient the following must be done (in order): 
 
1. 
You are entered into the Southwest Oncology Group Roster and issued a 
SWOG Roster ID Number,  
 
2. 
You are associated as an investigator or CRA/RN to the institution where 
a registration is occurring, and  
 
3. 
You are granted permission to use the Patient Registration program at 
that institution.  
 
For assistance with points 1 and 2 call the SWOG Operations Office at 210/614-
8808. For point 3 you must contact your Web User Administrator.  Each SWOG 
institution has one or more Web User Administrators who may set up Web Users 
at their institution and assign permissions and passwords to these users. For 
other password problems or problems with the Patient Registration program, 
please e-mail webreghelp@crab.org. Include your name, Roster ID Number, and 
telephone number, when the problem occurred, and exactly what you were 
doing. 
 
b.   
If the Web Reg program is not used, the registration must be done by phone. 
  
Member, Affiliate and CCOP Institutions 
 
Registration by phone of patients from member, affiliate and CCOP institutions 
must be done through the Southwest Oncology Group Data Operations Center in 
Seattle by telephoning 206/652-2267, 6:30 a.m. to 4:00 p.m. Pacific Time, 
Monday through Friday, excluding holidays. 
  
13.4  
For either method of registration, exceptions to Southwest Oncology Group registration 
policies will not be permitted. 
  
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
  
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 


Revised 9/25/06 
S0307 
Revised 7/25/08 
Page 36 
 
Revised 1/21/10 
 
 
 
13.5 
Institutions participating through the Cancer Trials Support Unit (CTSU), please refer to 
Appendix 19.1. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1  
Data must be submitted according to the protocol requirements for ALL patients 
registered, whether or not assigned treatment is administered, including patients deemed 
to be ineligible.  Patients for whom documentation is inadequate to determine eligibility 
will generally be deemed ineligible. 
 
14.2 
Master forms are included in Section 18.0 and (with the exception of the sample consent 
form and the Registration Form) must be submitted to the Data Operations Center in 
Seattle.  Data from approved SWOG institutions must be submitted on-line via the Web; 
see Section 14.3a for details.  Exceptions to online data submission are patient-
completed 
(e.g. 
Quality 
of 
Life) 
forms 
and 
source 
documents 
(e.g. 
pathology/operative/lab reports). 
 
14.3 
Data Submission Procedures.   
 
a. 
Southwest Oncology Group institutions must submit data electronically via the 
Web by using the SWOG CRA Workbench.  To access the CRA Workbench, go 
to the SWOG Web site (http://swog.org) and logon to the Members Area.  After 
you have logged on, click on the CRA Workbench link to access the home page 
for CRA Workbench website.  Next, click on the Data Submission link and follow 
the instructions.  For new users, the link to a "Starter Kit" of help files may be 
found by clicking on the Starter Kit link at the Members’ logon page. 
 
To submit data via the web the following must be done (in order): 
 
1.  
You are entered into the Southwest Oncology Group Roster and issued 
a SWOG Roster ID Number, 
2.  
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, and 
3.  
Your Web User Administrator has added you as a web user and has 
given you the appropriate system permissions to submit data for that 
institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  
For point 3, contact your local Web User Administrator (refer to the "Who is my 
Web User Administrator?" function on the swog.org Members logon page).  For 
other 
difficulties 
with 
the 
CRA 
Workbench, 
please 
email 
technicalquestion@crab.org.   
 
b. 
If you need to submit data that are not available for online data submission, the 
only alternative is via facsimile.  Should the need for this occur, institutions may 
submit data via facsimile to 800/892-4007 or 206/342-1680 locally.  Please do 
not use cover sheet for faxed data.  Please make sure that each page of all faxed 
data includes the SWOG patient number, study ID, and patient initials. 
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU), please 
refer to Appendix 19.1. 
 
 


Revised 6/12/06 
Revised 7/25/08 
S0307 
Revised 9/25/06 
Revised 7/13/09 
Page 37 
Amended 3/11/08 
Revised 1/21/10 
 
 
 
 
 
14.4 
WITHIN 14 DAYS OF REGISTRATION:   
 
Submit copies of the following: 
 
a. 
S0307 Prestudy Form (Form #20161) 
 
b. 
All pre-registration breast cancer pathology reports. 
 
c. 
Dental Examination Form (Form #30100) 
 
14.5 
DURING TREATMENT AT 6 MONTHS, 1 YEAR, 2 YEARS, AND 3 YEARS: 
 
Submit copies of the following: 
 
a. 
S0307 Treatment Summary Form (Form #31453) 
 
b. 
S0307 Adverse Event Summary Form (Form #22831) 
 
c. 
S0307 Serum Creatinine Reporting Form (Form #60188) 
 
14.6 
WITHIN 6 MONTHS OF DISCONTINUATION OF PROTOCOL TREATMENT:   
 
Submit the Dental Examination Form (Form #30100). 
 
14.7 
WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT: 
 
Submit copies of the following: 
 
a. 
Off Treatment Notice (Form #8756)  
 
b. 
S0307 Supplementary Off Treatment Form (Form #24801)  
 
c. 
Final S0307 Treatment Form (Form #31453) for current reporting period  
 
d. 
Final S0307 Adverse Event Summary Form (Form #22831)  
 
e. 
S0307 Serum Creatinine Reporting Form (Form #60188) 
 
14.8 
AFTER OFF TREATMENT- EVERY 6 MONTHS UNTIL YEAR 5, AND THEN 
ANNUALLY UNTIL YEAR 10 OR UNTIL DEATH, WHICHEVER COMES FIRST: 
 
Submit the Follow-Up Form (Form #64587) and S0307 Supplementary Follow-Up Form 
(Form #36846). 
 
14.9 
WITHIN 14 DAYS OF PROGRESSION/RELAPSE: 
 
Submit the following: 
 
a. 
Follow-up Form (Form #64587) documenting date, site and method for 
determining malignancy  
 
b. 
S0307 Supplementary Follow-Up Form (Form #36846)  
 
c. 
If patient was still on treatment, final S0307 Treatment Form (Form #31453) for 
current reporting period  
 
d. 
If patient was still on treatment, final S0307 Adverse Event Summary Form (Form 
#22831)  
 


 
S0307 
 
Page 37a 
 
Amended 3/11/08 
 
 
 
 
 
14.10 
WITHIN 4 WEEKS OF KNOWLEDGE OF SECOND MALIGNANCY: 
 
Submit the Follow-Up Form (Form #64587) documenting date, site and method of 
determining malignancy. 
 
14.11 
WITHIN 4 WEEKS OF KNOWLEDGE OF OSTEONECROSIS OF THE JAW: 
 
Submit the Osteonecrotic Jaw Lesion Form (Form #52641) (see Section 8.4). 
 
14.12 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death (Form #49467) documenting death information. 
 


Revised 6/12/06 
S0307 
Revised 9/25/06 
Page 38 
Amended 3/11/08 
Revised 7/13/09 
 
 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Institutions are encouraged to seek patient consent to submit tissue, whole blood and 
serum for banking (see Sections 15.3 and 15.4). 
 
15.2 
General specimen submission instructions 
 
a. 
All submitted specimens must be labeled with the protocol number (S0307), 
SWOG patient number, patient’s initials, and date of specimen collection. 
 
b. 
The federal guidelines for shipment are as follows: 
 
1. 
The specimen must be wrapped in an absorbable material. 
 
2. 
The specimen must be placed in an AIRTIGHT container (like a 
resealable bag.) 
 
3. 
Pack the resealable bag and specimen in a Styrofoam shipping 
container. 
 
4. 
Pack the Styrofoam shipping container in a cardboard box. 
 
5. 
The cardboard box must be labeled as "BIOHAZARD". 
 
c. 
Specimen Tracking System 
 
All specimen submissions for this protocol must be entered and tracked using the 
Southwest Oncology Group online Specimen tracking system.  Southwest 
Oncology Group Members may log on to the specimen tracking system via the 
CRA Workbench (https://gill.crab.org/txwb/logon.aspx) using their Southwest 
Oncology Group roster identification numbers and passwords.  First-time non-
Southwest Oncology Group users must refer to start-up instructions located at 
https://gill.crab.org/SpecTrack/. 
 
In the online Specimen Tracking system laboratory ID numbers are used to 
identify the laboratories to which specimens are shipped.  The laboratory 
numbers for specimen submission on this study are listed in Sections 15.3e and 
15.4d.3. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE NO 
EXCEPTIONS.   
 
To report technical problems with Specimen Tracking, such as database errors 
or connectivity issues, please send an email to technicalquestion@crab.org.  For 
procedural help with logging and shipping specimens, there is an introduction to 
the 
system 
on 
the 
Specimen 
Tracking 
main 
page 
(https://gill.crab.org/SpecTrack/Documents/Instructions.pdf); or contact the Data 
Operations Center at 206/652-2267 to be routed to the Data Coordinator for 
further assistance. 
 
15.3 
Tissue Bank Submission Instructions 
 
a. 
Institutions are encouraged to seek additional patient consent to submit 
tissue for banking.  The Southwest Oncology Group plans to collect one block 
of fixed tissue for the purpose of investigating PTHrP and other markers of 
preferential bone metastasis in the future. 
 
 


 
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Revised 9/25/06 
 
Amended 3/11/08 
 
 
 
 
 
b. 
For medical/legal reasons, the blocks will remain at the tissue repository while 
slides may be cut from them to send to labs doing approved research.  The 
blocks will only leave the tissue repository at the request of the originating 
institution; blocks are guaranteed to be returned within 48 hours of a written 
request.  Materials to be submitted are as follows: 
 
 
1. 
One block of the primary tumor should be submitted.   
 
2. 
If the institution is not able to release the block, a punch of the block plus 
25 unstained 5 micron sections on plus slides would be acceptable.  The 
bank will send a disposable punch instrument at the request of the 
submitting institution.   
 
3. 
At minimum, if no other tissues are available for submission, the tissue 
bank will accept 25 unstained 5 micron sections of the tumor block on 
plus slides.   
 
c. 
A copy of the shipment packing list produced by the Specimen Tracking System 
should be printed and sent with the blocks in a separate resealable bag.  A copy 
of the surgical pathology report should also be sent.   
 
d. 
If shipping slides, wait 24 hours prior to shipping.  Label all slides with protocol 
number (S0307), patient number, and date sectioned.  Place in slide mailer and 
send overnight to the address below.   
 
e. 
Tissue specimens should be submitted in a crush-proof mailing container (e.g. 
Styrofoam box or mailing tube).  Please ship tissue blocks on cold packs to 
prevent heat damage in warm climates.  Ship tissue samples (Monday through 
Thursday only) by overnight delivery to: 
 
SpecTrack Lab #78: 
SWOG Solid Tumor Tissue Bank 
University of Colorado HSC at Fitzsimons 
Department of Pathology 
RC-1 South, Room L18-5400A 
12801 East 17th Avenue 
Aurora, CO  80045 
 
Contact: 
Miguel Martinez 
Phone:   
303/724-3086 
E-mail:   
miguel.martinez@uchsc.edu 
 


Revised 6/12/06 
S0307 
Revised 7/13/09 
Page 40 
 
 
 
 
 
15.4 
Instructions for submission of serum and whole blood for banking 
 
a. 
Institutions are encouraged to seek additional patient consent to submit 
serum and whole blood for banking.  The Southwest Oncology Group plans to 
collect, process, and store baseline serum samples for analysis of circulating 
bone turnover-related proteins and for future studies such as proteomics as the 
technology advances; and to collect, process and store whole blood for 
pharmacogenomics. 
 
b. 
Blood collection:  Obtain a 10 mL serum sample (red-top tube, Vacutainer®) at 
prestudy (prior to initiation of treatment).   
 
Whole blood collection:  Obtain a 10 mL whole blood sample (EDTA, lavender 
top Vacutainer®) obtained at any single timepoint when blood is otherwise being 
drawn for laboratory assessments. 
 
c. 
Procedures: 
 
1. 
Prepare participant’s paper work to include SWOG STUDY NUMBER 
(S0307), participant ID number, visit number, collection date and time, 
and initials of the phlebotomist. 
 
2. 
Prepare collection material and make sure the ID of the participant to be 
drawn matches the demographics on the requisition of the draw. 
 
3. 
Seat the participant for at least five minutes prior to blood collection. 
 
4. 
Collect sample preferably under fasting conditions.  
 
5. 
Using the appropriate Vacutainer® blood collection tube (plastic 
vacutainer tubes preferred) and a double-ended Vacutainer® needle, draw 
blood.  Place the tube in a rack at room temperature for at least one hour 
and not more than two hours. See Table 1 for basic guide on frequently 
requested samples.   
 
6. 
Label specimen with SWOG STUDY NUMBER (S0307), visit number, 
collection date and time, initials of the phlebotomist, participant study ID 
number, and treatment cycle number. 
 
Reference 
 
1. 
CAP. So you are going to collect a blood specimen. An Introduction to 
Phlebotomy, 6th Ed., 1994 
 
2. 
Ernst, DJ, Calan, R.  NCCLS simplifies order of draw: a brief history, 
MLO, 2004 
 
3. 
Chance, J.  Blood testing, Choosing the right specimen, Clinical 
Laboratory News, AACC 2001, vol 27, No. 7 
 
Table 1 
 
 
 
 
 
 
 
 
 
 
 
Fill the red top tube (serum) prior to the EDTA tube (whole blood).  If 
drawn by syringe, fill applicable tubes with anticoagulant first. 
 
Type of 
Specimen 
Vacutainer® 
Collection Tube  
Anticoagulant 
Mix  
USE 
Serum 
Red Top or Serum 
Separator Tube 
(SST) 
None 
Do not mix Biomarkers 
Whole 
Blood 
Lavender Top 
EDTA 
Mix (by 
gentle 
inversion) 
Cells 
Nucleic acid


 
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Revised 9/25/06 
 
Amended 3/11/08 
 
Revised 8/30/10 
 
 
 
 
NOTES TO AVOID HEMOLYSIS: 
 
Do not use small-bore needles.   
Invert filled tubes gently.   
Do not keep tourniquet on too long. 
Allow the cleaned venipuncture site to dry completely before skin puncture. 
Do not expose to extreme heat or cold. 
Do not draw blood from a difficult site such has a hematoma or IV line.   
 
d. 
Shipping Instructions:   
 
1. 
Sample should be shipped within 24 hours of collection.  Sample can be 
stored at 4oC until ready for shipment.  Be sure tube is closed securely.   
 
2. 
Place specimen in a sealed biohazard bag and include absorbent 
material.   
 
3. 
Ship sample with an ice pack and the specimen collection form overnight 
in an appropriate shipping container (Monday through Thursday only.  
Do not collect sample on Friday or day before a holiday).   Ship 
sample to: 
 
SpecTrack Lab #78: 
SWOG Solid Tumor Tissue Bank 
University of Colorado HSC at Fitzsimons 
Department of Pathology 
RC-1 South, Room L18-5400A 
12801 East 17th Avenue 
Aurora, CO  80045 
 
Contact: 
Miguel Martinez 
Phone:   
303/724-3086 
E-mail:   
miguel.martinez@ucdenver.edu 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research  
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46). 
 


 
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Revised 3/28/14 
 
 
 
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312. 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are 
due January 31, April 30, July 31 and October 31. 
 
16.1 
Adverse Event Reporting Requirements  
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as 
well as those who will enroll in future studies using similar agents.  Adverse 
events are reported in a routine manner at scheduled times during a trial.  
(Directions for routine reporting are provided in Section 14.0.)  Additionally, 
certain adverse events must be reported in an expedited manner to allow for 
more timely monitoring of patient safety and care. The following guidelines 
prescribe expedited adverse event reporting for this protocol.  See also Appendix 
19.2 for general and background information about expedited reporting. 
 
b. 
Reporting methods 
 
This study requires that expedited adverse event reporting use the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS). 
CTEP’s guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted to the Southwest Oncology Group 
Operations Office electronically via the CTEP-AERS Web-based application 
located at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm.  
 
c. 
When to report an event in an expedited manner 
 
Some adverse events may require 24-hour notification (refer to Tables 16.1 and 
16.2) via CTEP-AERS. 
 
When the adverse event requires expedited reporting, submit the report within 
the number of calendar days of learning of the events as specified in Table 16.1 
or 16.2, as applicable. 
 


 
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Revised 3/28/14 
 
 
 
 
d. 
Other recipients of adverse event reports 
 
The Operations Office will forward reports and documentation to the appropriate 
regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable must also be reported according to 
local policy and procedures to the Institutional Review Board responsible for 
oversight of the patient. 
 
e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of 
the investigational agent(s) as part of the trial.  Reporting requirements are 
provided in Table 16.1. The investigational agents used in this study are 
clodronate and ibandronate.  If there is any question about the reportability of 
an adverse event or if on-line CTEP-AERS cannot be used, please telephone or 
email the SAE Specialist at the Operations Office, 210/614-8808 or 
adr@swog.org, before preparing the report. 
 


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Revised 7/13/09 
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Table 16.1: 
 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND or Non-CTEP IND:  CTEP-AERS 
Expedited Reporting Requirements for Adverse Events that Occur within 30 Days1,3 of the Last 
Dose of the Investigational Agents Clodronate and Ibandronate in this Study (Arm 2 and Arm 3, 
respectively). 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 5
2 
Grades 
4 & 5
2 
Unexpected 
and 
Expected 
Unexpected Expected
Unexpected 
Expected 
Unex-
pected 
Expected 
with 
Hospitali-
zation 
without 
Hospitali- 
zation 
with 
Hospitali-
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required
10 Calendar
Days 
Not 
Required 
10 
Calendar
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 Calendar 
Days 
Not 
Required
10 Calendar
Days 
10 
Calendar 
Days 
10 
Calendar
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of 
treatment with an agent under a CTEP IND or Non-CTEP IND require reporting as follows: 
 
CTEP-AERS 24-hour notification (via CTEP-AERS for CTEP IND agents; via email to adr@swog.org for agents in non-
CTEP IND studies) followed by complete report within 5 calendar days for: 
 
Grade 4 and Grade 5 unexpected events  
 
CTEP-AERS 10 calendar day report: 
 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
 
Grade 5 expected events    
 
2  Although a CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report is 
required as outlined in the table. 
 
3  Protocol-specific reporting requirements:  The adverse events listed below also require expedited reporting for this trial: 
 
Osteonecrosis of the jaw (regardless of grade, attribution or expectedness) 
     
 
March 2005 
 
Note:  All deaths on study require both routine and expedited reporting 
regardless of causality.  Attribution to treatment or other cause must be provided. 
 
 
Expedited AE reporting timelines defined: 
 "24 hours; 5 calendar days" – The investigator must initially report the AE via 
CTEP-AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
 "10 calendar days" - A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the event.  
 
 
Any medical event equivalent to CTCAE Grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse 
event reporting exclusions.   
 
 
Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS if 
the event occurs following treatment with an agent under a CTEP IND. 
 
 
Use the NCI protocol number and the protocol-specific patient ID assigned 
during trial registration on all reports. 


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Revised 1/21/10 
Revised 3/28/14 
 
 
 
 
f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Phase 2 and 3 Trials Utilizing an Agent under a Non-
CTEP IND: 
 
1) 
Group-specific instructions. 
 
Within 10 calendar days (5 calendar days if 24-hour reporting was 
required), submit the following to the Operations Office  by fax to 210-
614-0006 or mail to the address below: 
 
Printed copy of the first page of the CTEP-AERS report 
 
Copies of clinical source documentation of the event 
 
If applicable, and they have not yet been submitted to the 
SWOG Data Operations Center, copies of Off Treatment 
Notice and/or Notice of Death. 
 
g. 
Expedited reporting for commercial agents 
 
Commercial reporting requirements are provided in Table 16.2. The commercial 
agent used in this study is zoledronic acid.  If there is any question about the 
reportability of an adverse event, please telephone or email the SAE Program at 
the Operations Office, 210/614-8808 or adr@swog.org, before preparing the 
report. 
 
Table 16.2. Expedited reporting requirements for adverse events experienced by 
patients who have received zoledronic acid on this study. 
 
 
Attribution 
 
Grade 4 
 
Grade 5a 
(Option) Protocol-
Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
 
 
See footnote (b,c) 
for special 
requirements 
Unrelated or 
Unlikely 
 
 
CTEP-AERS 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
CTEP-AERS 
CTEP-AERS:  
Indicates an expedited report is to be submitted using the CTEP-AERS Commercial Drug 
pathway within 7 working days of learning of the event
b. 
24-Hr Report:  Indicates a report must be sent to [desired recipient of the report] and [method of reporting, 
e.g., phone or fax]. 
a This includes all deaths within 30 days of the last dose of treatment with a commercial agent(s), 
regardless of attribution. Any death that occurs more than 30 days after the last dose of treatment with a 
commercial agent(s) and is attributed (possibly, probably, or definitely) to the agent(s) and is not due to 
cancer recurrence must be reported according to the instructions above. 
 
b Submission of the on-line CTEP-AERS report plus any necessary amendments generally completes the 
reporting requirements. You may, however, be asked to submit supporting clinical data to the 
Operations Office in order to complete the evaluation of the event. If requested, the specified data 
should be sent by fax to 210-614-0006. 
 
c Protocol-specific expedited reporting requirements: The adverse events listed below also require 
expedited reporting for this trial:  Osteonecrosis of the jaw (regardless of grade, attribution or 
expectedness) 
 
d Any Group-specific instructions. The SWOG Operations Office will notify Novartis as required. 


Revised 1/21/10 
 
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Revised 4/21/11 
 
Page 45a 
Revised 3/28/14 
 
 
 
 
 
h. 
Reporting secondary AML/ALL/MDS 
 
1. 
All cases of acute myeloid leukemia (AML), acute lymphocytic leukemia 
(ALL), and myelodysplastic syndrome (MDS) that occur in patients on 
NCI-sponsored trials following chemotherapy for cancer must be 
reported in CTEP-AERS.  
 
i. 
In protocols using CTCAE Version 4.0 for SAE reporting, three 
options are available to describe treatment-related events: 
 
 
Leukemia secondary to oncology chemotherapy 
 
Myelodysplastic syndrome.  NOTE:  The only grading option 
for "Myelodysplastic syndrome" is Grade 4, life-threatening. 
If reporting MDS that is other than Grade 4, use “Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - 
Other, (specify,__)” and insert MDS as the specify term. 
 
Treatment related secondary malignancy 
 
ii. 
In protocols using CTCAE Version 3.0 for SAE reporting, the 
event(s) can be reported as “Secondary malignancy-Other 
(specify, ___)”.  Report MDS as “Myelodysplasia,” in the 
BLOOD/BONE MARROW category. 
 
iii. 
Secondary malignancies other than AML/ALL/MDS that are 
related to protocol treatment must also be reported in CTEP-
AERS. 
 
iv. 
Non-treatment related cases of AML/ALL/MDS must be reported 
as follows: 
 
In protocols using CTCAE Version 4.0 for SAE reporting, report 
as “Neoplasms benign, malignant and unspecified (incl cysts 
and polyps) - Other, specify” 
 
In protocols using CTCAE Version 3.0 for SAE reporting, report 
MDS as “Myelodysplasia” and Leukemias as “Blood/Bone 
Marrow - Other (Specify, __)” 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adve
rse_events.htm.  
 
2. 
The following supporting documentation must also be submitted within 
30 days: 
 
 
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis 
 
(if available) a copy of the cytogenetics report   
 
Submit the Report and documentation to: 
 
Investigational Drug Branch    and 
Southwest Oncology Group 
by fax at 301-230-0159  
 
ATTN: SAE Program 
 
 
4201 Medical Drive, Suite 250 
 
 
San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 


 
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17.0 
BIBLIOGRAPHY 
 
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Bell RM, Yellon DM.  Atorvastatin, administered at the onset of reperfusion, and independent of 
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42. 
Wilson SH, Herrmann J, Lerman LO, et al.  Simvastatin preserves the structure of coronary 
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Danesh FR, Sadeghi MM, Amro N, et al.  3-Hydroxy-3-methylglutaryl CoA reductase inhibitors 
prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/ p21 
signaling pathway: Implications for diabetic nephropathy. Proc Natl Acad Sci 99:8301-8305, 
2002. 
 
44. 
Umekita Y, Ohi Y, Sagara Y, et al.  Expression of maspin predicts poor prognosis in breast-
cancer patients. Int J Cancer 452-455, 2002. 
 
45. 
Urbich C, Dernbach E, Zeiher AM, et al.  Double-edged role of statins in angiogenesis signaling. 
Circ Res 90:737-44, 2002. 
 
46. 
Fenton JW, Jeske WP, Catalfamo JL, e al.  Statin drugs and dietary isoprenoids downregulate 
protein prenylation in signal transduction and are antithrombotic and prothrombolytic agents. 
Biochemistry 67:85-91, 2002. 
 
47. 
Graaf MR, Beiderbeck AB, Egberts ACG, et al.  The risk of cancer in users of statins. Proc Am 
Soc Clin Oncol, 2003 
 
48. 
Mortimer JE, Axelrod, R and Zimbro K.  Effect of statins on breast cancer incidence; Findings 
from the Sentara Health Plan. Proc Am Soc Clin Oncol 2003. 
 
49. 
Stein EA, Farnier M, Waldstreicher J, et al.  Effects of statins on biomarkers of bone metabolism: 
a randomised trial. Nutr Metab Cardiovasc Dis 11:84-7, 2001. 
 
50. 
Chan KK, Oza AM, Siu LL.  The statins as anticancer agents. Clin Cancer Res 9:10-9, 2003. 


Revised 6/12/06 
S0307 
Amended 6/18/07 
Page 49 
 
Revised 7/25/08 
 
 
 
 
 
51. 
Walker RA, Jones JL, Chappell S, et al.  Molecular pathology of breast cancer and its application 
to clinical management.  Cancer & Metastasis Reviews 16(1-2): 5-27, 1997. 
 
52. 
Powell GJ, Southby J, Danks JA.  Localization of parathyroid hormone-related protein in breast 
cancers increased incidence in bone compared with other sites.  Cancer Res 51, 3059-3061, 
1991. 
 
53. 
Rivkin SE, Gown A, Tickman R.  Parathyroid-related Protein (PTHrP) expression in breast cancer 
patients and its relationship to subsequent bone metastasis.  Proc Am Soc Clin Oncol 17:abs 
656, 1998. 
 
54. 
Kohno N, Kitazawa S, Fukase M, et al.  The expression of parathyroid hormone-related protein in 
human breast cancer with skeletal metastases.  Surgery Today 24(3): 215-220, 1994. 
 
55. 
Bundred NJ, Walls J, Ratcliffe WA.  Parathyroid hormone-related protein, bone metastases and 
hypercalcaemia of malignancy.  Ann Roy Coll Surg of Eng 78(4):354-358, 1996. 
 
56. 
Bouizar Z, Spyratos F, Deytieux S, de Vernejoul MC, Jullienne A.  Polymerase chain reaction 
analysis of parathyroid hormone-related protein gene expression in breast cancer patients and 
occurrence of bone metastases.  Cancer Res 53(21):5076-5078, 1993. 
 
57. 
Downey SE, Hoyland J, Freemont AJ, et al.  Expression of the receptor for parathyroid hormone-
related protein in normal and malignant breast tissue.  J Path 183(2):212-217, 1997. 
 
58. 
Carron JA, Fraser WD, Gallagher JA.  PTHrP and the PTH/PTHrP receptor are co-expressed in 
human breast and colon tumours.  Br J Cancer 78(8):1095-1098, 1997. 
 
59. 
Orr FW, Varani J, Gondetz MD, et al.  Chemotactic responses of tumor cells to products of 
resorbing bone.  Science 203:176-179, 1979. 
 
60. 
Hauschka PV, ChenTL, Mavrakos AE.  Polypeptide growth factors in bone matrix. Ciba Found 
Symp 136:207-225, 1988. 
 
61. 
van der Pluijm G, Lowik C, Papapoulos S, et al.  Tumor progression and angiogenesis in bone 
metastases from breast cancer: New approaches to an old problem.  Cancer Treat Rev 26:11-27, 
2000. 
 
62. 
Demers LM, Costa L, Lipton A.  Biochemical Markers and Skeletal Metastases.  Cancer 
Supplement 88(12); 2919-2926, 2000. 
 
63. 
Coleman R, Thorpe H, Cameron D, et al.  Zoledronic acid is well tolerated and can be safely 
administered with adjuvant chemotherapy-first safety data from the AZURE trial (BIG 01/04).  Br 
Cancer Res Treat 100, Abstract 2080, 2006. 
 
64. 
Liu PY, Dahlberg S. Design and analysis of multiarm clinical trials with survival endpoints.  
Control Clin Trials, 16:119-130, 1995.   
 
65. 
Lan KG, DeMets DL. Discrete sequential boundaries for clinical trial.  Biometrika, 70:659-663, 
1983.   
 
66. 
Gnant M, Mlineritsch B, Schippinger W, et al. Adjuvant ovarian suppression combined with 
tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women 
with endocrine-responsive, stage I and II breast cancer: First efficacy results from ABCSG-12. 
Proc Am Soc Clin Oncol, 26:1006S (Abstract# LBA4), 2008. 
 
67. 
Brufsky A, Bundred N, Coleman R, et al. Integrated analysis of zoledronic acid for prevention of 
aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer 
receiving adjuvant letrozole. Oncologist, 13:503-514, 2008. 
 


 
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Amended 3/11/08 
 
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Revised 7/13/09 
 
 
 
 
18.0 
MASTER FORMS SET 
 
18.1 
The Model Informed Consent Form is included in this section, preceded by "Notes for 
Local Institution Consent Form Authors" and "Notes for Local Investigators."  The study - 
as well as the local consent form meeting the guidelines noted in these documents - must 
be reviewed and approved by the Institutional Review Board prior to registration and 
treatment of patients on this study.  
 
18.2 
This section includes copies of all data forms which must be completed for this study.  
These include: 
 
a. 
S0307 Registration Form (Form #46563) and Southwest Oncology Group 
Registration Form Code Sheet (10/24/06) 
 
b. 
S0307 Prestudy Form (Form #20161) (8/15/06)  
 
c. 
S0307 Treatment Summary Form (Form #31453) (8/15/06)  
 
d. 
S0307 Adverse Event Summary Form (Form #22831)  
 
e. 
Follow-Up Form (Form #64587) (9/15/03) 
 
f. 
S0307 Supplementary Follow-Up Form (Form #36846) (6/1/08) 
 
g. 
Off Treatment Notice (Form #8756) (9/1/03) 
 
h. 
S0307 Supplementary Off Treatment Form (Form #24801) (11/15/05) 
 
i. 
Notice of Death (Form #49467) (9/1/03) 
 
j. 
Dental Examination Form (Form #30100) (11/15/05) 
 
k. 
Osteonecrotic Jaw Lesion Form (Form #52641) (10/15/04) 
 
l. 
S0307 Serum Creatinine Reporting Form (Form #60188) (6/1/08) 
 
 


 
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Amended 6/18/07 
 
 
 
 
Informed Consent Model for S0307 
 
*NOTES FOR LOCAL INSTITUTION INFORMED CONSENT AUTHORS:  
 
This model informed consent form has been reviewed by the DCT/NCI and is the official 
consent document for this study. Local IRB changes to this document are allowed.  (Institutions 
should attempt to use sections of this document that are in bold type in their entirety.)  Editorial 
changes to these sections may be made as long as they do not change information or intent.  If 
the institutional IRB insists on making deletions or more substantive modifications to the risks or 
alternatives sections, they may be justified in writing by the investigator and approved by the 
IRB.  Under these circumstances, the revised language, justification and a copy of the IRB 
minutes must be forwarded to the Southwest Oncology Group Operations Office for approval 
before a patient may be registered to this study.   
 
Please particularly note that the questions related to banking of specimens for future study 
are in bolded type and may not be changed in any way without prior approval from the 
Southwest Oncology Group Operations Office. 
Readability Statistics: 
(Statistics updated 6/18/07) 
Flesch Reading Ease  
57.6 
 (targeted above 55) 
Flesch-Kincaid Grade Level 9.3        (targeted below 8.5) 
 
 
Instructions and examples for informed consent authors are in [italics].  
 
A blank line,  __________, indicates that the local investigator should provide the 
appropriate information before the document is reviewed with the prospective 
research participant.  
 
The term "study doctor" has been used throughout the model because the local 
investigator for a cancer treatment trial is a physician.   If this model is used for a 
trial in which the local investigator is not a physician, another appropriate term 
should be used instead of "study doctor".  
 
The dates of protocol updates in the header and in the text of the consent is for 
reference to this model only and should not be included in the informed consent 
form given to the prospective research participant.  
 
The local informed consent must state which parties may inspect the research 
records. This includes the NCI, the drug manufacturer for investigational studies, 
any companies or grantors that are providing study support (these will be listed in 
the protocol's model informed consent form) and the Southwest Oncology Group.  
 
The "Southwest Oncology Group" must be listed as one of the parties that may inspect the 
research records in all protocol consent forms for which patient registration is being credited to 
the Southwest Oncology Group.  This includes consent forms for studies where all patients are 
registered directly through the Southwest Oncology Group Data Operations Office, all 
intergroup studies for which the registration is being credited to the Southwest Oncology Group 
(whether 


 
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the registration is through the SWOG Data Operations Office or directly through the other 
group), as well as consent forms for studies where patients are registered via CTSU and the 
registration is credited to the Southwest Oncology Group.  (format change 6/12/06) 
 
 
When changes to the protocol require revision of the informed consent document, 
the IRB should have a system that identifies the revised consent document, in order 
to preclude continued use of the older version and to identify file copies.  An 
appropriate method to identify the current version of the consent is for the IRB to 
stamp the final copy of the consent document with the approval date.  The stamped 
consent document is then photocopied for use.  Other systems of identifying the 
current version of the consent such as adding a version or approval date are 
allowed as long as it is possible to determine during an audit that the patient signed 
the most current version of the consent form.  
 
*NOTES FOR LOCAL INVESTIGATORS:  
 
The goal of the informed consent process is to provide people with sufficient 
information for making informed choices.   The informed consent form provides a 
summary of the clinical study and the individual's rights as a research participant.  
It serves as a starting point for the necessary exchange of information between the 
investigator and potential research participant.  This model for the informed 
consent form is only one part of the larger process of informed consent. For more 
information about informed consent, review the "Recommendations for the 
Development of Informed Consent Documents for Cancer Clinical Trials" prepared 
by the Comprehensive Working Group on Informed Consent in Cancer Clinical 
Trials for the National Cancer Institute.  The Web site address for this document is 
http://cancer.gov/clinicaltrials/understanding/simplification-of-informed-consent-
docs/ 
 
A blank line,  __________, indicates that the local investigator should provide the 
appropriate information before the document is reviewed with the prospective 
research participant.  
 
Suggestion for Local Investigators:  An NCI pamphlet explaining clinical trials is 
available for your patients.  The pamphlet is entitled: "If You Have Cancer…What 
You Should Know about Clinical Trials".  This pamphlet may be ordered on the 
NCI Web site at http://cissecure.nci.nih.gov/ncipubs/details.asp?pid=1035 or call 
1-800-4- CANCER (1-800-422-6237) to request a free copy.  
 
Optional feature for Local Investigators: Reference and attach drug sheets, 
pharmaceutical information for the public, or other material on risks.  Check with 
your local IRB regarding review of additional materials. 
 
*These notes for authors and investigators are instructional and should not be included in the 
informed consent form given to the prospective research participant.  


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S0307, "Phase III Trial of Bisphosphonates as Adjuvant Therapy for 
Primary Breast Cancer" 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial 
to you.   Clinical trials include only people who choose to take part. Please take your time to 
make your decision about taking part.  You may discuss your decision with your friends and 
family.  You can also discuss it with your health care team.  If you have any questions, you can 
ask your study doctor for more explanation.  
 
You are being asked to take part in this study because you have Stage I, II, or III breast cancer 
that is currently in remission. 
 
Why is this study being done? 
This study is investigational and is being done to find out if adding a drug (a 
bisphosphonate) to hormonal therapy or chemotherapy will help prevent cancer 
from spreading to the bones or other parts of the body.  "Bisphosphonates" are a 
group of drugs that have strong effects on the bones and have been shown to 
strengthen the bones in many patients who take them. 
 
How many people will take part in the study? 
About 5,400 women will take part in this study. (6/18/07)(7/13/09) 
 
What will happen if I take part in this research study?   
Before you begin the study …  
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to your study doctor. 
 
 Medical History and Physical Exam 
 Weight and Performance Status 
 Disease Assessment 
 Routine laboratory tests:  including a serum creatinine blood test (to measure kidney 
function) will be performed within 7 days prior to starting study   
 CT and bone scans (as needed for disease assessment):  a series of detailed pictures of 
areas inside the body from different angles; the pictures are created by a computer 
linked to an x-ray machine 
 Dental examination:  to be performed within 6 months prior to registration. 
 Women of child-bearing potential must have a pregnancy test performed within 72 
hours prior to initiation of treatment. (6/18/07) (3/11/08) 


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During the study …  
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests and procedures.  They are part of regular cancer care.  
 
 Medical History and Physical Exam 
 Weight and Performance Status 
 Disease Assessment 
 Routine laboratory tests (to measure your liver and kidney function):  You will need 
to have your kidney function tested every month for the first 6 months, and then once 
every 3 months while on treatment.  (6/12/06) 
 CT and bone scans (as needed for disease assessment); and at the end of treatment:  
series of detailed pictures of areas inside the body from different angles; the pictures 
are created by a computer linked to an x-ray machine 
 Dental examination (at the end of treatment):  It is important to undergo routine 
dental exam and care while on the study.  Be sure to discuss with your study doctor 
before having dental procedures while on chemotherapy. 
 
You will need these tests and procedures that are either being tested in this study or being done 
to see how the study is affecting your body.  A sample of your tumor tissue and your blood will 
be requested for current and further scientific studies.  At the end of this form you can indicate 
your preferences related to the use of these samples. 
 
 Tumor block for PTHrP testing and banking:  a sample of your tumor from the 
original biopsy will be removed and analyzed for parathyroid hormone related protein 
(PTHrP) to see if this predicts the risk of your breast cancer spreading to the bones.  
(7/25/08)  If you consent, any remaining sample will be stored frozen for future 
scientific studies. 
 Serum for N-telopeptide testing and banking:  an additional blood sample 
(approximately 10 mL or 2-3 teaspoons) will be collected at prestudy and analyzed 
for the substance n-telopeptide to see if high levels will predict if breast cancer will 
spread to the bones.  If you consent, any remaining sample will be stored frozen for 
future scientific studies. 
 Whole blood for genetic studies related to the development of side-effects to the 
kinds of drugs used on this study.  An additional blood sample (approximately 10 mL 
or 2-3 teaspoons) will be collected.  With your additional agreement, any remaining 
sample will be stored for future scientific studies.  (added 7/13/09) 
 
You will be "randomized" into one of the study groups described below.  Randomization 
means that you are put into a group by chance.  A computer program will place you in 
one of the study groups.  Neither you nor your doctor can choose the group you will be 
in. You will have an equal chance to be put in any treatment group that has not yet 
reached its goal. (sentence updated 7/13/09)  Group 3 (ibandronate) is limited to 1,400 
patients while Groups 1 (zoledronic acid) and 2 (clodronate) will recruit 2,000 patients, 
each.  (sentence added 7/13/09)   


 
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If you are in Group 1 (often called "Arm 1") you will be given 4 mg (or less based on 
how your kidneys are working) of zoledronic acid through a needle in your vein every 
month for the first six months and then once every three months after that for thirty 
months.  (7/25/08) 
 
If you are in Group 2 (often called "Arm 2") you will take 1,600 mg of clodronate by 
mouth once a day, every day for thirty-six months.   
 


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If you are in Group 3 (often called “Arm 3”) you will take ibandronate once a day, 
every day for thirty-six months. 
 
If you are assigned to either Group 2 or 3, it is strongly encouraged that you record the 
number of pills you take each day on a calendar.  During visits with your study doctor (at 
Months 6, 12, 24, and 36) you will be asked how many pills were missed during the last 
month of protocol treatment.  This will be done in order to determine if you are having 
any problems taking the drug and to confirm you are taking it as directed.  (paragraph 
added 6/12/06) 
 
Study Chart  
 
The chart below shows what will happen to you during this study, as explained previously.  The left-hand 
column shows the weeks in the study, and the right-hand column tells you what to do during that week. 
 
Day 
What you do 
Within 6 months before 
starting study 
 Get routine dental examination. 
 
Within 28 days before 
starting study 
 Get routine blood tests. 
 Get chest x-ray; chest CT and bone scans (as 
needed for disease assessment). 
 Get medical history, physical examination, and 
performance status. 
 Tissue from the original tumor biopsy will be 
submitted for research studies (if consent is 
established).  (6/12/06) 
Within 7 days prior to 
starting study (6/12/06) 
(1/25/07) 
 Get kidney function test.  (6/12/06, 1/25/07) 
Within 72 hours prior to 
starting study (6/18/07) 
(3/11/08) 
 If you are a woman of child-bearing potential, you 
will need to have a pregnancy test. 
Day 1 of Month 1 (6/12/06) 
 If using Zoledronic acid, you will receive an IV 
infusion at your clinical site. 
 If using Clodronate, begin taking until the end of 
study, unless told to stop by your health care team. 
 If using Ibandronate, begin taking until the end of 
study, unless told to stop by your health care team. 
Day 1 of Months 2-6 and 
Months 9, 12, 15, 18, 21, 24, 
27, 30, 33 and 36 (6/12/06) 
(9/25/06) 
 Get kidney function test. (1/25/07) 
Day 1 of Months 2, 4, 6, 9, 
12, 15, 18, 21, 24, 27, 30, 33, 
and 36 (6/12/06) 
 Get routine blood tests (including kidney function 
test).  (1/25/07) 
 Return to your doctor's office at ____________ 
(insert appointment time) for your next physical 
examination.  (6/12/06, 9/25/06, 1/25/07) 


 
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Day 
What you do (contd.) 
Within 14 days of end of 
treatment 
 Return to your doctor's office at ____________ 
(insert appointment time) for  your next physical 
examination  
 Get bone scan. 
Within 6 months after 
completing study or ending 
the study early (6/18/07) 

Get routine dental examination. 
 
After completing study, 
every 6 months for 5 years, 
then annually until year 10 or 
until death (6/12/06) 

Return to your doctor's office at ____________ 
(insert appointment time) for  your next physical 
examination 
 


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Version Date  3/28/14 
 
 
 
 
Study Plan 
 
Another way to find out what will happen to you during the study is to read the chart 
below.  Start reading at the top and read down the list, following the lines and arrows. 
 
Randomization (section revised 6/12/06) 
 
 
 
Arm 1 
Arm 2 
Arm 3  
Zoledronic acid (IV) 
Clodronate daily (by mouth)  
Ibandronate daily  
monthly for 6 months, then 
for 3 years 
(by mouth) 
once every 3 months for 2.5 years 
 
for 3 years 
 
 
 
 
When you are finished taking study drugs… 
 
You will need to see your study doctor for a physical examination and bone scan.  
Additionally, you will need to have a dental examination within 6 months of completing 
treatment or being removed from treatment.  (3/11/08) 
 
How long will I be in the study?  
You will be asked to take bisphosphonates for 3 years.  After you are finished taking 
bisphosphonates, the study doctor will ask you to visit the office for follow-up exams 
every year for a length of ten years from the time you entered the study.  (1/21/10) The 
follow-up evaluation tests that are standard to cancer care will include a medical history, 
physical examination, and performance status. 
 
 
Can I stop being in the study? 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
the zoledronic acid, clodronate, or ibandronate can be evaluated by your doctor.  Another 
reason to tell your doctor that you are thinking about stopping is to discuss what follow 
up care and testing could be most helpful for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she 
believes it is in your best interest; if you do not follow the study rules; or if the study is 
stopped. 
 
 


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Version Date  3/28/14 
 
 
 
 
What side effects or risks can I expect from being in the study?  
You may have side effects while on the study.  Everyone taking part in the study will 
be watched carefully for any side effects.  However, doctors don’t know all the side 
effects that may happen.  Side effects may be mild or very serious. Your health care 
team may give you medicines to help lessen side effects.  Many side effects go away 
soon after you stop taking the zoledronic acid, clodronate, or ibandronate.  In some 
cases, side effects can be serious, long lasting, or may never go away. 
 
You should talk to your study doctor about any side effects that you have while 
taking part in the study.    
 
Risks and side effects related to the zoledronic acid include the following: 
 
Likely 
 Fever 
 Nausea  
 Constipation  
 Shortness of breath  
 Low red blood cell counts which may cause fatigue or pale appearance  
 Loss of appetite  
 Muscle or bone pain 
 Fatigue or tiredness (added 4/21/11) (moved from Less Likely 10/11/11) 
 
Less Likely 
 
Vomiting 
 
Diarrhea  
 Alteration of serum calcium and phosphate levels in your blood (This can result in 
numbness and tingling sensations in the fingers and toes, muscle cramps, irritability 
or depression, seizures, symptoms of heart failure, and anemia. 
 Joint pain, arthritis 
 Bone pain/tingling 
 Rash 
 Abdominal pain 
 Swelling of the legs 
 Cough 
 Headache 
 Dizziness 
 Insomnia 
 Depression 
 Anxiety 
 Confusion 
 (added 4/21/11) (deleted 10/11/11) 
 (added 4/21/11) (moved to likely 10/11/11) 
 


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Rare, But Serious (updated 3/11/08) 
 Seizures 
 Abnormal kidney function or failure 
 Osteonecrosis of the jaw (permanent damage to the jawbone) 
 Atypical bone fractures (added 5/29/12) 
 Inflammation of the eyes can occur with zoledronic acid use.  Symptoms can include 
red eye, eye pain, and/or decreased/blurry vision.  In some cases, these events did 
not improve until the zoledronic acid was discontinued.   
 Allergic reaction:  There have been rare reports of allergic reaction with 
intravenous zoledronic acid including swelling in the mouth or throat making it 
difficult to breath.  Very rare cases of anaphylactic reaction/shock have also been 
reported. 
 
Irregular heartbeat:  In a recent study in post-menopausal women with osteoporosis, a 
small number of patients treated with zoledronic acid experienced an irregular heartbeat 
called atrial fibrillation. More patients who received zoledronic acid experienced this kind 
of irregular heartbeat than patients who did not receive zoledronic acid.  So far, this 
symptom has not been seen in cancer patients taking zoledronic acid.  Atrial fibrillation is a 
common condition which can be treated; however, more research is needed before the 
importance of this finding becomes clear.  (paragraph added 6/18/07) 
 
Risks and side effects related to the clodronate include the following:   
 
Likely 
 Nausea 
 
Less Likely 
 
Vomiting 
 
Diarrhea or constipation 
 Alteration of serum calcium in your blood (This can result in numbness and tingling 
sensations in the fingers and toes, muscle cramps, irritability or depression, 
seizures, and symptoms of heart failure.) 
 
Rash 
 Alterations of liver enzymes in your blood (a possible result of injury to the liver).   
 
Rare, But Serious 
 Abnormal kidney function or failure 
 Respiratory effects in patients with aspirin-sensitive asthma 
 Osteonecrosis of the jaw (permanent damage to the jawbone).  (added 6/12/06) 
 
Risks and side effects related to the ibandronate include the following:  
 
Likely  
 Diarrhea 
 Pain in extremities (arms or legs) 
 Upset stomach 
 Back pain 
 


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Less Likely 
 Pain or trouble with swallowing 
 Chest pain (non-cardiac) 
 Very bad heartburn or heartburn that does not get better 
 Low calcium levels in the blood which could cause shakiness and abnormal heart 
rhythms 
 Nausea  
 Myalgia (muscle pain) 
 
Rare, But Serious 
 Stomach ulcers (hole in the lining of the stomach) which may bleed and be life-
threatening 
 Increase of symptoms associated with gastroesophageal reflux disease, including 
difficulty swallowing, inflammation of the esophagus, and development of ulcers 
within the esophagus 
 Osteonecrosis of the jaw (permanent damage to the jawbone)  (6/12/06) 
 
Reproductive risks:  You should not become pregnant while on this study because the 
drugs in this study can affect an unborn baby.  Women should not breastfeed a baby while 
on this study.  It is important you understand that you need to use birth control while on 
this study.  Check with your study doctor about what kind of birth control methods to use 
and how long to use them.  Some methods might not be approved for use in this study.  
Women of child-bearing potential will have a pregnancy test. 
 
Osteonecrosis of the jaw:  Recent reports suggest a possible association between the use of 
intravenous bisphosphonates, such as zoledronic acid, and osteonecrosis of the jaw 
(permanent damage to the jawbone), a rare, but serious potential side effect.  (6/12/06)  
This condition may be painful and may happen after tooth extraction or other dental 
procedures such as tooth cleaning or when a patient is also getting chemotherapy while 
taking bisphosphonates.  A recent study of 3,360 patients receiving standard treatment 
with or without zoledronic acid reported seven cases of osteonecrosis of the jaw, all in the 
zoledronic acid arm, with an average of eight doses received at the time of the event.  This 
represented 0.4% of patients on the zoledronic acid arm.  (6/18/07)  Oral clodronate and 
ibandronate may also increase the risk of osteonecrosis of the jaw, although this link is not 
as well established.  (6/12/06) 
 
Severe bone pain:  Rare reports of severe and occasionally disabling bone, joint, and/or 
muscle pain has been reported with bisphosphonate use.  The severe bone, joint, and/or 
muscle pain may occur within days, months, or years after starting a bisphosphonate. 
Some patients have reported complete relief of symptoms after discontinuing the 
bisphosphonate, whereas others have reported slow or incomplete recovery. The risk 
factors that contribute to severe bone, joint, and/or muscle pain associated with 
bisphosphonates are unknown.  (paragraph added 3/11/08) 
 
For more information about risks and side effects, ask the study doctor. 


 
S0307 
 
Page 59a 
 
Version Date  3/28/14 
 
Amended 3/11/08 
 
Revised 7/25/08 
 
 
 
 
 
Are there benefits to taking part in the study? 
Taking part in this study may or may not make your health better.  While doctors 
hope zoledronic acid, clodronate, and ibandronate will be more useful against 
cancer compared to the usual treatment, there is no proof of this yet. We do know 
that the information from this study will help doctors learn more about 
bisphosphonates as a treatment for cancer.  This information could help future 
cancer patients. 
 
Some small trials of clodronate have suggested some possible benefit for that drug, 
although with conflicting results, and now a study with zoledronic acid showed 
benefit for dosing twice a year in pre-menopausal women, with estrogen-receptor 
positive breast cancer receiving ovarian suppression and not chemotherapy.  
However, at present, it is not standard of care to give these drugs in the majority of 
breast cancer patients.  (paragraph added 7/25/08) 
 
 
What other choices do I have if I do not take part in this study? 
Your other choices may include: 
 Getting treatment or care for your cancer without being in a study. 
 Taking part in another study involving bisphosphonate treatments. 
 Getting no treatment. 
 
There is currently no standard treatment for the prevention of bone metastasis in 
breast cancer.  Talk to your doctor about your choices before you decide if you will 
take part in this study. 


Amended 6/18/07 
S0307 
 
Page 60 
 
Version Date  3/28/14 
 
 
 
 
Will my medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at 
scientific meetings, your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
 Local Institutional Review Board (IRB)  
 The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people 
 The Southwest Oncology Group 
 Qualified representatives from the drug manufacturers for the three drugs used in this 
study.   
 
 [Note to Local Investigators: The NCI has recommended that HIPAA regulations be 
addressed by the local institution.  The regulations may or may not be included in the 
informed consent form depending on local institutional policy.] 
 
What are the costs of taking part in this study? 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  
 
Administration of the drug will be (provided free of charge/charged in the usual way).  The parts 
of the research consisting of keeping research records will be paid by those organizing and 
conducting the research.  The research requires that you receive certain standard medical tests 
and examinations.  These standard tests and examinations will be (charged in the usual 
way/provided at a reduced rate).  (local institutions must choose the option that best fits the 
hospital's situation) 
 
The drug manufacturers, Bayer Schering Pharma Oy and Roche, will provide you with the 
investigational agents, free of charge for this study.  (6/18/07)  Although zoledronic acid is 
commercially available, Novartis will provide this drug to you free of charge for this study.  If 
during this study any of these drugs becomes approved for use in your cancer, you and/or your 
health plan may have to pay for drugs as needed to complete the study. 
 
You will not be paid for taking part in this study. 
 
If you have a severe financial need, lack dental insurance, and do not have access to dental care 
by any other means, then financial assistance will be available for dental exams.   
 


 
S0307 
 
Page 61 
 
Version Date  3/28/14 
 
 
 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .    
You can print a copy of the "Clinical Trials and Insurance Coverage" information from this Web 
site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.   The study will not pay for medical 
treatment.   
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.   No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.    
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing the 
data from this research throughout the study. We will tell you about important new information 
from this or other studies that may affect your health, welfare, or willingness to stay in this 
study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.   
 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
 
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of people 


Revised 6/12/06 
Revised 7/25/08 
S0307 
Revised 1/25/07 
Revised 7/13/09 
Page 62 
Amended 6/18/07 
Version Date  3/28/14 
 
 
 
 
who review the research to protect your rights) at __________________ (telephone number).  
[Note to Local Investigator: Contact information for patient representatives or other individuals 
in a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can be listed here.]    
 
 *You may also call the Operations Office of the NCI Central Institutional Review Board 
(CIRB) at 888-657-3711 (from the continental US only).   [*Only applies to sites using the 
CIRB.] 
 
Please note:  This section of the informed consent form is about additional 
research studies that are being done with people who are taking part in the 
main study.   You may take part in these additional studies if you want to.  
You can still be a part of the main study even if you say ‘no’ to taking part in 
any of these additional studies. 
 
Future Contact  (section added 6/12/06) 
Occasionally, researchers working with the Southwest Oncology Group (SWOG) may have 
another research idea that relates to people who were on a SWOG study.  In some cases, to 
carry out the new research, we would need to contact participants in a particular study.  
You can agree or not agree to future contact. (paragraph added 6/18/07) 
I agree to allow my study doctor, or someone approved by my study doctor, to contact me 
regarding future research involving my participation in this study.  
Yes 
No 
 
You can say "yes" or "no" to each of the following studies.  Please mark your 
choice for each study.   
 
I agree to submit a tissue specimen for the analysis of the substance parathyroid hormone related 
protein (PTHrP) to see if this predicts the risk of my breast cancer spreading to the bones.  
(7/25/08)  This is an experimental test that may indicate a higher chance that breast cancer has 
spread to the bones.  Since the significance of this test is not proven, neither you nor your doctor 
will be given the results of this test.  (paragraph updated 1/25/07) (sentences italicized 7/25/08) 
 
YES 
 
NO 
 
I agree to submit a blood sample to be analyzed for the substance n-telopeptide to see if high 
levels will predict the risk of my breast cancer spreading to the bones.  (7/25/08)  This is an 
experimental test that may indicate a higher chance that breast cancer has spread to the bones.  
Since the significance of this test is not proven, neither you nor your doctor will be given the 
results of this test.   (paragraph updated 1/25/07) (sentences italicized 7/25/08) 
 
YES 
 
NO  
 
I agree to submit a whole blood sample for genetic studies related to the development of side-
effects to the kinds of drugs used in this study.  (added 7/13/09)   
 
YES 
 
NO  
Should any tissue or blood remain from these studies, we would like to store your specimens for 
future research studies.  The remaining sections of the informed consent document apply to 
specimens for research purposes.   


Revised 6/12/06 
Amended 3/11/08 
S0307 
Revised 9/25/06 
Revised 7/13/09 
Page 63 
Revised 1/25/07 
Version Date  3/28/14 
 
 
 
 
Consent Form for Use of Specimens for Research 
 
Where will my specimens be kept? 
 
(address updated 9/25/06, 1/25/07, 3/11/08) 
 
Southwest Oncology Group Solid Tumor Tissue Bank:   
University of Colorado HSC at Fitzsimons 
RC-1 South, Room L18-5400A   
12801 East 17th Avenue 
Aurora, CO  80045 
Phone:  303/724-3086 
 
(section deleted 6/12/06)   
 
About Using Specimens for Research  
(paragraph deleted 6/12/06)    
We would like to keep leftover tissue, whole blood and serum for future research.  (6/12/06) 
(7/13/09)  If you agree, these specimens will be kept and may be used in research to learn more 
about cancer and other diseases.  Please read the information sheet called "How Are Specimens 
Used for Research" to learn more about specimen research.  
Your specimens may be helpful for research whether you do or do not have cancer.  The research 
that may be done with your specimens is not designed specifically to help you.  It might help 
people who have cancer and other diseases in the future.  
Reports about research done with your specimens will not be given to you or your doctor.  These 
reports will not be put in your health record.  The research will not have an effect on your care. 
Things to Think About  
The choice to let us keep the left over specimens for future research is up to you.  No matter 
what you decide to do, it will not affect your care.  
If you decide now that your specimens can be kept for research, you can change your mind at 
any time.  Just contact us and let us know that you do not want us to use your specimens.  Then 
any specimens that remain will no longer be used for research.  


Revised 6/12/06 
S0307 
 
Page 64 
 
Version Date  3/28/14 
 
 
 
 
In the future, people who do research may need to know more about your health.  While the 
Southwest Oncology Group may give them reports about your health, it will not give them your 
name, address, phone number, or any other information that will let the researchers know who 
you are.  
Sometimes specimens are used for genetic research (about diseases that are passed on in 
families).  Even if your specimens are used for this kind of research, the results will not be put in 
your health records.  
Your specimens will be used only for research and will not be sold.  The research done with your 
specimens may help to develop new products in the future.  
Benefits 
 
The benefits of research using specimens include learning more about what causes cancer and 
other diseases, how to prevent them, and how to treat them.  
Risks  
The greatest risk to you is the release of information from your health records.  We will do our 
best to make sure that your personal information will be kept private.  The chance that this 
information will be given to someone else is very small.  
Making Your Choice  
Please read each sentence below and think about your choice. After reading each sentence, circle 
"Yes" or "No". If you have any questions, please talk to your doctor or nurse, or call our research 
review board at IRB's phone number.  
No matter what you decide to do, it will not affect your care. 
1.    
My specimens may be kept for use in research to learn about, prevent, or treat 
cancer.  
Yes 
No 
2.  
My specimens may be kept for use in research to learn about, prevent or treat other 
health problems (for example: diabetes, Alzheimer's disease, or heart disease).  
Yes 
No 
3.  
Someone may contact me in the future for my permission to allow other uses of my 
specimens.  (6/12/06)   
Yes 
No 
If you decide to withdraw your specimens from a Southwest Oncology Group Specimen 
Repository in the future, a written withdrawal of consent should be submitted through 
your treating physician to the Southwest Oncology Group Operations Office.  If you decide 
to withdraw your permission from the banking part of the study, your tissue will be 
returned to the treating institution, and any remaining blood specimens will be destroyed. 
(bolded 6/12/06) 


 
S0307 
 
Page 65 
 
Version Date  3/28/14 
 
Revised 6/12/06 
 
 
 
Where can I get more information? 
 
(section bolded 6/12/06) 
You may call the National Cancer Institute's Cancer Information Service at:  
 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
You may also visit the NCI Web site at http://cancer.gov/ 
 
 For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
 
 For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
 
 
You will get a copy of this form.  If you want more information about this study, ask your 
study doctor. 
 
Signature 
(section bolded 6/12/06) 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I 
have read it or it has been read to me.  I understand the information and have had my 
questions answered.  I agree to take part in this study. 
 
 
Participant  
 
 
Date _____________________________________ 
     


 
S0307 
 
Page 66 
 
Version Date  3/28/14 
 
 
 
 
Specimen Consent Supplemental Sheets 
 
How are Specimens Used for Research? 
 
Where do specimens come from? 
 
A specimen may be from a blood sample or from bone marrow, skin, toenails or other body materials.  
People who are trained to handle specimens and protect donors' rights make sure that the highest 
standards of quality control are followed by the Southwest Oncology Group.  Your doctor does not work 
for the Southwest Oncology Group, but has agreed to help collect specimens from many patients.  Many 
doctors across the country are helping in the same way.   
 
Why do people do research with specimens? 
 
Research with specimens can help to find out more about what causes cancer, how to prevent it, how to 
treat it, and how to cure it.  Research using specimens can also answer other health questions.  Some of 
these include finding the causes of diabetes and heart disease, or finding genetic links to Alzheimer's. 
 
What type of research will be done with my specimen? 
 
Many different kinds of studies use specimens.  Some researchers may develop new tests to find 
diseases.  Others may develop new ways to treat or even cure diseases.  In the future, some of the 
research may help to develop new products, such as tests and drugs.  Some research looks at diseases 
that are passed on in families (called genetic research).  Research done with your specimen may look for 
genetic causes and signs of disease. 
 
How do researchers get the specimen? 
 
Researchers from universities, hospitals, and other health organizations conduct research using 
specimens.  They contact the Southwest Oncology Group and request samples for their studies.  The 
Southwest Oncology Group reviews the way that these studies will be done, and decides if any of the 
samples can be used. The Southwest Oncology Group gets the specimen and information about you 
from your hospital, and sends the specimen samples and some information about you to the researcher.  
The Southwest Oncology Group will not send your name, address, phone number, social security number 
or any other identifying information to the researcher. 
 
Will I find out the results of the research using my specimen? 
 
You will not receive the results of research done with your specimen.  This is because research can take 
a long time and must use specimen samples from many people before results are known.  Results from 
research using your specimen may not be ready for many years and will not affect your care right now, 
but they may be helpful to people like you in the future. 
 
Why do you need information from my health records? 
 
In order to do research with your specimen, researchers may need to know some things about you.  (For 
example:  Are you male or female?  What is your race or ethnic group? How old are you?  Have you ever 
smoked?)  This helps researchers answer questions about diseases.  The information that will be given 
to the researcher may include your age, sex, race, diagnosis, treatments and family history.  This 
information is collected by your hospital from your health record and sent to the Southwest Oncology 
Group.  If more information is needed, the Southwest Oncology Group will send it to the researcher. 
 
 


 
S0307 
 
Page 67 
 
Version Date  3/28/14 
 
 
 
 
Will my name be attached to the records that are given to the researcher? 
 
No.  Your name, address, phone number and anything else that could identify you will be removed before 
they go the researcher.  The researcher will not know who you are. 
 
How could the records be used in ways that might be harmful to me? 
 
Sometimes, health records have been used against patients and their families.  For example, insurance 
companies may deny a patient insurance or employers may not hire someone with a certain illness (such 
as AIDS or cancer).  The results of genetic research may not apply only to you, but to your family 
members too.  For disease caused by gene changes, the information in one person's health record could 
be used against family members. 
 
How am I protected? 
 
The Southwest Oncology Group is in charge of making sure that information about you is kept private.  
The Southwest Oncology Group will take careful steps to prevent misuse of records.  Your name, 
address, phone number and any other identifying information will be taken off anything associated with 
your specimen before it is given to the researcher.  This would make it very difficult for any research 
results to be linked to you or your family.  Also, people outside the research process will not have access 
to results about any one person, which will help to protect your privacy. 
 
What if I have more questions? 
 
If you have any questions, please talk to your doctor or nurse, or call our research review board at (Insert 
IRB's Phone Number). 
 


9/1/2009
Patient's Date of Birth:
/
/
Patient Gender:
Female
Male
Patient's Race (select all that apply):
White
Black or African American
Native Hawaiian or Other Pacific Islander
Asian
American Indian or Alaska Native
Unknown
If a U.S. resident:
Patient Social Security Number:
-
-
Patient's ZIP Code:
If a resident of Canada:
Social Insurance Number:
-
-
Postal Code:
-
Country of Residence (if not USA):
Method of Payment:
Patient's Ethnicity:
Southwest  Oncology  Group  Registration Form
Activation Date: November 15, 2005
Last Amended Date: September 1, 2009
SWOG Study No.
S 0 3 0 7
Registration Step
1
Assigned Treatment Arm
SWOG Patient ID
Patient's Name
Phase III Trial of Bisphosphonates as Adjuvant
Therapy for Primary Breast Cancer
	

SWOG Investigator Number

/
/
	
/
/
	
/
/
SWOG Treating Institution Number
OR
OR
Other Group Investigator Name and Number
/
Other Group Institution Name and Number
/
Other Group Patient Number
Participating Group/
Protocol Number
INSTRUCTIONS: All of the information on this Registration Form and the Protocol Eligibility Section must be answered appropriately for
a patient to be considered eligible for registration.  This Registration Form must be entirely filled out and referred to during the
registration.  Do NOT submit this form as part of the patient data.
Date HIPAA Authorization signed:
/
/
(Not required for non-American sites)
Yes
No
Yes
No
Please indicate how the patient answered the following questions on the consent form:
4.  !"!#
$!!"!#
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!%"!&
Yes
No
3. 	!
%""'
 %"
!&
Yes
No
5. "$"!%"$
%!%()*%%'
!$%$&	

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

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
6. "$$!%"$
+%% %'!$
%$&	



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

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'"%
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&
2. ,!!$'"
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/%#%*&
Yes
No
Yes
No
Southwest Oncology Group Data Operations Center
C/o Cancer Research And Biostatistics
1730 Minor Ave Suite 1900
Seattle, WA 98101-1468
Patient Registration:
via WebReg at: http://swog.org
     (24 hours a day, 7 days a week, excluding downtimes for maintenance)
or call 206-652-2267 (Mon-Fri, 6:30am-4:00pm Pacific Time, excluding holidays)
Southwest Oncology Group Operations Office
14980 Omicron Drive
San Antonio, TX  78245-3217
Phone: (210) 450-8808
Fax: (210) 677-0006
0&"$ %$"%
+%'""%"!&
Yes
No
46563


 
 
 
10/24/2006 
Southwest Oncology Group Registration Form Code Sheet 
 
 
Patient’s race definitions: 
 
White or Caucasian:  a person having origins in any of the original peoples of Europe, 
Middle East, or North Africa. 
 
Black or African American:  a person having origins in any of the black racial groups 
of Africa. 
 
Native Hawaiian or Other Pacific Islander:  a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa and other Pacific islands. 
 
Asian:  a person having origins in any of the original peoples of the Far East, Southeast 
Asia, or the Indian subcontinent.  Including, for example, Cambodia, China, India, 
Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand and Vietnam. 
 
American Indian or Alaskan Native:  a person having origins in any of the original 
peoples of North, Central or South America, and who maintains tribal affiliations or 
community attachment. 
 
 
Patient’s ethnicity (Spanish/Hispanic Origin) options: 
Unknown 
 
 
 
 
Yes, Central American 
No (not Spanish) 
 
 
 
Yes, South American 
Yes, Mexican 
 
 
 
Yes, Other 
Yes, Puerto Rican  
 
 
Yes, NOS 
Yes, Cuban 
 
 
Method of Payment codes: 
Private 
 
 
 
 
No insurance (no means) 
Medicare 
 
 
 
 
Other, specify at registration 
Medicare and Private 
 
 
Unknown 
Medicaid 
 
 
 
 
Veterans Admin 
Medicaid and Medicare 
 
 
Military 
No insurance (self-pay) 
 
 
Other Group codes for use in the Web Registration program: 
9977 – ACOSOG 
 
 
 
9987 – MDACC  
9982 – CALGB 
 
 
 
9996 – NCCTG 
9976 – CTSU  
 
 
 
9981 – NCIC 
9995 – ECOG 
 
 
 
9983 – NSABP 
9984 – GOG  
 
 
 
9997 – RTOG 
 


SOUTHWEST ONCOLOGY GROUP
S0307 PRESTUDY FORM
Page 1 of 3
Patient Initials
(L, F M)
8/15/2006
SOUTHWEST ONCOLOGY GROUP
S0307 PRESTUDY FORM
Page 1 of 3
Participating Group:  Group Name/Study No./Patient ID
/
/
Physician
Institution / Affiliate
Patient Initials
(L, F M)
SWOG Patient ID
Instructions:  Submit this form within 14 days of registration.  All dates are MONTH, DAY, YEAR.  Explain any blank fields or blank
dates in the Comments section.  Place an    X    in appropriate boxes.  Circle AMENDED items in red and write AMENDED across top
of form.
8/15/2006
(PS0307)
SWOG Study No. S 0 3 0 7
Registration Step 1
continued on next page
DISEASE DESCRIPTION
Performance status:
0
1
2
Histologically confirmed primary invasive adenocarcinoma of the breast:
Stage I
Stage II
Stage III
 Renal:
Serum creatinine
Calculated creatinine clearance
LABORATORY VALUES
Document values in units listed
mg/dL
.
/
/
Collection date:
mg/dL
.
ULN
ELIGIBILITY VERIFICATION:
Each of the fields below corresponds to a criterion in Section 5 and must be completed for patient to be eligible.
Previous bisphosphonate:
IV
Oral
None
Date discontinued:
/
/
Date of dental examination:
/
/
Bone pain:
Yes
No
If Yes, bone metastasis?
Yes
No
ml/min
.
/
/
CONSENT FOR SUBMISSION AND BANKING
Accepted tissue submission
Declined tissue submission
Accepted serum submission
Declined serum submission
SWOG Patient ID
20161


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SOUTHWEST ONCOLOGY GROUP
S0307 PRESTUDY FORM
Page 3 of 3
Patient Initials
(L, F M)
8/15/2006
SWOG Study No. S 0 3 0 7
Registration Step 1
PRIOR TREATMENT RELATED TO THIS CANCER:
Comments:
Was sentinel node sampling performed?
Yes
No
Sentinel Node Biopsy Date:
/
/
Sentinel Node Biopsy Results:
Positive
Negative
Was axillary dissection performed?
Yes
No
Date of Axillary Dissection:
/
/
Date of Most Extensive Primary Surgery:
/
/
(If required, use last re-excision date)
PRIOR TREATMENT RELATED TO THIS CANCER
Partial mastectomy/lumpectomy/excisional biopsy
Mastectomy, NOS
Most Extensive Primary Surgery (select one):
SYSTEMIC TREATMENT FOR THIS CANCER
Chemotherapy (select one):
Currently receiving
Planned
Not planned
Completed
If completed, Date chemotherapy ended:
/
/
Hormone therapy (select one):
Currently receiving
Planned
Not planned
If currently receiving:
SERM (e.g., tamoxifen, raloxifene)
Aromatase inhibitor (e.g., anastrazole, letrozole, exemustane)
Ovarian suppression
SWOG Patient ID
20161


 SOUTHWEST ONCOLOGY GROUP
S0307 TREATMENT SUMMARY FORM
SWOG Patient ID
8/15/2006
SWOG Study No. S 0 3 0 7
Registration Step 1
Institution/Affiliate
Physician
(L, F M)
Patient Initials
Comments:
Page 1 of 1
DISEASE STATUS
Date of Last Clinical Assessment:
/
/
(submit Follow Up form if patient has relapsed)
Date of Last Contact or Death:
/
/
Vital Status:
Alive
Dead (submit Notice of Death form)
TREATMENT STATUS
Assigned Treatment Arm:
Arm 1
Arm 2
Arm 3
(TX0307)
Participating Group:  Group Name/Study No./Patient ID
/
/
Reporting Period:
0-6 months
6 mo-1 yr
1 yr-2 yr
2 yr-3 yr
Instructions: Please complete this form at 6 months, 1 year, 2 years, and 3 years.  All dates are MONTH, DAY, YEAR.  Explain any
blank dates or fields in the Comments section.  Place an   X   in appropriate boxes.  Circle AMENDED items in red and write AMENDED
across the top of the form.
Was the patient treated on the assigned arm during this reporting period?
Yes
No, specify reason in comments
Treatment End Date (for this reporting period):
/
/
Treatment Begin Date (for this reporting period):
/
/
Has the patient experienced a bone fracture since submission of the last treatment summary form?
Yes
No
If yes, indicate site:
Hip
Spine
Pelvis
Wrist
Arm
Leg
Ankle
Was the fracture traumatic (from greater than standing height)?
Yes
No
Has the patient had any grade of renal toxicity since the submission of the last treatment summary form?
No
Yes
If yes, Grade
Yes
No
Is the patient currently taking a statin: atorvastatin (Lipitor), pravastatin (Pravachol), simvastatin (Zocor), 
lovastatin (Mevacor), fluvastatin (Lescol), rosuvastatin (Crestor)?
If yes, submit Osteonecrotic Jaw Lesion Form
Has the patient had osteonecrosis or osteomyelitis of the jaw since submission of the last treatment summary
form?
No
Yes
No
Yes, planned (per protocol guidelines), specify in comments
Yes, unplanned (not per protocol guidelines), specify in comments
Were there any dose modifications or additions/omissions to protocol treatment (during this reporting period)?
If yes,
Did the patient receive any chemotherapy during this reporting period?
Yes
No
Did the patient receive radiation therapy during this reporting period?
Yes
No
Did the patient receive any hormone therapy during this reporting period?
Yes
No
SERM (e.g., tamoxifen, raloxifene)
Aromatase inhibitor (e.g., anastrazole, letrozole, exemestane)
Ovarian suppression
For Arms 2 and 3: In the past month, how many pills did the patient miss?
31453


 SOUTHWEST ONCOLOGY GROUP
S0307 ADVERSE EVENT SUMMARY FORM
SWOG Patient ID
SWOG Study No. S 0 3 0 7
Registration Step 1
Patient Initials
Institution/Affiliate
Physician
(L, F M)
FL01
Fever
SK11
Rash/desquamation
GI81
Dental: periodontal disease
GI20
Diarrhea
GI61
Esophagitis
GI00
Nausea
GI10
Vomiting
ME03
ALT, SGPT
ME04
AST, SGOT
ME05
Bilirubin
ME60
Calcium, serum-low
ME06
Creatinine
ME12
Proteinuria
MS31
Arthritis
MS09
Fracture
MS20
Osteonecrosis (avascular
necrosis)
NR30
Seizure
Pain
PAM02
Bone
PAM11
Joint
GU53
Renal failure
CTC Adverse Event Term
CTC Adverse Event Term
9/1/2009
* Attribution codes:    1-unrelated           2-unlikely           3-possible           4-probable         5-definite
CTCAE (3.0)
Grade
(1 - 5)
Participating Group:  Group Name/Study No./Patient ID
/
/
ADVERSE EVENTS
CTCAE (3.0)
Grade
(1 - 5)
CTC Adverse
Event
Attribution
Code*
CTC Adverse
Event
Attribution
Code*
Page 1 of 1
Reporting period start date:
/
/
(Day 1 of this period)
Reporting period end date:
/
/
(Day one of next period.  If final period,
date of first visit or contact after
resolution of acute adverse events.)
Comments: (Please explain any "other" adverse events reported above, e.g., PA99 Pain-other)
Instructions:  Please complete this form after 6 months, 1 year, 2 years, and 3 years.  Report all adverse events observed.
Document the worst Grade seen during the reporting period.  Do not code a condition existing prior to registration as an adverse
event unless it worsens.  Category lists may not include all adverse events from that category.  Record any observed adverse events
not listed on the blank lines at the end.  NOTE: If osteonecrosis of the jaw (ONJ) is detected, also submit the Osteonecrotic
Jaw Lesion Form. All dates are MONTH, DAY, YEAR.  Explain any blank dates or fields in the Comments section.  Place an  X   in
appropriate boxes.  Circle AMENDED items in red and write AMENDED across the top of the form.
Were adverse events assessed during this report period?
No
Yes, but no reportable adverse events occurred
Yes, and reportable adverse events occurred (report below)
CTC Adverse Event Term, Other
(specify using CTCAE 3.0 terminology)
22831


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SOUTHWEST ONCOLOGY GROUP
S0307 SUPPLEMENTARY FOLLOW UP FORM
6/1/2008
SWOG Patient ID
Physician
Institution / Affiliate
Page 1 of 1
Date of Patient Visit:
/
/
Date of diagnosis:
/
/
Has the patient been diagnosed with opposite breast cancer since submission of last follow-up form?
No
Yes
No
Yes
Date of First Local-Regional Progression:
/
/
Site(s) of First Local-Regional
Progression:
(select all that apply)
Axillary nodes
Ipsilateral breast
Chest wall
Internal mammary nodes
Infraclavicular nodes
Supraclavicular nodes
How was this progression information obtained?
Clinical assessment
Patient self-report only
Has the patient been diagnosed with first distant recurrence/progression (since submission of last follow-up
form)?
No
Yes
Date of First Distant Progression:
/
/
How was this progression information obtained?
Clinical assessment
Patient self-report only
Axilla
Site(s) of First Distant Progression:
Bone
(select all that apply)
Brain
Other CNS
Other, NOS:
Skin
Lung/pleura
Other Visceral
Has the patient been diagnosed with first local-regional recurrence (since submission of last follow-up form)?
(L, F M)
Patient Initials
Participating Group:  Group Name/Study No./Patient ID
/
/
Liver
Nodes
Other Soft Tissue
NOTICE OF PROGRESSION - ADJUVANT
If the patient has been previously diagnosed with first distant recurrence/progression at a site other than
bone, has the patient been diagnosed with a subsequent bone recurrence since submission of last
follow-up form?
No
Yes
Date of Subsequent Bone Progression:
/
/
Instructions:  Please submit at each follow up after completion of treatment until recurrence, at time of recurrence, and at protocol
specified intervals after recurrence.  All dates are MONTH, DAY, YEAR.  Place an   X   in appropriate boxes.  Circle AMENDED
items in red and write AMENDED across the top of the form.
Comments:
Has the patient experienced a bone fracture since submission of the last follow-up form?
Yes
No
If yes, indicate site:
Hip
Spine
Pelvis
Wrist
Arm
Leg
Ankle
Was the fracture traumatic (from greater than standing height)?
Yes
No
(FUS0307)
If yes, submit Osteonecrotic Jaw Lesion Form
Has the patient had osteonecrosis or osteomyelitis of the jaw since submission of the last follow-up form?
No
Yes
SWOG Study No. S 0 3 0 7
Registration Step 1
36846


9/1/2003
Comments:
SOUTHWEST ONCOLOGY GROUP
OFF TREATMENT NOTICE
SWOG Patient ID
SWOG Study No. S
Registration Step
Physician
Institution / Affiliate
Off Treatment Reason
Treatment completed per protocol criteria
Medically required, due to toxicity, specify:
Patient refused, due to toxicity, specify:
Patient refused, other than toxicity, specify:
Progression or relapse.  Sites:
Death (submit Notice of Death form)
Other, specify:
Treatment Start Date
(If more room is needed, please continue on a separate page)
Off Treatment Date
Date of completion, progression, death or decision to discontinue therapy:
/
/
Will patient receive further treatment?
No
Yes, specify:
Unknown
Date of Last Contact (or death):
/
/
(select one):
Vital Status:
Alive
Dead (submit Notice of Death form)
All dates are MONTH, DAY, YEAR.  Explain any blank fields or blank dates in the Comments section.
Place an   X   in appropriate boxes.  Circle AMENDED items in red.
Treatment End Date
Regimen or Procedure or Site(s)
Systemic Therapy:
List regimens, start and end dates.  For multidrug regimens, do not list individual drugs separately;
end date would be the date all drugs in the regimen were discontinued.
Surgery:
List type of surgery, and in the "end date" column, the date of surgery.
Radiation:
List sites, start and end dates (inclusive of boosts and implants).
(L, F M)
Patient Initials
Instructions:
For each registration step, submit this form within 2 weeks after completion (or discontinuation) of
treatment.
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
Page 1 of 1
Participating Group:  Group Name/Study No./Patient ID
/
/
8756


SOUTHWEST ONCOLOGY GROUP
S0307 SUPPLEMENTARY OFF TREATMENT FORM
Page 1 of 1
Participating Group:  Group Name/Study No./Patient ID
/
/
Physician
Institution / Affiliate
Patient Initials
(L, F M)
SWOG Patient ID
SWOG Study No. S 0 3 0 7
Registration Step 1
Instructions:  Submit this form after completion of end-of-study bone scan.  If bone scan was not done, explain in Comments.  All
dates are MONTH, DAY, YEAR.  Explain any blank fields or blank dates in the Comments section.  Place an    X    in appropriate
boxes.  Circle AMENDED items in red and write AMENDED across top of form.
11/15/2005
BONE SCAN
Did the patient have a bone scan after completion or discontinuation of protocol therapy?
Yes
No
If yes, date of bone scan:
/
/
Is a bone metastasis present?
Yes
No
Note: After completion or discontinuation of protocol therapy, patient should also receive a dental check-up
and submit the Dental Examination Form.
Comments:
PATIENT PREFERENCE
If oral and intravenous bisphosphonates are equally effective in preventing breast cancer recurrence in the
bone, which would the patient prefer to receive?
Oral (taken daily)
Intravenous (by vein - given once a month for the first 6 months, and once every 3 months after)
(S0307SUPPOFF)
24801


9/1/2003
Comments:
SOUTHWEST ONCOLOGY GROUP
NOTICE OF DEATH
Autopsy?
No
Yes
Unknown
If cancer was the primary cause or if cancer possibly or definitely contributed to death, and the patient
had had multiple tumor types, specify those which were causes of death:
No
Primary Cause
Contributory
Possible
Unknown
Any cancer (select one):
CAUSES OF DEATH
(month / day / year)
Date of Death:
/
/
SWOG Patient ID
Most Recent SWOG Study No. S
Physician
Institution / Affiliate
(L, F M)
Patient Initials
Cancer of most recent SWOG study, specify cancer:
Cancer of other SWOG study, specify cancer:
Other cancer, specify:
If Primary Cause, Contributory or Possible, specify treatment and toxicity:
No
Primary Cause
Contributory
Possible
Unknown
Toxicity from disease related treatment (select one):
If Primary Cause, Contributory or Possible, specify:
No
Primary Cause
Contributory
Possible
Unknown
Non-cancer and non-treatment related causes (select one):
Source(s) of death information:
Autopsy report
Medical record / Death certificate
Physician
Relative or friend
Other, specify:
Instructions:  Answer all questions and explain any blank fields or blank dates in the Comments section.
Place an   X   in appropriate boxes.  Circle AMENDED items in red.
Participating Group:  Group Name/Study No./Patient ID
/
/
Page 1 of 1
49467


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


SOUTHWEST ONCOLOGY GROUP
DENTAL EXAMINATION FORM
Patient Initials
(L, F M)
11/15/2005
Page 2 of 2
OSTEONECROTIC JAW LESIONS
Associated factor(s):
Signature of examining dentist
date
Comments:
Site:
Size:
Date of onset:
/
/
Site:
Size:
Date of onset:
/
/
Periodontal infection
Dental extraction
Denture trauma
Other dental surgery
No identified factor
SWOG Patient ID
Time:
Prestudy
End of protocol treatment
SWOG Study No. S
Registration Step
30100


Participating Group:  Group Name/Study No./Patient ID
/
/
Physician
Institution / Affiliate
Patient Initials
(L, F M)
SWOG Patient ID
SOUTHWEST ONCOLOGY GROUP
OSTEONECROTIC JAW LESION FORM
Page 1 of 1
10/15/2004
Number of osteonecrotic lesions:
1
2
3
Any signs/symptoms of infection (e.g., mucosal erythema, swelling, pus, bad taste)?
Yes
No
Date of onset:
/
/
Comments:
Lesion 3:
Site of lesion (select all that apply):
Maxilla:
Mandible:
Anterior
Posterior
Buccal
Lingual
Alveolar ridge
Mylohyoid plate
Associated factor(s) (select all that apply):
Periodontal infection
Dental extraction
Denture trauma
Other dental surgery
No identified factor
Associated factor(s) (select all that apply):
Associated factor(s) (select all that apply):
STEROID USE
Did the patient receive steroids within 12 months of occurrence of the current jaw lesion(s)?
Yes
No
If Yes, agent name:
Agent begin date:
/
/
Agent end date:
/
/
SWOG Study No. S
Registration Step
Instructions:  Submit this form each time a new osteonecrotic lesion(s) is detected.  All dates are MONTH, DAY, YEAR.  Explain any
blank fields or blank dates in the Comments section.  Place an    X    in appropriate boxes.  Circle AMENDED items in red and write
AMENDED across top of form.
Date Form Completed:
/
/
Anterior
Maxilla:
Mandible:
Posterior
Buccal
Lingual
Alveolar ridge
Mylohyoid plate
Site of lesion (select all that apply):
Lesion 1:
Anterior
Posterior
Buccal
Lingual
Alveolar ridge
Palate
(OSTEOLES)
mm
Size of lesion:
Lesion 2:
Site of lesion (select all that apply):
Maxilla:
Mandible:
Anterior
Posterior
Buccal
Lingual
Alveolar ridge
Mylohyoid plate
Anterior
Posterior
Buccal
Lingual
Alveolar ridge
Palate
mm
Size of lesion:
Periodontal infection
Dental extraction
Denture trauma
Other dental surgery
No identified factor
Anterior
Posterior
Buccal
Lingual
Alveolar ridge
Palate
mm
Size of lesion:
Periodontal infection
Dental extraction
Denture trauma
Other dental surgery
No identified factor
52641


6/1/2008
 SOUTHWEST ONCOLOGY GROUP
S0307 SERUM CREATININE REPORTING FORM
Comments:
Registration Step 1
SWOG Study No. S 0 3 0 7
SWOG Patient ID
(L, F M)
Patient Initials
Page 1 of 1
(S0307CREAT)
Participating Group:  Group Name/Study No./Patient ID
/
/
Institution/Affiliate
Physician
Reporting Period:
0-6 months
6 mo-1 yr
1 yr-2 yr
2 yr-3 yr
Please report all serum creatinine values obtained during this reporting period, and date obtained.
CREATININE VALUES
1.
/
/
2.
/
/
3.
/
/
4.
/
/
Collection Date
Instructions:  Please complete this form at 6 months, 1 year, 2 years, and 3 years.  All dates are MONTH, DAY, YEAR.  Explain
any blank fields or blank dates in the Comments section.  Place an   X   in appropriate boxes.  Circle AMENDED items in red and write
AMENDED across the top of the form.
ULN
Serum Creatinine
mg/dL
.
mg/dL
.
mg/dL
.
mg/dL
.
mg/dL
.
mg/dL
.
mg/dL
.
mg/dL
.
8.
/
/
7.
/
/
mg/dL
.
mg/dL
.
mg/dL
.
mg/dL
.
6.
/
/
5.
/
/
mg/dL
.
mg/dL
.
mg/dL
.
mg/dL
.
60188


 
S0307 
 
Page 83 
 
Revised 6/12/06 
 
Revised 7/13/09 
 
Revised 1/21/10 
 
 
 
 
19.0 
APPENDIX 
 
19.1 
Cancer Trials Support Unit (CTSU) Participation Procedures 
 
19.2 
Determination of Expedited Adverse Event Reporting Requirements 
 
19.3 
Translational Medicine Study – Germ-line Single Nucleotide Polymorphisms in Farnesyl 
Diphosphate Sythase and the Adverse Event of Acute Phase Reactions 
 
19.4 
S0307 Statistical Analysis Plan 
 
 


 
S0307 
 
Page 84 
 
Revised 6/12/06 
 
Revised 1/25/07 
 
 
 
 
19.1 
Cancer Trials Support Unit (CTSU) Participation Procedures 
 
Registration/Randomization 
 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of the CTSU.  Each investigator must have an NCI investigator number and 
must maintain an 'active' investigator registration status through the annual submission of 
a complete investigator registration packet (FDA Form 1572 with original signature, 
current CV, Supplemental Investigator Data Form with signature, and Financial 
Disclosure Form with original signature) to the Pharmaceutical Management Branch, 
CTEP, DCTD, NCI.  These forms are available on the CTSU registered member website 
or by calling the PMB at 301/496-5725 Monday through Friday between 8:30 a.m. and 
4:30 p.m. EST. 
 
Each CTSU investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation to the 
CTSU Regulatory Office before they can enroll patients.  Study centers can check the 
status of their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU member web site at http://members.ctsu.org  
 
All forms and documents associated with this study can be downloaded from the S0307 
web page on the CTSU registered member Web site (https://members.ctsu.org).  
Patients can be registered only after pre-treatment evaluation is complete, all eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
 
 
Requirements for S0307 site registration: 
• 
CTSU IRB Certification 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet 
 
Prestudy requirements for patient enrollment on S0307: 
• 
Patient must meet all inclusion criteria, and no exclusion criteria should apply. 
• 
Patient has signed and dated all applicable consents and authorization forms. 
• 
All baseline laboratory tests and prestudy evaluations performed. 
• 
Patients who wish to participate in the tissue and serum submissions for banking as 
outlined in Sections 15.3 and 15.4 must consent to the procedures.  Written informed 
consent must be obtained prior to submitting samples. 
  
CTSU Procedures for Patient Enrollment 
 
1.   
Contact the CTSU Patient Registration Office by calling 1-888/462-3009. Leave a 
voicemail to alert the CTSU Patient Registrar that an enrollment is forthcoming.  
For immediate registration needs, e.g. within one hour, call the registrar cell 
phone at 301/704-2376. 
 
2.   
Complete the following forms: 
• 
CTSU Patient Enrollment Transmittal Form 
• 
Eligibility Criteria Checklist (Section 5.0 of the protocol) 
• 
SWOG Registration Form (Complete all sections of form except for SWOG-
specific data fields) 
 


Revised 6/12/06 
S0307 
Revised 1/25/07 
Page 85 
 
Amended 3/11/08 
 
 
 
 
3. 
Fax these forms to the CTSU Patient Registrar at 1-888-691-8039 between the 
hours of 9:00 a.m. and 5:30 p.m., Mon-Fri, Eastern Time (excluding holidays). 
The CTSU registrar will check the investigator and site information to ensure that 
all regulatory requirements have been met. The registrar will also check that 
forms are complete and follow-up with the site to resolve any discrepancies. 
 
4. 
Once investigator eligibility is confirmed and enrollment documents deemed 
complete, the CTSU registrar will contact the Southwest Oncology Group to 
obtain assignment of a treatment arm and assignment of a unique patient ID (to 
be used on all future forms and correspondence).  The CTSU registrar will 
convey this information to the enrolling site and follow up with a confirmation via 
e-mail or fax.  
 
Patients must begin study treatment within five working days of registration. 
 
Data Submission and Reconciliation 
 
1.  
All case report forms (CRFs) associated with this study must be downloaded 
from the S0307 web page located on the CTSU registered member website 
(https://members.ctsu.org). Sites must use the current form versions and adhere 
to the instructions and submission schedule outlined in the protocol.   
 
2.  
Submit all completed CRFs (with the exception of patient enrollment forms), 
clinical reports, and transmittals directly to the SWOG Data Operations Center. 
The preferred method of sending data is via fax at 800/892-4007, (large volumes 
of data may be sent via post, see contacts table for mailing address). Do NOT 
include a cover sheet for faxed data. 
 
3.  
The SWOG Data Operations Center will send query notices and delinquency 
reports directly to the site for reconciliation. Please fax query responses and 
delinquent data to the SWOG Data Operations Center and do not copy the 
CTSU Data Operations. When faxing data, include the query sheet that was 
originally sent from SWOG.  
 
4.  
Each site should have a designated CTSU Administrator and Data Administrator 
and must keep their CTEP AMS account contact information current. This 
will ensure timely communication between the clinical site and the SWOG data 
center.   
 
Special Materials or Substudies 
 
1. 
All specimens submitted for this study must be entered and tracked using the 
SWOG on-line Specimen Tracking System, as specified in protocol Section 
15.2c. 
 
2. 
You can also access the Tracking System from the CTSU Member Web Site. Go 
to the S0307 protocol page and click on the link provided under the Case Report 
Forms header. 
 
3. 
Specimen collection for correlative studies (see protocol Section 15.0) 
• 
Tissue banking:  Tissue blocks for banking should be submitted with 
patient’s consent.  Submit materials as specified in Section 15.3. 
• 
Serum banking:   Serum for banking should be submitted with patient’s 
consent.  Submit materials as specified in Section 15.4.   
 


 
S0307 
 
Page 86 
 
Revised 6/12/06 
 
Revised 1/25/07 
 
Amended 6/18/07 
 
Revised 3/28/14 
 
 
 
 
Serious Adverse (AE) Reporting (Section 16.0) 
 
1. 
CTSU sites must comply with the expectations of their local Institutional Review 
Board (IRB) regarding documentation and submission of adverse events.  Local 
IRBs must be informed of all reportable serious adverse reactions.  
 
2.  
CTSU sites will assess and report adverse events according to the guidelines 
and timelines specified in the protocol.  You may navigate to the CTEP Adverse 
Event Reporting System (CTEP-AERS) from either the Adverse Events tab of the 
CTSU member homepage (https://members.ctsu.org) or by selecting Adverse 
Event Reporting Forms from the document center drop down list on the S0307 
web page.  
 
3. 
Do not send adverse event reports to the CTSU. 
 
4. 
Secondary AML/MDS/ALL reporting:  Report occurrence of secondary AML, 
MDS, or ALL via the NCI/CTEP AML-MDS Report Form in lieu of CTEP-AERS. 
Submit the completed form and supporting documentation as outlined in the 
protocol. 
 
Drug Procurement (Section 3.0) 
 
Information on drug formulation, procurement, storage and accountability, administration, 
and potential toxicities are outlined in Section 3.0 of the protocol.   
 
Investigational 
agents: 
Clodronate 
(Bonefos®), 
Ibandronate 
(Ibandronic 
acid, 
Bonedronat®). 
 
Clodronate and ibandronate will be provided free of charge by Bayer Schering Pharma 
Oy and Roche, respectively.  Both drugs will be distributed by UVI, Inc. 
 
Commercial Agents: Zoledronic Acid (Zometa®) 
 
Zoledronic acid will be provided free of charge by Novartis and distributed by UVI, Inc. 
     
Regulatory and Monitoring 
 
Study Audit 
 
To assure compliance with Federal regulatory requirements [CFR 21 parts 50, 54, 56, 
312, 314 and HHS 45 CFR 46] and National Cancer Institute (NCI)/Cancer Therapy 
Evaluation Program (CTEP) Clinical Trials Monitoring Branch (CTMB) guidelines for the 
conduct of clinical trials and study data validity, all protocols approved by NCI/CTEP that 
have patient enrollment through the CTSU are subject to audit. 
 
Responsibility for assignment of the audit will be determined by the site’s primary 
affiliation with a Cooperative Group or CTSU. For Group-aligned sites, the audit of a 
patient registered through CTSU will become the responsibility of the Group receiving 
credit for the enrollment. For CTSU Independent Clinical Research Sites (CICRS), the 
CTSU will coordinate the entire audit process. 
 


 
S0307 
 
Page 86a 
 
Appended 1/25/07 
 
 
 
 
For patients enrolled through the CTSU, you may request the accrual be credited to any 
Group for which you have an affiliation provided that Group has an active clinical trials 
program for the primary disease type being addressed by the protocol. (e.g., NSABP 
members may only request credit for protocols pertaining to breast or colorectal cancers).  
Registrations to protocols for other disease sites may still take place through CTSU 
without receiving credit for your NSABP activities.  Per capita reimbursement will be 
issued directly from CTSU. 
 
Details on audit evaluation components, site selection, patient case selection, materials 
to be reviewed, site preparation, on-site procedures for review and assessment, and 
results reporting and follow-up are available for download from the CTSU Operations 
Manual located on the CTSU Member website. 
 
Health Insurance Portability and Accountability Act of 1996 (HIPAA) 
 
The HIPAA Privacy Rule establishes the conditions under which protected health 
information may be used or disclosed by covered entities for research purposes. 
Research is defined in the privacy rule referenced in HHS 45 CFR 164.501. Templated 
language addressing NCI-U.S. HIPAA guidelines are provided in the HIPAA 
Authorization Form located on the CTSU website.  
 
The HIPAA privacy rule does not affect participants from outside the United States. 
Authorization to release protected health information is NOT required from patients 
enrolled in clinical trials at non-U.S. sites. 
 
Clinical Data Update System (CDUS) Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. The 
sponsoring Group fulfills this reporting obligation by electronically transmitting to CTEP 
the CDUS data collected from the study-specific case report forms. 
 
 


 
S0307 
 
Page 87 
 
Revised 6/12/06 
 
 
 
 
 
19.2 
Determination of Expedited Adverse Event Reporting Requirements 
 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial. (Directions for routine reporting are 
provided in Section 14.0.) Additionally, certain adverse events must be reported in an 
expedited manner to allow for more timely monitoring of patient safety and care. 
Expedited adverse event reporting principles and general guidelines follow; specific 
guidelines for expedited adverse event reporting on this protocol are found in Section 
16.0. 
 
Reporting requirements may include the following considerations: 1) whether the patient 
has received an investigational or commercial agent; 2) the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy (attribution), and 
the prior experience (expectedness) of the adverse event; 3) the Phase (I, II, or III) of the 
trial; and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event.  
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Submission (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead 
from a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules 
apply. 
 
• 
Concurrent administration: When an investigational agent(s) is used in 
combination with a commercial agent(s), the combination is considered to be 
investigational and expedited reporting of adverse events would follow the 
guidelines for investigational agents. 
• 
Sequential administration: When a study includes an investigational agent(s) and 
a commercial agent(s) on the same study arm, but the commercial agent(s) is 
given for a period of time prior to starting the investigational agent(s), expedited 
reporting of adverse events that occur prior to starting the investigational 
agent(s) would follow the guidelines for commercial agents. Once therapy with 
the investigational agent(s) is initiated, all expedited reporting of adverse events 
should follow the investigational guidelines. 
 
Steps to determine if an adverse event is to be reported in an expedited manner 
 
Step 1: Identify the type of event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE). The CTCAE provides descriptive terminology and a grading 
scale for each adverse event listed. A copy of the CTCAE can be downloaded from the 
CTEP home page (http://ctep.cancer.gov). Additionally, if assistance is needed, the NCI 
has an Index to the CTCAE that provides help for classifying and locating terms. All 
appropriate treatment locations should have access to a copy of the CTCAE. 
 
Step 2: Grade the event using the NCI CTCAE version specified. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy 
(investigational or commercial). Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite. 


 
S0307 
 
Page 88 
 
Revised 6/12/06 
 
 
 
 
 
Step 4: Determine the prior experience of the adverse event. Expected events are those 
that have been previously identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in  
 
• 
the current NCI Agent-Specific Adverse Event List (for treatments using agents 
provided under an NCI-held IND); 
• 
the drug package insert (for treatments with commercial agents only); 
• 
Section 3.0 of this protocol. 
 
Step 5: Review Tables 16.1 and 16.2 in the protocol to determine if there are any 
protocol-specific requirements for expedited reporting of specific adverse events that 
require special monitoring.  
 
Step 6: Determine if the protocol treatment given prior to the adverse event included an 
investigational agent(s), a commercial agent(s), or a combination of investigational and 
commercial agents. 
 
NOTE: If the patient received at least one dose of investigational agent, follow the 
guidelines in Table 16.1. If no investigational agent was administered, follow the 
guidelines in Table 16.2. 
 
NOTE: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed possibly, probably, or definitely to the agent(s) must be reported according to 
the instructions above.  
 


 
S0307 
 
Page 89 
 
Revised 7/13/09 
 
 
 
 
 
19.3 
Translational Medicine Study – Germ-line Single Nucleotide Polymorphisms in Farnesyl 
Diphosphate Synthase and the Adverse Event of Acute Phase Reactions 
 
Primary study objective: 
• 
To 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 patients with early stage 
breast cancer who have been randomly assigned to one of three adjuvant 
bisphosphonates on clinical trial S0307. 
 
Secondary study objectives: 
• 
To investigate whether the association between inherited germ-line single 
nucleotide polymorphisms (SNPs) in farnesyl diphosphate synthase (FDPS) and 
the adverse event of acute phase reactions in patients with early stage breast 
cancer is specific to one of the three bisphosphonates under study in S0307, or 
is generic to the entire class of drugs or only to the nitrogen containing 
bisphosphonates. 
• To investigate whether there is an association between inherited germ-line single 
nucleotide polymorphisms in target SNPs and toxicities other than acute phase 
reactions as defined and collected in patients with early stage breast cancer 
within study in S0307. 
• To establish a well-annotated data base and germ line DNA specimen collection 
in patients with early stage breast cancer who have been randomly assigned to 
one 
of 
three 
adjuvant 
bisphosphonates 
on 
clinical 
trial 
S0307 
for 
pharmacogenomic investigations, either by a candidate gene approach or by 
genome-wide association studies (GWAS), of genes affecting bone metabolism, 
effects of bisphosphonate therapy and/or outcomes of cancer and its therapies. 
 
Brief justification: 
 
Pharmacogenomics.  Pharmacogenomics investigates the inherited variation in genes 
that dictate drug response and explores ways that these variations can be used to predict 
whether a patient will have a good response to a drug, a bad response to a drug, or 
perhaps, no response at all.  In the practice of medical oncology, it is common to treat 
many patients, when only a few actually derive distinct benefit from a specific drug 
therapy. The admixing of pharmacology, genetics and oncology offers the opportunity to 
practice individualized medicine.  
 
The Consortium on Breast Cancer Pharmacogenomics (COBRA) was established in 
2001 to study pharmacogenomics of breast cancer therapies.  COBRA, which is a funded 
consortium within the NIH Pharmacogenomic Research Network (PGRN), is led by Dr. 
David Flockhart at Indiana University, in collaboration with co-PI’s, Dr. Daniel F. Hayes at 
University of Michigan and Dr. Vered Stearns at the Sidney Kimmel Cancer Center at 
Johns Hopkins.  Recently, under the direction of Dr. Eric Winer, the Dana Farber Cancer 
Institute has also become a full member of COBRA. In addition, COBRA actively 
collaborates with other consortia within PGRN, specifically with the Mayo Clinic group. 
Thus, several cooperative groups (SWOG: University of Michigan; ECOG: Indiana, Johns 
Hopkins; CALGB: DFCI; NCCTG: Mayo) are represented within COBRA and are 
collaborators within PGRN.  Dr. Van Poznak, the study chair of this proposed 
amendment to S0307, is a member of COBRA through U. Michigan, and she is a chair 
for a study investigating bisphosphonate related genes within the consortium. 


 
S0307 
 
Page 90 
 
Revised 7/13/09 
 
 
 
 
 
 
COBRA and other investigators have demonstrated that inherited variations in candidate 
genes responsible for metabolism, distribution, and activity of tamoxifen may affect 
pharmacokinetics, non-tumor effects, and even cancer outcomes (Dezentje, 2009)   
COBRA is now prospectively addressing pharmacogenomics of the aromatase inhibitors 
(AI) and the anti-angiogenic agent, bevacizumab. In addition to the candidate gene 
approach, recent studies have demonstrated the ability to interrogate the entire genome 
for SNPs through genome wide analysis studies (GWAS). The technology to conduct 
these sorts of studies is advancing rapidly. Indeed, these technologies were reviewed in 
a recent summit convened by TBCI and PGRN in Bethesda in March, 2008 
(http://ctep.cancer.gov/resources/tbci/nci_summit_2008.html) to stimulate collaborations 
between the two groups, such as is proposed in this amendment.  
 
Bisphosphonates in Breast Cancer.  Bisphosphonates are firmly established treatment 
for patients with breast cancer metastases to bone, and several studies have suggested 
that these agents not only prevent AI-induced osteoporosis but that they may prevent 
bone metastases and even non-bone metastases and effect mortality. The impact of 
adjuvant bisphosphonate therapy on the risk of breast cancer recurrence is central to the 
objectives of S0307. However, not all patients who receive bisphosphonates are likely to 
obtain clinical benefit, and these agents are associated with modestly common, 
bothersome side effects (such as acute phase reactions) and occasional serious toxicity, 
such as osteonecrosis of the jaw and renal dysfunction. 
 
SWOG Protocol S0307.  S0307 is the ideal clinical trial to investigate genes that impact 
on the response to bisphosphonate therapy and breast cancer outcome. In S0307, 
patients with early stage breast cancer are randomized to receive one of three 
bisphosphontes as adjuvant therapy in an attempt to decrease the risk of breast cancer 
recurrence. The three bisphosphonates in S0307 are clodronate (non-nitrogen 
containing), ibandronate (nitrogen containing) and zoledronic acid (nitrogen containing 
and the highest potency bisphosphonate).  S0307 provides opportunity to examine genes 
affected by both nitrogen and non-nitrogen containing bisphosphonates.   
 
The objectives of S0307 include comparing disease free survival and overall survival 
between the study arms. S0307 compares the site of first recurrence between study 
treatments and assesses adverse events, markers of bone resorption (N-telopeptide) 
and parathyroid hormone related protein. In addition, serum and tumor tissue specimens 
are being collected in S0307 for future translational studies.  The well annotated data 
base generated in S0307 with clinical outcomes, adverse events and bone specific out 
come data provides the best environment to investigate genes (with a focus on genetic 
variability through SNPs analysis)  associate with bone metabolism and the effects of 
bisphosphonate therapy.  The multiple specimen types (serum, germline DNA, and tumor 
tissues) collected for this study will permit in depth translational investigations. 
 
Diagnostic utility of genetic biomarkers to direct bisphosphonates use in the 
adjuvant setting 
 
This study investigates potential genetic biomarkers to aid in predicting which patients 
may be at increased risk for acute phase reactions. In addition, the amendment to S0307 
will create a DNA resource for future study of questions as they pertain to breast cancer 
and its therapies. The impact that this amendment will have on patient care hinges on the 
outcome of the 2 completed, but not yet reported, adjuvant bisphosphonate studies 
(NSABP B-34 & AZURE) and the results of S0307. Although the clinically relevant 
anticancer affects of bisphosphonates have not yet been defined, it is known that 
zoledronic acid carries a 10-20% risk of a patient having a toxicity of moderate intensity, 
such as a fever and myalgias and arthralgias that may last for 1-7 days.  
 


 
S0307 
 
Page 91 
 
Revised 7/13/09 
 
 
 
 
 
 
The FDA alert of 1/7/2008 warned of a pain syndrome with bisphosphonate therapy. The 
FDA highlighted the “possibility of severe and sometimes incapacitating bone, joint, 
and/or muscle (musculoskeletal) pain in patients taking bisphosphonates. Although 
severe musculoskeletal pain is included in the prescribing information for all 
bisphosphonates, the association between bisphosphonates and severe musculoskeletal 
pain may be overlooked by healthcare professionals, delaying diagnosis, prolonging pain 
and/or impairment, and necessitating the use of analgesics.” 
 
The bisphosphonates, particularly the intravenous nitrogen containing bisphosphonates, 
are associated with acute phase reactions which are characterized by fever, chills, bone 
pain, myalgias and arthralgias. Acute phase reactions are unpleasant and can affect a 
patient’s therapeutic decisions. 
 
If the results of S0307 demonstrate efficacy for the adjuvant use of bisphosphonates, 
then the medical community may be administering drugs such as zoledronic acid to 
approximately 100-150,000 woman annually (over 200,000 women are diagnosed with 
breast cancer in the USA yearly, but probably not all will be candidates for adjuvant 
bisphosphonate therapy) and roughly 10,000-30,000 women (10-20% of those treated 
with bisphosphonate therapy) could be at risk for an acute phase reactions annually. The 
proposed amendment to S0307 seeks identify which individuals are at risk of acute 
phase reactions. This information could be used to improve counseling the patient on the 
associated, personalized, risks of bisphosphonate therapy, and/or to direct timing of 
bisphosphonate therapy to avoid treating at a time that could interfere with life events 
(work, social, etc) and, possibly, if the efficacy of the 3 bisphosphonates examined in 
S0307 are equal, the genetic data could be used to select one drug over another 
(nitrogen versus non-nitrogen containing bisphosphonate) based on predicted toxicity 
profiles. If such an acute phase reaction were predictable on an individualized basis, and 
if alternative therapies were available, then personalized medicine could be practiced. 
 
Genetic evaluation is commonly done in assessing oncology patients prior to exposure to 
irinotecan for toxicity, or for KRAS for efficacy. The resource developed within a S0307 
DNA bank could be used for future pharmacogenomic investigations that may include 
study of site specific relapse (bone versus viscera, versus both) or other cancer related 
outcomes. Simple genotyping could potentially aid in predicting response to therapy.   
 
The FDA Guidance for Industry has encouraged the submission of pharmacogenomic 
data with new drug applications, likely increasing the demand for both more efficient 
genotyping/phenotyping technologies and for clinical study sites with the technology, 
expertise, and experience to carry out such studies. The field of pharmacogenomics can 
be viewed as having multiple layers of complexity including, determining the role of 
genetics in drug response, screening and identifying genetic markers, validating genetic 
markers, clinical utility assessment and pharmacoeconomic impact (Huang 2009). 
 
In addition to study of bisphosphonate efficacy and toxicity, the DNA bank generated 
through the proposed amendment to S0307 could be used for future studies including the 
identification of genes that associate with risk of relapse and/or site specific risk of 
relapse (such as bone).  An example for identifying genes associated with site specific 
relapse:  Preclinical work has suggested that genes associated with metastases to bone 
include CXCR4, MMP1, CTGF, FGF5, IL-11, OPN (Kang 2003).  It is possible that a 
specific SNP in such a gene may predispose (or protect) bone metastases at a greater 
frequency. Data indicating that an individual is an increased risk for bone metastases 
may direct adjuvant drug selection to impact on that risk.  
 
 


 
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Bisphosphonate Pharmacogenomics.  All bisphosphonates are “hard drugs,” meaning 
that they are metabolically inert; bisphosphonates are excreted unchanged by the 
kidneys. Therefore, there is no role for pharmacogenomic studies of candidate genes of 
metabolism; however, there are targets that may have genetic variability in the pathways 
affected by the bisphosphonates. 
 
The nitrogen containing bisphosphonates (alendronate, ibandronate, risedronate and 
zoledronic acid) bind their target enzyme, farnesyl diphosphate synthase (FDPS) and 
inhibit protein prenylation, thereby preventing the prenylation of small GTPases, which 
are essential for osteoclast function. Hence, FDPS is an enzyme of importance to 
investigate as a mediator of nitrogen containing bisphosphonate activity.  
 
The gene encoding for FDPS is polymorphic and therefore this gene stands as a 
reasonable candidate for pharmacogenomic associations of activity of the nitrogen 
containing bisphosphonates.  Clodronate, a non-nitrogen containing bisphosphonate, 
inhibits osteoclast activity by interfering with ATP metabolism. Therefore, one would not 
hypothesize that polymorphisms in FDPS gene would be associated with activity or 
toxicity of clodronate.  The non-nitrogen containing bisphosphonates (such as clodronate 
and etidronate) are incorporated into non-hydrolyzable analogs of adenosine 
triphosphate (ATP) and are resistant to hydrolysis by the ATP dependant enzymes, 
These nonhyrolyable ATP analogs and their intracellular accumulation inhibit numerous 
intracellular metabolic enzymes thereby having a detrimental effect on cell function and 
lead to apoptosis. Thus, the contrast between and among the bisphosphonates is of 
interest in S0307, in which patients are randomly assigned to clodronate, ibandronate or 
zoledronic acid. 
 
Other candidate genes may be associated with activity of the bisphosphonates as a 
class, or with specific agents.  Emerging evidence from in vitro and in vivo preclinical 
studies in several tumor types suggests that nitrogen containing and non-nitrogen 
containing bisphosphonates can reduce tumor burden in bone and soft tissue, inhibit 
angiogenesis, prevent tumor cell invasion and adhesion in bone, and induce tumor cell 
apoptosis (Guise, Cancer Treatment Reviews 2008). The anti-angiogenic effect of 
bisphosphonates suggests that the VEGF pathway is another target to explore for SNPs 
in associate with the efficacy of adjuvant bisphosphonate therapy.  As noted, COBRA 
investigators have recently reported that SNPs within the VEGF pathway has 
demonstrated a relationship to outcomes and toxicity of bevacizumab treatment and 
similar investigations will be applied in queries to be performed in S0307. 
 
The primary objective of this proposal is to investigate whether there is an association 
between FDPS SNP rs2297480 and the adverse event of acute phase reactions in 
patients with early stage breast cancer who have been randomly assigned to one of three 
adjuvant bisphosphonates on clinical trial SWOG 0307. The secondary objectives of this 
study will investigate additional SNPs within FDPS, CYP2C8, and the VEGF pathway as 
they associate with the efficacy and toxicity of the 3 adjuvant bisphosphonate therapies 
administered in S0307.  
 
Primary Objective and SNP rs2297480 The literature indicates that the FDPS SNP 
rs2297480 is biologically relevant; hence this SNP serves as the primary gene of interest.   
 
The Adenosine (A)/Cytosine (C) polymorphisms in FDPS SNP rs2297480 was 
investigated for modulation of response to nitrogen containing bisphosphonate treatment 
(alendronate or ibandronate) in postmenopausal Danish women with osteoporosis 
(Marini Curr Med Res Opin 2008).  In this study, baseline bone mineral density in the 
spine and femur did not show any relationship with FDPS polymorphisms. At 2 years of 
treatment with nitrogen containing bisphosphonate there were similar findings in the AA 
and AC genotypes; while the CC genotype demonstrated a lower BMD response (p=0.60 
at the spine and p=0.59 at the femur). At 2 years of nitrogen containing bisphosphonate  
 


 
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therapy there was a statistically significant difference (p<0.05) in the urinary markers of 
bone metabolism in the CC genotype which showed decreased response of bone of 
bone turnover markers to nitrogen containing bisphosphonate therapy.  This data 
suggests that FDPS, the target enzyme of the nitrogen containing bisphosphonates, may 
contain SNPs that affect response to nitrogen containing bisphosphonate therapy.  
 
In a separate study investigating SNPs in FDPS in community dwelling Caucasian 
women age 65 or older, the same SNP, rs2297480, was found to show that CC or CA 
genotypes were associated with a lower bone mineral density (Levy Maturitas 2007).  
Interestingly, the “parent” study (Greenspan JAMA 2003) from which the patients were 
genotyped, included randomization to hormonal replacement therapy with or without 
alendronate (a nitrogen containing bisphosphonate), yet the SNP paper (Levy Maturitas 
2007) does not identify whether or not study genotyped patients had been exposed to 
nitrogen containing bisphosphonate therapy. Therefore, this report does not permit direct 
comparisons to that of the Marini et al, although both studies suggest that the CC allele 
confers a diminished response to nitrogen containing bisphosphonates.  
 
The proposal submitted here to investigate rs2297480 within S0307 will build upon these 
findings and will investigate additional SNPs and pathways that may be predictive of 
response (efficacy and/or toxicity) to bisphosphonate therapy. This data may be 
applicable to patients receiving bisphosphonate therapy for breast cancer risk reduction 
but may also lend itself to the broader public health concern of osteoporosis and its 
therapies.   
 
Primary Outcome to be assessed: Acute Phase Reactions: The nitrogen containing 
bisphosphonates are associated with acute phase reactions with the associated fever, 
chills, bone pain, myalgias and arthralgias and may occur with oral or intravenous 
bisphosphonate therapy. Fever has been reported in 9–44% of patients receiving 
intravenous nitrogen containing bisphosphonates. Typically occurring within 48 hours of 
infusion, fever is usually low-grade, though occasionally associated with rigors. 
Accompanying bone pain has also been reported in over half of the patients and the 
reactions typically are self-limited and resolve completely within 24-48 hours although 
patients may experience significant discomfort during this time. Most often the acute 
phase reaction occurs with the initial dosing of the intravenous nitrogen containing 
bisphosphonates and typically does not occur or is less severe with subsequent doses. 
Presently there is no mechanism to predict which patients may experience this toxicity.  
 
In a clinical trial investigating bone health in postmenopausal women comparing orally 
administered nitrogen containing bisphosphonates (alendronate and ibandronate), the 
acute phase reaction symptoms were higher with ibandronate (6.8%) that with 
alendronate (3.0%) (Miller, Curr Med Res Op 2008). Of note, this study of 
postmenopausal women with osteoporosis used a lower dose of ibandronate (150 mg 
orally monthly) then S0307 uses (50mg orally daily). The frequency of acute phase 
reactions may vary with the different dosing regimens and the disease process being 
treated.  Data investigating the ibandronate dosed at 50mg daily for metastatic bone 
disease suggests that the acute phase reaction occurs in 2% of patients while zoledronic 
acid dosed at 4mg intravenously is associated with 26-27% of patients experiencing an 
acute phase reaction (Devitt Ther Clin Risk Mang 2008). The differences between rates 
of acute phase reactions may be attributed to the different biochemical structure of each 
of the bisphosphonates. Of note, not all patients experience the acute phase reaction, 
suggesting the possibility that this outcome may related to a genetic variable such as 
variability within the binding pocket of FDPS. 


 
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Acute-Phase Reactions Reported Within 14 Days of the First and Second Infusion in 
Patients with Breast Cancer or Multiple Myeloma 
 
Zoledronic acid 4 mg 
Infusion 
First 
Second 
Patients treated, n 
563 
542 
Arthralgia, n (%) 
18 (3.2) 
10 (1.8) 
Bone pain, n (%) 
85 (15.1) 
55 (10.1) 
Fever, n (%) 
65 (11.5) 
24 (4.4) 
Myalgia, n (%) 
16 (2.8) 
20 (3.7) 
http://www.medscape.com/content/2003/00/46/23/462348/462348_tab.html 
 
S0307 captures the adverse events (symptoms and grading of symptoms) associated 
with each of the three bisphosphonates, clodronate, ibandronate and zoledronic acid and 
provides the ideal study design to test the hypothesis that SNPS within FDPS correlate 
with toxicity. 
  
Patients with significant toxicities are of interest to this pharmacogenomic study. 
However, it is possible that patients who had enrolled on S0307 earlier and experienced 
a significant acute phase reaction (or other adverse event or outcome) may not be 
available now to donate circulating leukocytes for DNA studies. To address this, 
consideration will be given to assessing paraffin embedded tissues from these individuals 
for analysis, should appropriate consents be in place and tissue be available from that 
individual. S0307 includes collection of paraffin embedded tumor tissue and there is an 
evolving body of data demonstrating that many SNPs are concordant between germline 
DNA of leukocytes and that of somatic tumor tissue. A study ongoing at the University of 
Michigan (PI: C. Van Poznak) is investigating concordance of FDPS, VEGF and other 
bisphosphonate related genes within circulating leukocytes and paraffin embedded 
tissues. Since cancers contain a variety of mutations, circulating leukocytes remain a 
standard tissue for germline assessments, unless study SNP concordance has been 
shown with somatic tissue.  
 
The adverse events to be used within this proposed analysis include: fever, flu like 
syndrome, musculoskeletal pain (back, bone, joint, limb, muscle) and pain (other). These 
will be pooled as a conglomerate “acute phase reaction” and patient may have multiple 
symptoms such as fever and bone pain.  
 


 
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Reporting of these adverse events in S0307, as of August 28, 2008, has demonstrated 
the following findings (collapsed over treatment assignment): 
 
 
Grade of adverse event 
Adverse Event 
≤ 1 
2 
3 
4 
5 
Fever 
881 
1 
1 
0 
0 
Flu like syndrome 
881 
2 
0 
0 
0 
Musculo Pain: Back 
877 
5 
1 
0 
0 
Musculo Pain: bone 
846 
20 
17 
0 
0 
Musculo Pain: joint 
833 
37 
13 
0 
0 
Musculo Pain: limb 
877 
5 
1 
0 
0 
Musculo Pain: muscle 
871 
6 
6 
0 
0 
Pain Other 
880 
2 
1 
0 
0 
 
Since a patient can have multiple toxicities we computed the percentage having any of 
these toxicities.  Twelve percent had a toxicity of Grade 2 or higher and 3% had a Grade 
3 toxicity. These are limited to toxicities possibly, probably, or definitely related to 
bisphosphonate treatment. 
 
Study Target Genes: The study genes (and SNPs) have been identified from the 
literature and through Cancer Genome Anatomy Project, HapMap and National Center 
for Biotechnology Information. The lead study SNP FDPS rs2297480 and the lead 
outcome measures are outlined here.  
 
The Primary Study Objective is to assess SNP FDPS rs 2297480 for association with 
acute phase reactions. The Secondary Objectives include assessing additional SNPs in 
SNP FDPS as well as other pathways, including VEGF, that may be critical to the 
efficacy, or toxicity, of bisphosphonate therapy.  
 
Based on the present literature, additional genes of interest include those outlined in the 
below table and illustrating the frequency of SNP identification in the northern and 
western European population identified by HAPMAP. Allelic frequencies in other 
populations are not illustrated here to conserve space, but are available through the 
National Center for Biotechnology Information http://www.ncbi.nlm.nih.gov. When the 
frequency is low or unknown, the analysis will be exploratory. 


 
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Genes 
SNP rs number   
Allele Frequency 
In European populations 
identified by HAPMAP 
FDPS -1 (SNP of Primary 
Objective)  
rs2297480 
A:0.692; C: 0.308 
FDPS - 2 
rs11264359 
A: 0.683; G: 0.317 
FDPS -3 
rs11264361 
T: 0.692; G: 0.308 
CYP2C8 - 1 
rs1934951 
A: 0.192; G 0.808 
CYP2C8 - 2 
rs1934980 
C: 0.208; T:0.792 
CYP2C8 - 3 
rs1341162 
A: 0.195 G:0.805 
CYP2C8 – 4  
rs17110453 
A: 0.891; C: 0.119 
VEGF – 1: 1498 
rs 833061 
C: 0.420; T: 0.580 
VEGF -2:  1154 
rs 1570360 
G > A: unknown 
VEGF -3: 2578 
rs 699947 
A: 0.408; C: 0.592 
VEGF - 4:  634 
rs 2010963 
G: 0.800; C:0.200 
VEGF -5: 936 
rs 3025039 
C: 0.886; T: 0.114 
 
The well annotated DNA specimen resource generated will provide materials 
investigation of additional genes and outcomes as well as serve as a resource for 
Genome-Wide Association Studies (GWAS). The use of GWAS may permit study of 
genetic variation across the entire human genome to identify genetic associations with 
observable traits or the presence or absence of a disease or condition. Whole genome 
information, when combined with clinical and other phenotype data, offers the potential 
for increased understanding of basic biological processes affecting human health, 
improvement in the prediction of disease and patient care, and ultimately the realization 
of the promise of personalized medicine. Details GWAS investigations within this 
resource will be proposed under separate cover at a future date. 
 
Genotyping Analysis for specific SNP assessment: The DNA will be extracted from 
circulating leukocytes at the SWOG Solid Tumor Tissue Bank in Colorado. An aliquot of 
DNA will be sent to the Rae laboratory at the University of Michigan for genetic analysis 
as outlined here. The SNPs to be investigated will be detected using Taqman® Allelic 
Discrimination Assay (Foster City, CA). DNA samples will be assayed for SNPs in our 
candidate genes. Briefly, a 2ul DNA sample will be added to a 25ul reaction containing 
forward and reverse primers along with 2 allele specific labeled probes (one wild-type 
and one variant allele specific). The PCR and fluorescence measurements will be 
performed using the ABI Prism 7700 sequence detection system. Since the genotyping 
field is rapidly evolving, the best approach available will be employed, and this may 
change over time. If a polymorphisms cannot be reliably genotyped using the Taqman 
Allelic Discrimination, then an alternative method(s) such allele specific PCR and 
restriction fragment length polymorphisms PCR (RFLP-PCR will be used.  
 
 


 
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Circulating Leukocytes: As per published methods (Rae 2003) (Miller 1988) the buffy 
coat will be created from the whole blood collected and DNA will be extracted using 
Qiagen DNeasy Tissue kit and the QIAamp DNA Blood Midi kit (Quiagen Inc, Valencia 
CA) according to manufacturer’s instructions. The DNA yield will be assessed by 
spectrophotometery (Beckman DU 640, Beckman Coulter, Fullerton CA). 
 
Management of the specimens and study assays are to be performed by leaders in the 
pharmacogenomic translational science field. 
 
The research team has experience with pharmacogenomics within Intergroups and 
COBRA.  Data generated through SWOG and Gynocologic Oncology Group related 
pharmacogenomic research performed by Dr. Ambrosone (Kuptsova Blood 2007) (Krivak 
JCO 2008) and Dr. Hayes through the NIH Pharmacogenetic Research Network (PGRN) 
and the Consortium on Breast Cancer Pharmacogentics (COBRA) (Jin JCO 2008) has 
demonstrated the viability of patient directed therapies and of individualized medicine. 
The PI of this proposed amendment (Van Poznak) has experience investigating 
biomarkers in breast cancer and bone including study of correlation between breast 
tumor estrogen receptor status and bone mineral density (BMD), effect of breast cancer 
therapy on BMD and markers of bone metabolism, toxicities of bisphosphonates (renal 
and osteonecrosis of the jaw), genes associated with site specific metastases in 
preclinical studies, and biomarkers associated with taxane sensitivity. Dr. Van Poznak is 
presently conducting a clinical study investigating concordance of FDPS and VEFG 
genes across a variety of tissues.  Drs Van Poznak and Gralow are lead investigators of 
SWOG S0702, “A Prospective Observational Multicenter Cohort Study to Assess the 
Incidence of Osteonecrosis of the Jaw (ONJ) in Cancer Patients with Bone Metastases 
Starting Zoledronic Acid Treatment.”  S0702 banks serum and DNA for study of the 
effects of bisphosphonate therapy on the risk of ONJ. It is likely that the 
pharmacogenomic generated within S0307 and S0702 will complement each other and 
permit genomic validation of biologically important pathways.   
 
Statistical Plan: 
 
This translational study seeks to collect circulating leukocytes from as many, if not all 
patients, enrolled on S0307 to build a well annotated DNA bank for present and future 
investigations relating to bisphosphonate therapy and cancer outcomes, as well as other 
potential pharmacogenomic questions.  As of May 1 there were 3,425 of the 4,500 
patients accrued to S0307, with an accrual rate of approximately 293 patients within the 
last month. If 60-70% of enrolled patients donate DNA, then approximately 3000 patients 
will participate in this amendment, with an estimated 1000 patients per bisphosphonate 
arm (clodronate, ibandronate, zoledronic acid). There is some possibility that the accrual 
goal will be increased back to the original goal of 6,000 patients since the rapid accrual is 
shortening the overall follow-up period and therefore fewer events would be observed.  
That proposed amendment is currently under review by CTEP. 
 
The power to investigate SNP FDPS rs2297480 and acute phase reactions within S0307 
is outlined below. The specific sample size required for each SNP investigation is not 
presented here, as the study SNPs may evolve over time. 


 
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Primary Objective: 
To investigate whether there is an association between inherited germ-line SNP FDPS 
rs2297480 and acute phase reactions in patients with early stage breast cancer who 
have been randomly assigned to one of three adjuvant bisphosphonates on clinical trial 
SWOG 0307.  
 
FDPS SNP rs number   
Allele Frequency 
rs2297480 
A:0.692; C: 0.308 
 
We assume that the overall rate of an acute phase reaction Grade 2 or higher for the 
entire class of bisphosphonates is 12% based on the current data. We would like to 
detect a 5% absolute difference in acute phase reactions due to SNP effects.  The 5% is 
large enough to be a clinically meaningful difference.  To detect such a difference with 
90% power (2-sided α = 0.05) we would need 2,272 samples.  That is, the minor allele 
(C) would have a toxicity rate of 15.4% and the major allele (A) a rate of 10.4% (5% 
difference; 12% overall rate).  If we are able to obtain the expected 3,000 patients, then 
the power increases to 96%.  That sample size would allow us to detect a 4.4 % 
difference or larger between the minor and major alleles with 90% power.    The analysis 
would use logistic regression on the outcome (acute phase reaction) by allele type 
stratified by treatment type.  Additive, dominant, and recessive models will be considered 
for the three genotypes as well. The additive model uses (0,1,2) coding for AA, AC, and 
CC, respectively.  The dominant model uses coding (0,1,1) and the recessive model 
(0,0,1). 
 
Secondary Objectives: 
The proposed amendment will investigate whether the study SNP FPDS rs2297480 and 
acute phase reactions associate together specifically in the setting of one 
bisphosphonate or the nitrogen containing bisphosphonates or appears generic to the 
class of drugs. 
If we wish to detect a difference in acute phase reactions within each drug (n=1000), then 
with 90% power using a 2-sided α = 0.05, we could detect a 7.8% difference (17.4% 
versus 9.6%) between the minor and major alleles.   To demonstrate that the acute 
phase reaction rate depends on which drug, we would look for an interaction between 
treatment and allele type.  Suppose that one treatment shows no effect of allele type 
(12% for both major and minor alleles), but that the other treatment shows a 10.2% 
difference (19.1% versus 8.9%), then we would have 90% power to detect that 
interaction.  The analysis would use logistic regression on the outcome (acute phase 
reaction) by allele type, treatment type, and their interaction. 
The proposed amendment will investigate the association of SNPs in FDPS with other 
toxicities and outcomes as collected within S0307.  This sample size is determined by the 
sample size of the primary question, since the same DNA is being used.  Power would 
increase with events higher than 12%, but would decrease with more rare toxicities.  We 
are also interested in exploratory analysis of other Snip’s shown below.  For these we set 
a 2-sided α = 0.005 to guard against spurious findings due to multiple comparisons.  The 
power to detect a 6% difference is given below as well as the detectable difference at 
90% power keeping the overall event rate at 12% and accounting for the differences in 
allele frequencies is the following. 


 
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Genes 
SNP 
rs number 
Allele Frequency 
In European populations 
identified by HAPMAP 
Power to Detect a 
6% Change 
Detectable 
Difference 
FDPS - 2 
rs11264359 
A: 0.683; G: 0.317 
96% 
5.5% 
FDPS -3 
rs11264361 
T: 0.692; G: 0.308 
95% 
5.5% 
CYP2C8 - 1 
rs1934951 
A: 0.192; G 0.808 
84% 
6.8% 
CYP2C8 - 2 
rs1934980 
C: 0.208; T:0.792 
86% 
6.6% 
CYP2C8 - 3 
rs1341162 
A: 0.195 G:0.805 
84% 
6.8% 
CYP2C8 – 
4 
rs17110453 
A: 0.891; C: 0.119 
58% 
8.5% 
VEGF – 1: 
1498 
rs 833061 
C: 0.420; T: 0.580 
98% 
5.1% 
VEGF -2:  
1154 
rs 1570360 
G > A: unknown 
Depends on 
frequencies 
Depends on 
frequencies 
VEGF -3: 
2578 
rs 699947 
A: 0.408; C: 0.592 
97% 
5.1% 
VEGF - 4:  
634 
rs 2010963 
G: 0.800; C:0.200 
85% 
6.5% 
VEGF -5: 
936 
rs 3025039 
C: 0.886; T: 0.114 
61% 
8.3% 
 
We will establish a well annotated data base and germline DNA specimen collection for 
future studies involving candidate gene investigation or GWAS for correlation with bone 
metabolism, effects of bisphosphonate therapy and/or cancer and its therapies.  


 
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19.4 
S0307 Statistical Analysis Plan 
 
Overview 
S0307 compares three bisphosphonate agents, none of which constitute standard of 
care at the current time.  Clodronate is currently being tested against placebo in the 
NSABP B-34 trial, but no results are available.  The other two agents, ibandronate and 
zoledronic acid, are higher potency bisphosphonates, but efficacy compared to 
clodronate is unknown. Consequently, we consider a comparison of all three agents with 
no one agent presumed to be inferior or superior a priori. Therefore, all statistical 
comparisons are 2-sided. 
 
We will compare all three agents simultaneously to determine if there is a significant 
difference among the three agents (called the omnibus or global test).  If the omnibus test 
shows a significant overall effect at level α, then we will proceed with three pairwise 
comparisons, each at level α (Liu and Dahlberg, 1995).  This conditional sequence is 
more powerful than using a Bonferroni procedure testing each pairwise comparison at 
α/3 without the preliminary overall test.  Alpha is determined by the timing of the analysis 
(e.g. interim analysis or final). 
 
Endpoints 
The primary endpoint is invasive disease-free survival (DFS). This is the time from 
registration (randomization) to death by any cause, local, regional or distant recurrence, 
or a new breast primary whichever comes first.  In situ disease is not counted as a 
recurrence.  Patients not having an event are censored at the last follow-up visit.  The 
primary secondary outcomes are overall survival and toxicity.  Overall survival is time 
from registration to death by any cause.  Site of first metastases is a secondary endpoint 
of interest since bisphosphonates should prevent metastases to bone. 
 
Stratification 
Due to the large sample size, randomization was not stratified by any prognostic factors.  
Time of randomization will be a stratifying variable in the analysis as described below.  
 
Interim analysis 
Interim analysis begins when approximately 31% of the expected failures are recorded.  
This should occur early in 2011.  Annual interim analyses are performed thereafter.  
Decision making following a significant interim analysis is described in the protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Accrual goal 
This trial has a complex history with regard to the accrual goal.  The trial was designed to 
include 6,000 patients with 2,000 per arm.  Accrual was expected to be 125 per month.  
After the trial was activated, accrual was very slow.  This was possibly due to reports of 
osteonecrosis associated with bisphosphonates, particularly zoledronic acid. After one 
year, NCI clinical trial guidelines require amendment of the sample size goals such that 
projected monthly accrual is consistent with actual accrual.  The trial was amended to 
accrue 62.5 patients per month, consistent with the observed accrual at that time.  The 
Year 
Analysis 
Percent of 
Events 
Alpha Level  
for Test  
Cumulative 
probability 
4 
Interim 1 
31% 
0.0010 
0.0010 
5 
Interim 2 
46% 
0.0012 
0.0022 
6 
Interim 3 
60% 
0.0068 
0.0077 
7 
Interim 4 
74% 
.0158 
0.0158 
8 
Interim 5 
87% 
.0265 
0.0265 
9 
Final 
100% 
.0391 
0.0500 


 
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sample size goal was lowered to 4,500 based on the slower accrual and hence longer 
median follow-up time.  The same effect sizes were used so only accrual and follow-up 
time considerations were changed. After the change in sample size goals, the 
pharmaceutical manufacturer of ibandronate revised the contract to provide support for a 
total of 1,500 patients instead of 2,000.  The other two contracts remained at 2,000 
patients.    
 
Immediately after the amendment to change the accrual goal, accrual picked up 
dramatically. It was further accelerated by a report at ASCO in June 2008 of the benefit 
of zoledronic acid found in another trial (ABCSG-12).  By early 2009 accrual had reached 
300 patients per month.  It became clear that the accrual goal of 4,500 patients would be 
met two years early and thus median follow-up time would be too short.  We submitted a 
new amendment to increase the total accrual goal to 5,400 patients. This would restore 
the accrual goal to 2,000 per arm for zoledronic acid and clodronate, but limit accrual to 
only 1,400 patients for ibandronate.  Ibandronate was no longer going to be marketed in 
the U.S. market for this indication and the manufacturer did not want to increase its level 
of support.  The amendment was approved July 23, 2009. 
 
At the end of July 2009, SWOG announced that the trial would close temporarily on 
August 24, 2009 due to a change in design.  The change in accrual would require a 
change in the random allocation to treatment since the informed consent specified equal 
allocation to the three arms and thus any change in random allocation would require a 
revised informed consent.  It was necessary to close the trial so that sites could update 
their IRB approval before they would be allowed to open the trial again.  The pending 
closure sparked increased demand such that 488 patients were registered in a 3-week 
period corresponding to a rate of 600/month. By the time the trial closed temporarily on 
8/24/09 there were 4,747 patients with 1,567 allocated to ibandronate. This exceeded the 
goal in this arm by 167 patients. The trial was designated to re-open on September 1, 
2009 with only two arms since the ibandronate arm was complete. All institutions had to 
renew IRB approval before being allowed to register patients again.  Accrual has started 
to reach its former levels, reaching 256 patients in December 2009.  In order to obtain 
2,000 patients in the two remaining arms, the total accrual will be approximately 5,600 
since the ibandronate arm was overaccrued.  At the current rate this should occur very 
early in 2010.  Accrual to the trial will close on February 1, 2010.  The change in the 
randomization allocation has an impact on the analysis plan as described below. 
 


 
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0
50 100 150 200 250 300 350 400 450 500
Accrual per month
Jan06
Jul06
Jan07
Jul07
Jan08
Jul08
Jan09
Jul09
Jan10
Calendar Month
Monthly accrual
Original monthly accrual goal (125)
Revised monthly accrual goal (62.5)
August 2009 accrual before temporary closure
S0307 Monthly Accrual Rate
 
Power 
While the accrual rates and total accrual goals have changed, the underlying expected 
effect sizes have been held constant for the duration of the trial.  It was assumed that all 
pairwise comparisons were of equal interest and would be 2-sided. For the purpose of 
power calculations, clodronate was assumed to have the lowest expected DFS of 80% at 
five years.  The best treatment was expected to have a 5-year DFS of approximately 
83.4% or a hazard ratio of 1.25 for clodronate versus the best treatment. The 
intermediate treatment would have a HR between 1.25 to 1.00 when clodronate is 
compared to it. Power is a function of the actual location of this intermediate treatment 
and ranges from 78% to 93% for the omnibus test for the 5,400 sample size.  Power is 
the lowest if the intermediate treatment is exactly in the middle of the two extremes and 
highest when the intermediate treatment is closer to one of the extremes. Power for the 
pairwise comparison of clodronate versus zoledronic acid ranges from 85% to 89% if 
HR=1.25. Power for ibandronate versus the other two agents individually is 77-85% for a 
HR=1.25 due to the smaller sample size.  Power for the pairwise comparisons includes 
conditioning on a significant overall omnibus test.  Power calculations were also 
computed for the Bonferroni approach which showed lower power than the chosen 
approach. 
 
When the accrual goals and rates were changed officially, power in the range 80%-90% 
was maintained in most likely scenarios by changing the accrual goal to fit the actual 
expected accrual rate. In the last revision of the accrual goal, the change in accrual by 
month was incorporated into the power calculations (i.e. uniform accrual was not 
assumed). Actual outcome rates in the trial were never used to make changes in the 
accrual goals.  Power was always based on the same effect treatment effects as used in 
the initial trial design.        
 


 
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Analysis 
The primary analysis of DFS is a comparison of all three groups using a log-rank test 
performed at level α. If significant, this would be followed by three pairwise comparisons 
also performed at level α.  The change in randomization probabilities must be considered 
as well since it could affect the results if not accommodated in the analysis.  Suppose 
that over the course of the trial that overall DFS actually increased due to better adjuvant 
treatment, but that the hazard ratios linking the three groups were fixed over the duration 
of the study.  Assuming that the treatment hazard ratios are constant over the study 
duration is the usual assumption in any randomized trial.  However, there could still be 
“temporal drift” in absolute survival over time that affects all three groups equally.  This 
drift poses no problem for the analysis if the randomization allocation does not change 
over time since all three groups are affected in the same way.  However, in this case the 
allocation probabilities were changed since the ibandronate group was closed in August 
2009.  This change needs to be accommodated in the analysis.  Even if the ibandronate 
group was not closed, but had a highly reduced allocation probability (e.g. from 33.3% to 
1%) that change must be considered in the analysis as shown below. 
 
Let s=1, 2 where s=1 is the period of equal randomization to three groups (up to 8/09) 
and s=2 is the period of changed allocation. In this study it is randomization to the two 
groups in equal allocation from 9/09 on.  However, it could be any dramatic change in 
randomization (e.g. metering ibandronate to 1% so that there is still randomization to 
three groups over the course of the trial).  Our underlying model for the hazard rate is the 
following: 
 
1
2
0
( ;
)
( )
zoledronic
ibandronate
s
s
t trt
t e
β
β
λ
λ
+
=
  
(1) 
where 
0 ( )
s t
λ
is the baseline hazard rate for clodronate in randomization period 1 or 2.   
The baseline hazard rates for the two periods need not be the same since temporal drift 
may have occurred.  Because of the stratification, patients are compared only within their 
own stratum, i.e. during the same contemporaneous randomization period. In stratum 2, 
there are no patients randomized to ibandronate so there is no contribution to the 
estimate of β2 in that period.  We do assume that the hazard ratio of zoledronic acid to 
clodronate is the same in both periods.  This can be seen in the more general model: 
 
1
2
3 (
1)*
0
( ;
)
( )
zoledronic
ibandronate
s
zoledronic
s
s
t trt
t e
β
β
β
λ
λ
+
+
−
=
(2) 
where β3 would represent a change in the HR between zoledronic acid and clodronate 
from the first randomization period to the next. In fact, the estimates β1  and β2 in model 
(2) exactly correspond mathematically to what would be obtained by excluding all 
patients randomized after the change in randomization to two arms. Therefore, model (2) 
is very inefficient since it assumes a change in HR.  Model (1) represents the usual 
assumptions in randomized trials about constant treatment hazard ratios during the 
conduct of the trial, but allows the baseline hazard to change by randomization period. 
Furthermore, contemporaneous randomization is retained since patients are compared 
only within their own stratum.  
 
The omnibus test corresponds to a joint test of 
1
2
0
β
β
=
=
 from Model (1).  The 
stratified log-rank test is the score test corresponding to the test of this hypothesis.  If that 
test is significant, than we proceed with pairwise comparisons.  For the pairwise 
comparisons, only the comparison of zoledronic acid to clodronate is based on both 
randomization periods.  Essentially, it is the test of 
1
0
β
=
 from Model (1).  The pairwise 
comparisons of ibandronate to (1) clodronate and (2) zoledronic acid will be based only 
on period 1.  These tests are mathematically equivalent to testing (1) 
2
0
β
=
 and (2) 


 
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(
)
2
1
0
β
β
−
=
 in Model (2). There is a slight loss of power in the pairwise comparisons 
involving ibandronate since only data from the first time period are used. Thus, all 
pairwise comparisons are performed in contemporaneous periods, while the omnibus 
test is based on the stratified model (1). 
 
In the absence of temporal drift, stratification is not strictly necessary, but accounting for 
it causes little loss in power.  If there is temporal drift, then failure to account for it could 
lead to bias when changing allocation probabilities.  Simulation for extreme drift in DFS 
over time shows that alpha is inflated to 7% under the null hypothesis when stratification 
is not used. Even if the third group is “metered” (randomization for ibandronate continues 
at a low level), there is still inflation of alpha in the presence of temporal drift.  This is due 
to imbalance in projected outcomes since patients have different projections over time. 
Thus, any change in randomization allocation must be addressed in the analysis.  Our 
simulation shows that alpha is correctly maintained by stratification in the presence of 
temporal drift.  
 
With regard to power, maximal power is obtained using stratified model (1) above for the 
omnibus test.  Power is 85% to 92% depending on the distribution of the three groups. 
Pairwise comparisons range in power from 83% to 90% for the two extreme groups. 
These estimates are based on an expected final sample size of 5,600. 
 
Therefore, the primary analysis will be based on Model (1) to obtain the significance of 
the overall comparison and the pairwise comparison of zoledronic acid to clodronate.  
The two remaining pairwise comparisons (ibandronate vs. clodronate and ibandronate 
vs. zoledronic acid) are based on the first time period only when there was randomization 
to ibandronate. 
 
Secondary comparisons will include adjustment for prognostic factors such as HER2 
status, AJCC stage, and hormone-receptor status.  Subgroup analysis will include 
determination of the hazard ratios (compared to clodronate) separately by age group, 
race, Her2 status, hormone-receptor status, AJCC stage, and type of adjuvant treatment 
received.  These will be presented in a forest plot so that apparent discrepancies from 
the overall results will be visually apparent.  These latter analyses are exploratory as 
there are no expected interactions of treatment with these prognostic factors. 
 
Reference 
 
Liu PY, Dahlberg S. Design and analysis of multiarm clinical trials with survival endpoints.  
Controlled Clinical Trials. 1995; 16:119-130.