Clinical trial NCT01074970
Conditions: Breast Cancer
Keywords: PARP inhibition + breast cancer breast cancer PARP inhibitor Triple negative
Sponsor: Hoosier Cancer Research Network
Start date: 2010-02-01; Completion date: 2018-12-15
Enrollment: 135 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial is to evaluate 2-year disease-free survival in this patient population treated with single agent cisplatin and patients treated with cisplatin in combination with Rucaparib following preoperative chemotherapy. Side effects and tolerability of this treatment in patients with residual disease following preoperative chemotherapy will also be observed and characterized.

Detailed description:
OUTLINE: This is a multi-center study.

Safety Run-in will be for the first 12 patients on study only (6 in cohort 1 and 6 in cohort 2). Patients in the safety run will be included in the efficacy analysis on intent to treat basis:

Cisplatin 75 mg/m2 IV D1 every 3 weeks x 4 cycles; Rucaparib 16-30 mg IV D 1,2,3 every 3 weeks x 4 cycles

If cycle 1 is well tolerated, the dose of Rucaparib will be escalated from 16 mg to 24 mg for subsequent cycles in the cohort 1, and 24 mg to 30 mg in the cohort 2.

If ≤ 1 of 6 patients in cohort 1 experiences DLT, cohort 2 will commence. If 2 or more of 6 patients in cohort 1 experience DLT, the study will be suspended and an amendment to explore lower doses will be considered.

If ≤ 1 of 6 patients in cohort 2 experiences DLT, the randomized portion of the study will commence. If 2 or more of 6 patients experience DLT, the study will be suspended and an amendment to proceed with the randomized portion at the cohort 2 dose (24 mg) will be considered.

During the randomized portion of the study, patients will be randomized to either Arm A or Arm B.

Stratification factors:

* Anthracycline vs. not
* Residual LN involvement vs. No Residual LN involvement

Arm A (Cisplatin Monotherapy) Cisplatin 75 mg/m2 IV D1 every 3 weeks x 4 cycles

Arm B (Combination Therapy) Cisplatin 75 mg/m2 IV D1 every 3 weeks x 4 cycles; Rucaparib 16-30 mg IV D1,2,3 every 3 weeks x 4 cycles

Rucaparib maintenance 30 mg IV weekly x 24 weeks

ECOG Performance Status 0-1

Life Expectancy: Not Specified

Hematopoietic:

* Hemoglobin (Hgb) \> 9.0 g/dL
* Platelets \> 100 K/ mm3
* Absolute neutrophil count (ANC) \> 1.5 K/mm3

Hepatic:

* Bilirubin \< upper limit of normal (except in patients with documented Gilbert's disease, who must have a total bilirubin \< 3.0 mg/dL)
* Aspartate aminotransferase (AST, SGOT) \< 2.5 x ULN
* Alanine aminotransferase (ALT, SGPT) \< 2.5 x ULN

Renal:

* Calculated creatinine clearance of \> 50 cc/min using the Cockcroft-Gault formula

Cardiovascular:

* Left ventricular ejection fraction within normal limits.
* Patients with an unstable angina or myocardial infarction within 12 months of study entry are excluded.
* No clinically significant arrhythmia or baseline ECG abnormalities in the opinion of the treating investigator.

Arms: arm 1: Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles arm 2: Rucaparib 24mg C1,30mg C2-4, D1,2,3 every 21 days for 4 cycles

Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles
Interventions: intervention 1: Cisplatin intervention 2: Rucaparib intervention 3: Cisplatin
Intervention descriptions: intervention 1: Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles intervention 2: Rucaparib 24mg C1,30mg C2-4, D1,2,3 every 21 days for 4 cycles intervention 3: Cisplatin 75 mg/m2 IV infusion over 60 minutes, D1 every 21 days for 4 cycles

Protocol documents:
Prot_SAP_000.pdf: 
Hoosier Oncology Group BRE09-146 
                                                           Version Date 27SEPT2011 
 
 
Confidential 
1 
 
 
351 West 10th Street, Suite 330, Indianapolis, IN 46202-4122 
317-921-2050  Fax 317-921-2053 
www.hoosieroncologygroup.org 
 
 
 
Protocol Title 
PARP Inhibition after Preoperative Chemotherapy in Patients with Triple Negative Breast Cancer 
or ER/PR +, HER2 negative with known BRCA1/2 Mutations:  
Hoosier Oncology Group BRE09-146 
 
 
Sponsor Investigator 
Kathy D. Miller, MD 
Indiana University Melvin and Bren Simon Cancer Center 
 
Co-Investigators  
Sunil Badve, MD 
George Sledge, MD 
Indiana University Melvin and Bren Simon Cancer Center 
 
Statistician 
Susan Perkins 
Indiana University School of Medicine 
 
Trial Supported by  
Clovis 
 
Investigational New Drug (IND) Application  
107321 
 
Initial Protocol Version Date: 25SEP2009 
Amendment # 1: Protocol version date: 21DEC2009 
Amendment #2:  Protocol version date:  16NOV2010 
Amendment #3:  Protocol version date:  17MAR2011 
Amendment #4:  Protocol version date:  19MAY2011 
Amendment :5: Protocol version date:  27SEP2011 
 
 
 


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PROTOCOL SIGNATURE PAGE  
 
PARP Inhibition after Preoperative Chemotherapy in Patients with Triple Negative Breast 
Cancer or ER/PR +, HER2 Negative with Known BRCA1/2 Mutations: 
Hoosier Oncology Group BRE09-146 
 
VERSION DATE:  27SEP2011 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the individual.  
I will accept the monitor’s overseeing of the study.  I will promptly submit the protocol to 
applicable ethical review board(s). 
 
 
 
 
 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Investigator 
 
 
 
 
 
       Date 
 
 
____________________________________ 
 Investigator Name (print or type) 
 
 
____________________________________ 
 Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
____________________________________ 
 Not Submitting to IRB 
 Expected IRB Approval Date 
 
PLEASE COMPLETE AND FAX TO THE HOG OFFICE AT 317.921.2053 
 
Instructions to the investigator:  Please SIGN and DATE this signature page.  
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date.  Fax the 
completed form to the Hoosier Oncology Group at 317.921.2053 and keep a 
copy for your files. 


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HOG Protocol: BRE09-146 
TITLE
PARP Inhibition after Preoperative Chemotherapy in Patients with Triple Negative Breast 
Cancer or ER/PR +, HER2 negative with known BRCA1/2 Mutations: Hoosier Oncology Group
STUDY PHASE  
II
OBJECTIVES 
Primary Objective: 
• 
To evaluate 2-year disease-free survival (DFS), in patients with confirmed 
TNBC or ER/PR + HER2-,  known BRCA1/2 mutations treated with single 
agent cisplatin and patients treated with cisplatin in combination with 
rucaparibfollowing preoperative chemotherapy 
 
Secondary Objectives:  
• 
To characterize the side effects and tolerability of cisplatin and cisplatin plus 
rucaparib in patients with residual disease following preoperative chemotherapy. 
• 
To evaluate 1-year DFS 
• 
To determine 5-year overall survival  
• 
To collect limited  pharmacokinetic data, in patients receiving study drug to 
compliment ongoing PK analyses in other trials with rucaparib 
• 
To collect archived tumor specimens, and genomic DNA to explore potential 
correlates of PARP inhibition, recurrence and toxicity. To compare limited PK 
parameters between the IV and oral formulation of rucaparib 
 
STUDY DESIGN 
Safety Run-in Cohorts
Drug interaction and increased toxicity is not anticipated, however there is no clinical experience 
with cisplatin + rucaparib. To exclude prohibitive toxicity, 6 patients will be treated with 
combined therapy as outlined in Table 1.   
Table 1: Treatment plan for Safety Run-in Cohorts 
Drug 
Dose 
Frequency of 
administration
Route of 
administration 
Number 
of cycles 
Rucaparib 
(administe
red as the 
phosphate 
salt 
Cohort 1: 
16 mg C1* 
24 mg C2-
4 
 
Cohort 2: 
24 mg C1* 
30 mg C2-
4 
D1,2,3 every 
21 days 
IV ** followed in 
one hour by 
Cisplatin  
4 
Cisplatin 
75 mg/m2 
D1 every 21 
days 
IV infusion per 
institutional 
guidelines 
4 
*NOTE: rucaparib dose should be increased to 24 mg for cohort 1 or 30 mg 
for cohort 2 during cycles 2-4 in the absence of dose limiting toxicity (as 
defined in Table 2) in cycle 1. 
 
**NOTE:  
• 16 mg dose:  ~32 minute infusion time, ~117 mL infusion volume 
• 24 mg dose: ~33 minute infusion time, ~120 mL infusion volume 
• 30 mg dose:  ~34 minute infusion time, ~124 mL infusion volume 


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Volume calculated using an assumed standard overfill of 9 mL in a 100 mL 
commercial bag of D5W plus the required volume of reconstituted drug 
product for a specific dose. 
 
Randomization Portion of Study: 
During the randomized portion of the study, patients will be randomized to either Arm A or Arm 
B.  
 
Arm A (cisplatin monotherapy) 
Table 3: Treatment Plan – Arm A 
Drug
Dose
Frequency of 
administration 
Route of administration
Number of cycles
Cisplatin 
75 mg/m2 
D1 every 21 days 
IV infusion per 
institutional 
guidelines 
4 
Arm B (combination therapy) 
 
Table 4: Treatment plan - Arm B 
Drug
Dose
Frequency of 
administration 
Route of administration
Number 
of cycles 
Rucaparib
24 mg C1*
30 mg C2-4 
D1,2,3 every 21 
days 
IV ** followed in one 
hour by Cisplatin 
4
Cisplatin 
75 mg/m2 
D1 every 21 days 
IV infusion per 
institutional guidelines 
4 
*NOTE:  Rucaparib dose should be increased to 30 mg for cycles 2-4 in the absence of dose 
limiting toxicity (as defined in Table 2) in cycle 1 
**NOTE: 24 mg dose: ~ 33 minute infusion time, ~120 mL infusion volume* 
30 mg dose:  ~34 minute infusion time, ~124 mL infusion volume* 
*Volume calculated using an assumed standard overfill of 9 mL in a 100 mL commercial bag of 
D5W plus the required volume of reconstituted drug product for a specific dose. 
 
Rucaparib maintenance therapy for Safety Run-in and Arm B 
 
Table 5: Treatment plan – IV Maintenance therapy 
NOTE: All patients should proceed with oral rucaparib maintenance therapy after approval of 
Amendment #5 and when oral drug available.  
Drug
Dose
Frequency of 
administration 
Route of 
administration 
Number of 
weeks 
Rucaparib
30 mg
Weekly
IV ** 
24
**NOTE:  
30 mg dose:  ~34 minute infusion time, ~124 mL infusion volume 
Volume calculated using an assumed standard overfill of 9 mL in a 100 mL commercial bag of 
D5W plus the required volume of reconstituted drug product for a specific dose. 


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Table 6: Treatment plan – Oral maintenance therapy 
 
Drug
Dose
Frequency of 
administration 
Route of 
administration 
Number of 
weeks 
Rucaparib 
(administered as 
the camsylate 
salt) 
100 mg total 
 
(1-60 mg tab 
+  
1-40 mg tab)
Weekly
Oral
24
 
 
 
NUMBER OF 
PATIENTS
Total number of patients = 135 
ELIGIBILITY 
• 
Written informed consent and HIPAA authorization for release of personal health 
information. 
NOTE:  HIPAA authorization may be included in the informed consent or obtained 
separately. 
• 
Age > 18 years at the time of consent. 
• 
ECOG Performance Status 0 or 1 within 30 days prior to registration for protocol 
therapy. 
• 
Women of childbearing potential and males must be willing to use an effective method 
of contraception from the time consent is signed until 4 weeks after treatment 
discontinuation. 
• 
Women of childbearing potential must have a negative pregnancy test within 14 days 
prior to registration for protocol therapy.    
NOTE:  Women are considered not of child bearing potential if they are surgically 
sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or they are postmenopausal. 
• 
Women must not be breastfeeding. 
• 
Must have histologically or cytologically confirmed triple negative (ER-/PR-/HER2-) 
invasive breast cancer, stage I-III at diagnosis (AJCC 6th edition) based on initial 
evaluation by clinical examination and/or breast imaging.  
NOTE:  ER- and PR- should meet one of the following criteria:   
•        Local Pathology report classifies them as negative 
•        Allred Score of 2 or below 
•         <5% weakly positive staining 
Patients with ER+ and/or PR+ may enroll ONLY if they are known carriers of a 
deleterious mutation in BRCA1 or BRCA2. Patients with HER2+ tumors may not enroll 
regardless of BRCA status. 
• 
Must have completed preoperative (neoadjuvant) chemotherapy.  
NOTE: Acceptable preoperative regimens include an anthracycline or a taxane, or both. 
Patients may NOT have received cisplatin as part of their neoadjuvant therapy regimen. 
Patients who received preoperative therapy as part of a clinical trial may enroll. No 
adjuvant chemotherapy after surgery other than that specified in this protocol is allowed. 
Adjuvant bisphosphonate use is allowed. 
• 
Must have completed definitive resection of primary tumor. The last surgery for breast 


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cancer must have been completed at least 14 daysprior to registration for protocol 
therapy.  
NOTE: Negative margins for both invasive and ductal carcinoma in situ (DCIS) are 
desirable, however patients with positive margins may enroll if the treatment team 
believes no further surgery is possible and patient has received radiotherapy. Patients 
with margins positive for lobular carcinoma in situ (LCIS) are eligible. Either 
mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) 
is acceptable. Sentinel node biopsy is allowed but axillary dissection is strongly 
encouraged in patients with lymph node involvement. 
• 
Must have significant residual invasive disease at the time of definitive surgery 
following preoperative chemotherapy.  Significant residual disease is defined at least 
one of the following: 
o Miller-Payne response in the breast of 0-25. (Please refer to Study Procedure 
Manual[SPM]) 
o Residual Cancer Burden (RBC) classification II or III6 
o Residual carcinoma in one or more regional lymph nodes that would meet AJCC 
6th edition criteria for N1 - N3 disease.  
o Alternatively, if Miller-Payne or RCB grading is not available, the patient will 
be eligible if the pathology report indicates that the area of residual invasive 
disease in the breast measures at least 2 cm following preoperative therapy. The 
presence of DCIS without invasion does not qualify as residual disease in the 
breast. 
• 
Whole breast radiotherapy is required for patients who underwent breast conserving 
therapy, including lumpectomy or partial mastectomy. Patients receiving adjuvant 
radiation therapy must have completed radiotherapy at least 14 days prior to registration 
for protocol therapy. 
NOTE: Post-mastectomy radiotherapy is required for all patients with a primary tumor 
> 5 cm or involvement of 4 or more lymph nodes. For patients with primary tumors < 5 
cm or with < 4 involved lymph nodes, provision of post-mastectomy radiotherapy is at 
the discretion of the treating physician.  
• Patients must enroll within 84 days of surgery (for those patients who do not 
require radiation) or within 84 days of completion of radiation when radiation is 
required 
• 
No stage IV (metastatic) disease, however no specific staging studies are required in the 
absence of symptoms or physical exam findings that would suggest distant disease. 
• 
No treatment with any investigational agent within 30 days prior to registration for 
protocol therapy.  
• 
No history of chronic hepatitis B or C 
Laboratory values must be obtained within 14 days prior to registration for protocol 
therapy.   
• 
Hemoglobin (Hgb) > 9.0 g/dL 
• 
Platelets > 100 K/ mm3 
• 
Absolute neutrophil count (ANC) > 1.5 K/mm3 
• 
Calculated creatinine clearance of > 50 cc/min using the Cockcroft-Gault formula: 
o Males:  (140 – Age in years) × Actual Body Weight in kg 
o 72 × Serum Creatinine (mg/dL) 
• 
Females:  Estimated creatinine clearance for males × 0.85 
• 
Bilirubin < upper limit of normal (except in patients with documented Gilbert’s disease, 


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who must have a total bilirubin < 3.0 mg/dL)
• 
Aspartate aminotransferase (AST, SGOT) < 2.5 × ULN 
• 
Alanine aminotransferase (ALT, SGPT)  < 2.5 × ULN 
• 
Left ventricular ejection fraction within normal limits obtained within 30 days prior 
to registration for protocol therapy.  
 
NOTE: Patients with an unstable angina or myocardial infarction within 12 months of 
study entry are excluded.  
• 
No clinically significant infections as judged by the treating investigator. 
• 
Must consent to allow submission of archived tumor tissue sample from definitive 
surgery. 
• 
Must consent to collection of blood samples for PK analysis.  
• 
No clinically significant arrhythmia or baseline ECG abnormalities in the opinion of the 
treating investigator. 
 
STATISTICAL 
CONSIDERATIONS
 
Sample Size Justification
The primary endpoint for this trial is 2 year DFS. In order to detect an improvement of the 
fraction of patients free from disease at 2-year from 40% in the control arm to 63.2% in the 
rucaparib arm (corresponding to an HR=0.5), 38 events are needed to have 80% power to detect 
a difference in DFS using a one-side log-rank test with 0.10 level of significance (calculation 
done using nQuery Advisor 7.0 and assuming exponential survival).  In order to observe 38 
events we need to accrue about 102 patients, with an accrual time of about 13-18 months and an 
overall study duration around 25-30 months.  In addition, 6 patients will be needed at the lower 
dose (cohort 1). Assuming ~20% will not be confirmed to have TNBC on central review; the 
total sample size will be increased to 128 to ensure 102 in the primary analysis (using cohort 2 
and the randomized patients) and 6 in the safety analysis for cohort 1.  
 Patient Characteristics 
Patient characteristics will be summarized by treatment group for demographics, baseline 
disease characteristics, and medical history.  The two treatment groups will be compared using 
standard methods such as t-tests and chi-square tests. 
 Interim Safety Analyses 
The first 12 patients (6 in cohort 1 and 6 in cohort 2) will be assigned to the PF-01367338 arm 
for an initial safety run-in. A safety analysis will be done after all six patients in each cohort 
have completed cycle 2.  All toxicities will be tabulated.  The study will move forward to cohort 
2 if  1 of 6 in cohort 1 experience a DLT (as defined in Section 5.1).  If > 2 of 6 in cohort 1 
experience a DLT, the study will be suspended and an amendment to explore alternate dosing 
schemes will be considered. Similarly, if  1 of 6 in cohort 2 experience a DLT (as defined in 
Section 5.1), the randomized portion will commence.  If > 2 of 6 in cohort 2 experience a DLT, 
the study will be suspended and an amendment to proceed with the randomized portion with the 
cohort 1 dose will be considered. 
Once the decision is made to move forward with the randomized portion a second safety analysis 
will be conducted after the first 40 patients (~20 from each group) have been randomized and 
completed 2 cycles of treatment.  Toxicity counts and rates will be tabulated by treatment arm in 
a blinded fashion. The study will be terminated if the probability that the DLT rate equals 20% 
or less in either arm drops below .10.  Accrual will continue during the interim analysis. The 
results of the analysis will be submitted to the CTMC for external review. 
 Analysis of Primary Objective   
The comparison of DFS between the two groups will be made using an unstratified Kaplan-
Meier analysis with a log-rank test to test for differences using the patients in safety run-in 
cohort 2 and the randomized portion of the study.  A specific comparison of 2-year DFS will be 


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made using a two-sample test based on the complementary log-log transformation as suggested 
in Klein, et al32.  As supportive analysis, a stratified log-rank test will be done using the stratified 
randomization factors neoadjuvant anthracycline versus not and lymph node involvement at time 
of definitive surgery versus not. In addition, sensitivity analyses using Cox regression may be 
carried out to identify prognostic factors and provide adjusted estimates of the treatment group 
differences in DFS. 
Analysis of Secondary Objectives 
As support for the primary objective, overall DFS and 2-year DFS will be compared using the 
same techniques above using only the subjects in the randomized part of the study.  One-year 
DFS will be tested using the test described above for 2-year DFS. Safety and tolerability 
variables will be tabulated separately for the two groups. Incidences of selected adverse events 
from the two treatment arms may be compared using Fisher’s Exact tests on an exploratory 
basis. OS will be compared between treatment groups using the same methodology as DFS. PK 
levels will be described using summary statistics. In addition characteristics of tumor specimens 
and genomic DNA will be correlated with PARP inhibition, recurrence and toxicity. Continuous 
measures will be correlated with binary variables (e.g. recurrence and toxicity) using maximal 
chi-square tests and continuous variables (e.g. PARP inhibition) using Pearson or Spearman 
correlations. Binary variables such as tumor and genomic characteristics will be correlated 
recurrence and toxicity using chi-square or Fisher’s Exact test. All of the analyses with the PK 
and correlative data are exploratory and are designed to complement efforts in other trials with 
this agent. 
 
 
 
 


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PARP Inhibition after Preoperative Chemotherapy in Patients with Triple Negative Breast 
Cancer (TNBC) or ER/PR + and HER2 negative with known BRCA1/2 Mutations:  
Hoosier Oncology Group BRE09-146 
 
 
INDEX  
 
SECTION                                                                                                                 
PAGE 
 
 
 
SCHEMA ........................................................................................................................................ 10 
1.0 
BACKGROUND & RATIONALE .................................................................................... 11 
2.0 
OBJECTIVES ..................................................................................................................... 15 
3.0 
ELIGIBILITY CRITERIA ................................................................................................ 16 
4.0 
PATIENT REGISTRATION ............................................................................................. 18 
5.0 
TREATMENT PLAN ......................................................................................................... 19 
6.0 
DOSE MODIFICATIONS ................................................................................................. 24 
9.0 
BIOLOGICAL CORRELATIVES ................................................................................... 39 
10.0 CTM INFORMATION & ADVERSE EVENTS MANAGEMENT .............................. 40 
11.0 REPORTING ADVERSE EVENTS & SERIOUS ADVERSE EVENTS ..................... 45 
12.0 STATISTICAL CONSIDERATIONS .............................................................................. 47 
13.0 TRIAL MANAGEMENT ................................................................................................... 49 
14.0 REFERENCES .................................................................................................................... 52 
 
 


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SCHEMA 
 
PARP Inhibition after Preoperative Chemotherapy in Patients with Triple Negative Breast Cancer (TNBC) or ER/PR+, HER2 negative with Known 
BRCA1/2 Mutations: Hoosier Oncology Group BRE09-146 
 
 
 
 
 
Safety Run-inB 
 
 
 
        
 
 
 
 
 
 
 
 
 
Arm A 
 
 
 
 
 
      
 
  
 
 
 
 
 
 
Arm B  
 
APatients with 
significant 
residual 
invasive 
disease after 
neoadjuvant 
Cisplatin x 4 cycles 
Cisplatin +  
rucaparibDx 4 cycles 
R
A
N
D
O
M
I
Z
E 
APatients must have triple negative (ER-/PR-/HER2-) breast cancer or if ER/PR + must have a known mutation of BRCA1 or BRCA2. Patients with 
HER2+ disease are excluded regardless of BRCA mutation status. 
B Safety Run-in will be for the first 12 patients on study only (6 in cohort 1 and 6 in cohort 2). Patients in the safety run will be included in the efficacy 
analysis on intent to treat basis 
CIf cycle 1 is well tolerated; the dose of rucaparib will be escalated from 16 mg to 24 mg for subsequent cycles in the cohort 1, and 24 mg to 30 mg in the 
cohort 2 
 Arm A 
Cisplatin 75 mg/m2 IV D1 every 3 weeks x 4 cyclesSafety Run-in and Arm B 
Cisplatin 75 mg/m2 IV D1 every 3 weeks x 4 cycles rucaparib 16-30 mg IV D 1,2,3 every 3 weeks x 4 cycles 
Rucaparib maintenance 30 mg IV weekly OR 100 mg orally once weekly x 24 week’s total 
D Rucaparib will be escalated from 24mg to 30mg during the treatment phase of the study.
rucaparib 
maintenance x 24 
weeks 
Follow up for DFS  
Follow up for DFS 
APatients with 
significant 
residual 
invasive 
disease after 
neoadjuvant 
Cisplatin  +  
rucaparibC x 4 
cycles 
rucaparib 
maintenance x 24 
weeks 
Follow up for 
Disease Free 
Survival (DFS) 


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1.0 
BACKGROUND & RATIONALE 
 
1.1 
Primary (neoadjuvant) Chemotherapy for Breast Cancer 
Neoadjuvant chemotherapy has a well-established role in the management of both 
early-stage and locally advanced breast cancer. Providing treatment prior to definitive 
surgery not only improves the ability to achieve breast conservation, but also allows 
determination of in vivo sensitivity to therapy and offers an ideal platform for clinical 
research. Although many will experience shrinkage in tumor volume with neoadjuvant 
therapy, at the time of surgery only about 15-25% of patients will experience a 
pathologic complete response (pCR) with complete lack of invasive tumor tissue in the 
surgical specimen. Long-term follow-up of neoadjuvant studies consistently 
demonstrates significantly improved survival in individuals with pCR, with 
comparatively inferior outcomes in those with residual disease at surgery1-3. The 
impact of residual disease is more striking in patients with triple negative (ER-/PR-
/HER2-) disease compared to patients with other molecular phenotypes4. 
Unfortunately, patients with triple negative disease who have substantial(Miller-Payne 
classification5 1 or 2 or residual cancer burden classification II or III6) residual disease 
at the time of surgery have a dismal prognosis with only 35-40% remaining free of 
recurrence at 2 years.7 In short, the presence of viable invasive tumor after appropriate 
neoadjuvant chemotherapy reflects inherent resistance and portends an exceedingly 
high risk of subsequent recurrence. No standard therapy exists in this clinical setting. 
 
1.2 
Associations between Triple Negative Breast Cancer, BRCA Mutation Status, and     
DNA damaging chemotherapy 
Recent studies illustrate the aggressive nature of triple negative breast cancer (TNBC), a 
subtype of breast cancer that is clinically negative for the expression of the estrogen and 
progesterone receptors (ER and PR) and the Her2 protein 8-10. The associations between 
basal-like breast cancer (BBC), TNBC and BRCA pathway dysfunction have apparent 
therapeutic implications.  Although important to clarify that the terms “triple negative 
(TN)” and “basal-like” are not entirely synonymous, the clinico-pathologic TN 
(ER/PR/Her2 negative) phenotype is classified as basal-like via cDNA microarray 80-
90% of the time11-14.  In addition, TNBC expresses a high proportion of “basal-like” 
cytokeratins (CK) 1, 10, 13, as well as p-cadherin and Her1/epithelial growth factor 
receptor (EGFR)15-19.  As a clinically-applicable test for the basal molecular 
classification has yet to be developed, the triple negative phenotype is a reasonable 
surrogate for the basal-like subtype -- a subtype of breast cancer commonly seen among 
BRCA1 mutation carriers20.  Moreover, a recent study of over 400 women reports TNBC 
among two-thirds of patients who carried a BRCA1 mutation21.  The tight association 
between BRCA1 mutations, BBC and TNBC has raised the question as to whether 
BRCA1 loss of function through other mechanisms participates in the pathogenesis of 
sporadic basal-like and TNBC – an association which could be exploited therapeutically.  
Pre-clinically tumors that harbor BRCA mutations are more sensitive to DNA damaging 
chemotherapy agents such as cisplatin. Two recent clinical trials reported high pCR rates 
with cisplatin monotherapy regimens in patients with known BRCA mutations (72% in 
Gronwald et al, ASCO 2009, #502)  or cisplatin in combination with bevacizumab in 
those with TNBC regardless of mutation status (36% in Ryan et al, ASCO 2009 #551). 
This pre-clinical and emerging clinical data supports the use of cisplatin in patients with 
TNBC who harbor substantial residual disease after standard neoadjuvant therapy. 


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1.3 
PARP Inhibition 
PARP is an abundant, constitutively-expressed nuclear enzyme that catalyzes the transfer 
of ADP-ribose polymers from NAD+ to target proteins, through which it facilitates DNA 
repair, cellular proliferation, and signaling to other critical cell cycle proteins and 
oncogenes8-22-27. At sites of DNA damage, PARP activates intracellular signaling 
pathways that modulate DNA repair and cell survival through poly (ADP-ribosyl)ation 
of a number of nuclear proteins involved in the chromatin architecture and DNA 
metabolism. Immediate catalytic activation of PARP in response to DNA single- and 
double-strand breaks has been reported at levels up to 500-fold26,28. 
 
BRCA1 and BRCA2 genes encode for proteins critical for DNA integrity and genomic 
stability29-31.  BRCA1 and BRCA2 are tumor-suppressor proteins essential for cell 
division, DNA error control, DNA repair and apoptosis. In 2005 Bryant32 and Farmer33 
showed that BRCA-deficient cells were extremely sensitive to PARP inhibition. Single 
agent PARP inhibitors led to impaired SSB repair causing double strand breaks (DSBs) 
in replicative cells. In BRCA wild type cells DSBs are repaired via homologous 
recombination (HR), but in BRCA “altered” cells HR is impaired and alternative 
pathways lead to complex rearrangements, loss of repair mechanisms and cell death 
(“synthetic lethality”)34. Significant single agent activity was recently reported with the 
PARP inhibitor olaparib in patients with previously treated BRCA-deficient metastatic 
breast cancer. Overall responses ranged from 22% (100 mg bid) to 41% (400 mg bid) 
with minimal toxicity35 
 
Importantly, due to molecular and pathologic similarities between TNBC and BRCA-
associated breast cancers36,37, whose homologous recombination-dependent DNA repair 
is impaired, pharmacological inhibition of PARP is predicted to specifically and 
irreversibly augment the existing instability of these tumors.  
 
In summary, there are at least three roles of PARP inhibitors in cancer treatment: 
chemotherapy and radiotherapy sensitization, synthetic lethality in patients with 
hereditary mutations in BRCA1/2 genes (inherited defect in homologous recombination), 
and finally leveraging of “BRCA-like” defects tumors with spontaneous defects in DNA 
repair such as triple negative breast cancer. 
 
1.4 
Rucaparib 
Rucaparib (also known as CO-338, formerly known as AG-14699 and/or PF-01367338) is 
a small molecule inhibitor of PARP being developed for cancer indications, to be used in 
conjunction with temozolomide, irinotecan, and other chemotherapeutic agents where 
PARP-related DNA repair may impede their maximum therapeutic effect.  In addition, 
rucaparib is being investigated as a single agent in BRCA1 and BRCA2 patients with 
advanced/pretreated breast or ovarian neoplasia.  
Results of studies with animal models suggest that rucaparib exposures that inhibit PARP 
will be associated with enhanced antitumor activity of temozolomide and other 
chemotherapeutic agents.  Hence, the clinical program assessed bioactivity and safety in 
patients with malignancies, commonly treated with the selected chemotherapeutic agents.  
Based on the in vitro IC90 against the target, adjusted for protein binding, a sustained 


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plasma concentration of >5.9 ng/mL was projected to be needed in humans to inhibit 
PARP and enhance antitumor activity of chemotherapeutic agents.  This target was 
reached at the 2 highest rucaparib doses (8 and 12 mg/m2) in Part 1 of the Phase 1 study 
A4991002.  Among the 3 patients who received the PID of 12 mg/m2, concentrations of 
10.6, 10.6, and 46.5 ng/mL, respectively, were observed 24 hours after rucaparib infusion 
on Day 1. 
Non-clinical evaluation has demonstrated exquisite sensitivity of BRCA1 or BRCA2 
homozygous cell lines, which is attributed to PARP inhibition alone, and provides a 
rationale for the clinical assessment of rucaparib as a single agent in patients with BRCA1 
and BRCA2 deficient tumors. 
Following administration of an IV dose of [14C]-labeled drug to intact rats, mean urine, 
and fecal recoveries were 33% and 61%, respectively, with a mean cumulative recovery 
of 95% of dose.  Mean recovery of radioactivity in urine, bile, and feces from bile 
duct-cannulated rats was 49%, 31%, and 17%, respectively, with a mean cumulative 
recovery of 98%.  Careful dose titration should be used in subjects with impaired renal 
and/or hepatic function.  Following a single IV dose in rodents, dogs, or monkeys, mean 
systemic clearance was moderate to rapid, the apparent volume of distribution was large, 
and the terminal half-life was relatively short (t1/2: 2.8 hours in rats, 4.5 hours in dogs, 
5.2 hours in monkeys).   
Nonclinical safety studies performed to date have identified the target organs for 
rucaparib to be the bone marrow, lymphoid organs (eg, thymus, lymph nodes), and heart, 
with emesis being dose-limiting in the dog.  At doses tested above the NOAEL in rats 
and dogs, cardiac effects (structural and functional) were observed in addition to 
potential QT liability detected in vitro by positive findings in the hERG - IKr assay.  At 
the high-dose (40 mg/kg/day) in dogs, histopathologic findings in the heart were limited 
to endocardial hemorrhage, ECG abnormalities (persistent sinus tachycardia, 
atrioventricular nodal rhythm), and sudden death (2 of 12 dogs) were also noted at this 
rucaparib dose.  The cardiac effects in the acute and multidose studies were observed at 
concentrations significantly higher than those predicted to inhibit PARP in humans.  
Peak human exposure at the projected efficacious dose of 20 mg/m2 is estimated to be 
89 ng/mL, which is 25-fold and 176-fold lower than the observed exposures associated 
with cardiovascular toxicity in rats and dogs, respectively. 
Based on nonclinical cardiac findings, collection of ECGs was required in Phase 1 study 
A4991002 during the screening period; before and after rucaparib infusion on Days -7, 1, 
and 4 of the first cycle; before the first AG-014699 infusion of every other cycle 
thereafter; and at the post treatment follow-up visit.  All patients completed at least 
1 ECG during screening and 1 ECG after infusion.  Four patients had at least 1 abnormal 
ECG after treatment.  Two of the patients also had abnormal ECGs at screening.  
T inversion was observed in 1 patient in Cohort 3 before receiving cycle 3.  There were 
no changes to suggest myocardial infarction and the ECG change was not believed by the 
investigator to be related to study drug.  Subsequent ECGs were normal. Another patient, 
who was enrolled in Cohort 4, had an abnormal ECG on Day 4 of the first cycle. The 
patient entered the study with a normal, but flattened T-wave, which became inverted on 
Day 4.  Follow-up ECGs were normal and the finding was not believed to be clinically 


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significant. Based on this experience, further ECG monitoring in subsequent trials was 
not recommended 
Complete information on the preclinical pharmacokinetics and drug metabolism rucaparib 
may be found in the current Investigators’ Brochure.  
1.5 
Rucaparib + Chemotherapy 
In vitro studies in human tumor cells lines of rucaparib and similar compounds have 
shown that the combination of the PARP inhibitor with ionizing radiation, 
temozolomide, the topoisomerase I inhibitor camptothecin, and bleomycin increased the 
cytotoxicity of the DNA damaging agent. In the Phase 1 clinical study A4991002, 32 
patients received at least 1 dose of rucaparib together with temozolomide.  There were no 
deaths related to rucaparib.  Two (6%) patients had nonfatal SAEs that were considered 
related to rucaparib.  Many of the other events were related to the co-administered 
temozolomide and consistent with the known safety profile of temozolomide. 
 
In the Phase 2 clinical study A4991005 of rucaparib and temozolomide forty-six patients 
were assigned to treatment and received at least 1 cycle of rucaparib (administered 
intravenously at a dose of 12 mg/m2/day from Day 1 to 5 every 4 weeks) and 
Temozolomide (administered orally at a dose of 200 mg/m2/day from Day 1 to 5 every 
4 weeks).  Eleven patients completed the study and 35 were discontinued early. All 
patients experienced treatment-related adverse events.  The majority of CTC Grade 3 or 
4 adverse events were myelotoxicities and occurred in cycle 1.  The incidence of 
haematological toxicities appeared to be controlled by reducing the dose of 
temozolomide. 
 
An ongoing phase I study is evaluating the safety, pharmacokinetic and 
pharmacodynamic of rucaparib administered with full combination doses of carboplatin, 
paclitaxel, cisplatin and pemetrexed. 
 
1.6 
Rucaparib (CO-338/AG-014699/PF-01367388) Starting Dose Rationale 
In the Phase 1 clinical study A4991002 the rucaparib Recommended Phase 2 Dose 
(RP2D) has been determined to be 12 mg/m2/day for 5 days every 28 day cycle with full 
dose of Temozolomide. 
Moreover from a pharmacokinetic point of view, whether a drug should be administered 
on a fixed dose or Body Surface Area (BSA) normalized dose depends on whether the 
pharmacokinetics of the drug changes with BSA. The effect of BSA on systemic 
exposure of rucaparib (AUC 0-24) was evaluated for this purpose. It is observed that the 
AUC 0-24 normalized for actual dose and the AUC (0-24) normalized for mg/m2 dose 
do not correlate with BSA. Furthermore, inter-subject variability is similar for actual 
dose normalized AUC (0-24) (53.9%) and mg/m2 dose normalized AUC (0-24) (54.1%). 
This suggests that rucaparib can be given either as a fixed dose or on a mg/m2 based dose. 
The starting dose for rucaparib in the current study will be the fixed dose of 16 mg/day, 
lower than the 24 mg/day that would correspond to the “per square meter” RP2D of 12 
mg/m2/day determined in study A4991002. A single dose escalation to 30 mg/day will be 
allowed in patients without significant toxicity in cycle 1. In addition, as the 


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chemotherapy regimen being studied will be administered on a 3-week basis, the 
rucaparib schedule has been modified accordingly. rucaparib will thus be administered 
from Day 1 to Day 3 every 21 days. A similar dosing strategy has been employed in the 
planned/ongoing phase I trial evaluating rucaparib in combination with multiple 
chemotherapy regimens. 
Complete information for rucaparib may be found in the current Investigator’s Brochure. 
1.7 
Rucaparib (CO-338/AG-014699/PF-01367338) Oral Formulation 
The oral formulation of rucaparib contains the camsylate salt of the active agent 
rucaparib.  All dosage strengths are express as the weight of free base rucaparib. Two 
strengths of oral rucaparib, 40 mg and 60 mg, are available as immediate release film 
coated tablets.  The physical appearances of the tablets are unique in order to ensure 
proper identification.  40 mg rucaparib tablets are 9.5 mm round convex in shape, while 
60 mg tablets are 15.4 mm x 8 mm oval in shape.  In addition to active agent, tablets 
contain microcrystalline cellulose, sodium starch glycolate, dicalcium phosphate, and 
magnesium stearate.  The cosmetic white film coating is Opadry II containing HPMC 
2910, hypromellose 6cP, macrogol/PEG3350, triacetin, titanium dioxide, and lactose 
monohydrate. 
 
In the on-going Phase I study of rucaparib in combination with chemotherapy, 
administration of the oral formulation is associated with average bioavailability is 30-
40%, thus 100 mg is the estimated bioequivalent dose for the 30mg IV dose. Use of the 
oral dose during maintenance therapy will increase patient convenience and decrease the 
risk of infusion and/or access device related complications.  
 
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective:  
• 
To evaluate 2-year disease-free survival (DFS), in patients with confirmed TNBC 
or ER/PR + HER2-,  known BRCA1/2 mutations treated with single agent cisplatin 
and patients treated with cisplatin in combination with rucaparib following 
preoperative chemotherapy 
 
2.2 
Secondary Objectives:  
• 
To characterize the side effects and tolerability of cisplatin and cisplatin plus 
rucaparib in patients with residual disease following preoperative chemotherapy. 
• 
To evaluate 1-year DFS. 
• 
To determine 5-year overall survival.  
• 
To collect limited pharmacokinetic data, in patients receiving study drug to 
compliment ongoing PK analyses in other trials with rucaparib. 
• 
To collect archived tumor specimens and genomic DNA to explore potential 
correlates of PARP inhibition, recurrence and toxicity.  
• 
To compare limited PK parameters between the IV and oral formulation of 
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3.0 
ELIGIBILITY CRITERIA 
 
3.1 
Written informed consent and HIPAA authorization for release of personal health 
information. 
NOTE:  HIPAA authorization may be included in the informed consent or obtained 
separately. 
 
3.2 
Age > 18 years at the time of consent. 
 
3.3 
ECOG Performance Status 0 or 1 within 30 days prior to registration for protocol 
therapy. 
 
3.4 
Women of childbearing potential and males must be willing to use an effective method 
of contraception from the time consent is signed until 4 weeks after treatment 
discontinuation. 
 
3.5 
Women of childbearing potential must have a negative pregnancy test within 14 days 
prior to registration for protocol therapy.    
NOTE:  Women are considered not of child bearing potential if they are surgically 
sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or they are postmenopausal. 
 
3.6 
Women must not be breastfeeding. 
 
3.7 
Must have histologically or cytologically confirmed triple negative (ER-/PR-/HER2-) 
invasive breast cancer, stage I-III at diagnosis (AJCC 6th edition) based on initial 
evaluation by clinical examination and/or breast imaging. 
 
NOTE: ER- and PR- should meet one of the following criteria:   
• Local Pathology report classifies them as negative 
•        Allred Score of 2 or below 
•         <5% weakly positive staining 
Patients with ER+ and/or PR+ may enroll ONLY if they are known carriers of a 
deleterious mutation in BRCA1 or BRCA2. Patients with HER2+ tumors may not enroll 
regardless of BRCA status. 
 
3.8 
Must have completed preoperative (neoadjuvant) chemotherapy.  
NOTE: Acceptable preoperative regimens include an anthracycline or a taxane, or both. 
Patients may NOT have received cisplatin as part of their neoadjuvant therapy regimen. 
Patients who received preoperative therapy as part of a clinical trial may enroll. No 
adjuvant chemotherapy after surgery other than that specified in this protocol is allowed. 
Adjuvant bisphosphonate use is allowed. 
 


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3.9 
Must have completed definitive resection of primary tumor. The last surgery for breast 
cancer must have been completed at least 14 days prior to registration for protocol 
therapy.  
 
NOTE: Negative margins for both invasive and ductal carcinoma in situ (DCIS) are 
desirable, however patients with positive margins may enroll if the treatment team 
believes no further surgery is possible and patient has received radiotherapy. Patients 
with margins positive for lobular carcinoma in situ (LCIS) are eligible. Either 
mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) 
is acceptable. Sentinel node biopsy is allowed but axillary dissection is strongly 
encouraged in patients with lymph node involvement. 
 
3.10 
Must have significant residual invasive disease at the time of definitive surgery following 
preoperative chemotherapy.  Significant residual disease is defined at least one of the 
following: 
• 
Miller-Payne response in the breast of 0-25. (Please refer to Study Procedure 
Manual[SPM]). 
• 
Residual Cancer Burden (RBC) classification II or III6. 
• 
Residual carcinoma in one or more regional lymph nodes that would meet AJCC 6th 
edition criteria for N1 - N3 disease.  
• 
Alternatively, if Miller-Payne or RCB grading is not available, the patient will be 
eligible if the pathology report indicates that the area of residual invasive disease in 
the breast measures at least 2 cm following preoperative therapy. The presence of 
DCIS without invasion does not qualify as residual disease in the breast. 
 
3.11 
Whole breast radiotherapy is required for patients who underwent breast conserving 
therapy, including lumpectomy or partial mastectomy. Patients receiving adjuvant 
radiation therapy must have completed radiotherapy at least 14 days prior to registration 
for protocol therapy. 
NOTE: Post-mastectomy radiotherapy is required for all patients with a primary tumor > 
5 cm or involvement of 4 or more lymph nodes. For patients with primary tumors < 5 cm 
or with < 4 involved lymph nodes, provision of post-mastectomy radiotherapy is at the 
discretion of the treating physician.  
 
3.12 
Patients must enroll within 84 days of surgery (for those patients who do not require 
radiation) or within 84 days of completion of radiation when radiation is required 
 
3.13 
No stage IV (metastatic) disease, however no specific staging studies are required in the 
absence of symptoms or physical exam findings that would suggest distant disease. 
 
3.14 
No treatment with any investigational agent within 30 days prior to registration for 
protocol therapy.  
 
3.15 
No history of chronic hepatitis B or C 
 
Laboratory values must be obtained within 14 days prior to registration.   
 


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3.16 
Hemoglobin (Hgb) > 9.0 g/dL 
 
3.17 
Platelets > 100 K/ mm3 
 
3.18 
Absolute neutrophil count (ANC) > 1.5 K/mm3 
 
3.19 
Calculated creatinine clearance of > 50 cc/min using the Cockcroft-Gault formula: 
 
Males:  (140 – Age in years) × Actual Body Weight in kg 
 72 × Serum Creatinine (mg/dL) 
 
Females:  Estimated creatinine clearance for males × 0.85 
 
3.20 
Bilirubin < upper limit of normal (except in patients with documented Gilbert’s disease, 
who must have a total bilirubin < 3.0 mg/dL) 
 
3.21 
Aspartate aminotransferase (AST, SGOT) < 2.5 × ULN 
 
3.22 
Alanine aminotransferase (ALT, SGPT)  < 2.5 × ULN 
 
3.23 
Left ventricular ejection fraction within normal limits obtained within 30 days prior to 
registration for protocol therapy.  
 
3.24 
Patients with an unstable angina or myocardial infarction within 12 months of study 
entry are excluded.  
 
3.25 
No clinically significant infections as judged by the treating investigator. 
 
3.26 
Must consent to allow submission of archived tumor tissue sample from definitive 
surgery. 
 
3.27 
Must consent to collection of blood samples for PK analysis. 
 
3.28 
No clinically significant arrhythmia or baseline ECG abnormalities in the opinion of the 
treating investigator. 
 
 
4.0 
PATIENT REGISTRATION  
 
All patients must be registered through the Hoosier Oncology Group’s Electronic Data 
Capture system.  
 
Detailed guidelines for patient registration and electronic case report form (eCRF) 
completion can be found in the Study Procedures Manual (SPM).   
 
Patients must be registered prior to starting protocol therapy and begin therapy within 5 
working days of registration and randomization.   


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NOTE: For patients enrolled after the safety run-in period randomization will occur 
immediately after registering a patient. Patients will be registered through the HOG’s 
Electronic Data Capture system. 
 
 
Blinding:  The study treatment is not blinded to the patient or the investigator 
 
 
5.0 
TREATMENT PLAN 
 
All cisplatin doses will be based on the patient’s actual weight. The actual weight at 
screening should be used for calculating body surface area (BSA). The BSA may be 
recalculated based on the actual weight at the start of each treatment cycle but 
recalculation is only required if a patient’s weight changes by  10%. 
 
NOTE: rucaparib dose is fixed, not based on body weight or body surface area (mg/M2). 
As such, rucaparib dose is not adjusted for changes in the patient’s weight. 
 
NOTE: Prophylactic use of white blood cell growth factors (i.e. Neulasta, Neupogen, 
Leukine, or similar agent) is not allowed.  However, white blood cell growth factors may 
be used in accordance with ASCO guidelines if neutropenic fever occurs. 
 
Recombinant erythropoietin or similar compound may NOT be administered for anemia 
due to restrictions on their use in patients being treated with curative intent. 
 
5.1 
Pre-medication  
It is strongly recommended that all patients receive adequate anti-emetics with cisplatin.  
NOTE:  Pre-medication for cisplatin may be given prior to the rucaparib drug infusion.  
The specifics of the pre-medication regimen are at the discretion of the treating 
physician, provided adequate control of nausea is achieved. One potential regimen 
consists of 20 mg of oral dexamethasone and a high dose of oral or IV 5HT3 antagonist 
(such as 2 mg oral or 10 mcg/kg IV granisetron, or 32 mg oral or IV ondansetron) on the 
day of cisplatin administration. Followed by additional anti-emetics consisting of 4 days 
of oral dexamethasone (8 mg po bid for 2 days (days 2, 3) then 4 mg po bid for 2 days 
(days 4, 5) and scheduled metoclopramide or 5HT3 antagonist for days 2-5 for delayed 
emesis NOTE: Dexamethasone dose should be reduced by 50% when administered with 
aprepitant. 
 
Hydration guidelines may be modified at the discretion of the treating physician provided 
adequate pre and post cisplatin hydration is achieved and renal function remains 
adequate. One suggested regimen consists of administering cisplatin in 500 cc to 1000 cc 
of IV fluids following adequate hydration and the establishment of adequate urinary 
output. It is suggested the pre-cisplatin hydration consist of NS at 500 cc/hr x 1 liter and 
post-cisplatin hydration consist of ½ NS + 10 meq KCl/liter + 1 gram magnesium 
sulfate/liter + 25 grams mannitol/liter at 500 cc/hr for at least one hour, followed by 
additional hydration at the discretion of the investigator. 
 
 


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5.2 
Drug Administration 
 
5.2.1 
Safety Run-in Cohorts 
Drug interaction and increased toxicity is not anticipated, however there is no clinical 
experience with cisplatin + rucaparib. To exclude prohibitive toxicity, up to 12 patients (6 
in cohort 1 and 6 in cohort 2) will be treated with combined therapy as outlined in Table 
1. If a patient goes off study before completing the DLT observation period of safety run-
in for reasons other than DLT, then that patient should be replaced.  
 
Table 1: Treatment plan for Safety Run-in Cohorts 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Rucaparib
Cohort 1: 16 
mg C1* 
24 mg C2-4 
 
Cohort 2: 24 
mg C1* 
30 mg C2-4 
D1,2,3 every 21 
days 
IV ** followed in one 
hour by Cisplatin  
4 
Cisplatin 
75 mg/m2 
D1 every 21 
days 
IV infusion per 
institutional 
guidelines 
4 
*NOTE: Rucaparib dose should be increased to 24 mg for cohort 1 or 30 mg for cohort 
2 during cycles 2-4 in the absence of dose limiting toxicity (as defined in Table 2) in 
cycle 1. 
 
**NOTE:  
• 16 mg dose:  ~32 minute infusion time, ~117 mL infusion volume 
• 24 mg dose: ~33 minute infusion time, ~120 mL infusion volume 
• 30 mg dose:  ~34 minute infusion time, ~124 mL infusion volume 
Volume calculated using an assumed standard overfill of 9 mL in a 100 mL commercial 
bag of D5W plus the required volume of reconstituted drug product for a specific dose. 
 
NOTE: After completing combined treatment, patients in the safety run-in cohorts will 
proceed with rucaparib monotherapy as described in Section 5.2.2, Table 5. 
 
Accrual will be suspended after the initial 6 patients in cohort 1 have been enrolled. 
All patients in run-in cohort 1 will be observed for at least 3 weeks after 
administration of cycle 2 for dose limiting toxicity (DLT) as defined in table 2: 
 
 
 
 
 
 
 


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Table 2: Definition of Dose Limiting Toxicities 
Toxicity Category 
Criteria Defining a DLT 
Hematological 
Grade 4 neutropenia lasting for > 7 days  
Febrile neutropenia 
Grade 3 thrombocytopenia lasting ≥7 days associated with 
bleeding or Grade 4 thrombocytopenia lasting >4 days 
Non-hematological 
Grade ≥3 toxicity despite the use of adequate/maximal medical 
interventions and/or prophylaxis as dictated by local institutional 
clinical practices or the judgment of the Investigator.    
Grade 2 neurotoxicity that does not recover to Grade ≤1 within 
2 weeks of planned treatment 
Any toxicity that results in a >14 day delay in cycle 2 Day 1 or cycle 3 Day 1 dosing will 
also be considered a DLT 
 
If < 1 of 6 patients in cohort 1 experiences DLT, cohort 2 will commence. If 2 or more of 
6 patients in cohort 1 experience DLT, the study will be suspended and an amendment to 
explore lower doses will be considered. 
 
As with cohort 1, accrual will be suspended after the 6 patients in cohort 2 have 
been enrolled. All patients in run-in cohort 2 will be observed for at least 3 weeks 
after administration of cycle 2 for dose limiting toxicity (DLT) as defined in Table 2. 
 
If < 1 of 6 patients in cohort 2 experiences DLT, the randomized portion of the study will 
commence. If 2 or more of 6 patients experience DLT, the study will be suspended and 
an amendment to proceed with the randomized portion at the cohort 2 dose (24 mg) will 
be considered. 
 
5.2.2 
Randomization 
During the randomized portion of the study, patients will be randomized to either Arm A 
or Arm B.  
 
Stratification factors:  
• Anthracycline vs. not 
• Residual LN involvement vs. No Residual LN involvement 
  
Arm A (cisplatin monotherapy) 
 
 
 
 
 


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Table 3: Treatment Plan – Arm A 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
cycles 
Cisplatin 
75 mg/m2
D1 every 21 
days 
IV infusion per 
institutional 
guidelines 
4 
Note:  Infusions may be given ±3 days for reasons such as observed holidays, inclement 
weather, scheduling conflicts, etc. The reason for the schedule variation should be clearly 
documented in patient’s chart and case report forms. 
 
Arm B (combination therapy) 
 
Table 4: Treatment plan - Arm B 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number 
of 
cycles 
rucaparib
24 mg C1* 
30 mg C2-4 
D1,2,3 every 21 
days 
IV ** followed in 
one hour by Cisplatin
4 
Cisplatin 
75 mg/m2 
D1 every 21 
days 
IV infusion per 
institutional 
guidelines 
4 
*NOTE:  Rucaparib dose should be increased to 30 mg for cycles 2-4 in the  
absence of dose limiting toxicity (as defined in Table 2) in cycle 1 
 
**NOTE:  
• 24 mg dose:  ~33 minute infusion time, ~120 mL infusion volume 
• 30 mg dose:  ~34 minute infusion time, ~124 mL infusion volume 
Volume calculated using an assumed standard overfill of 9 mL in a 100 mL commercial 
bag of D5W plus the required volume of reconstituted drug product for a specific dose. 
 
Rucaparib maintenance therapy for Safety Run-in and Arm B 
 
Table 5: Treatment plan – IV maintenance therapy  
NOTE: All patients should proceed with oral rucaparib for maintenance therapy after approval 
of Amendment #5 and when oral drug available. 
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
weeks 
Rucaparib
30mgI 
WeeklyII 
IV *  
24 
*NOTE: 30 mg dose:  ~34 minute infusion time, ~124 mL infusion volume. Volume 
calculated using an assumed standard overfill of 9 mL in a 100 mL commercial bag of 
D5W plus the required volume of reconstituted drug product for a specific dose. 
 
I: Patients receiving < 30 mg during combined therapy should begin maintenance 
therapy with 30 mg weekly.  


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II: The first week of maintenance therapy should begin 3 weeks after Day 1 of the last 
cycle of combination therapy unless a delay is required to allow recovery from toxicity.  
 
NOTE: Patients unable to initiate maintenance therapy within 6 weeks after day 1 of the 
last cycle of combination therapy should discontinue protocol treatment. 
 
Table 6: Treatment plan – Oral maintenance therapy  
Drug 
Dose 
Frequency of 
administration 
Route of 
administration 
Number of 
weeks 
Rucaparib
100mgI 
WeeklyII 
Oral 
24 
I: Patients receiving < 30 mg IV during combined therapy should begin maintenance 
therapy with 100 mg orally weekly.  
 
II: The first week of maintenance therapy should begin 3 weeks after Day 1 of the last 
cycle of combination therapy unless a delay is required to allow recovery from toxicity.  
 
NOTE: Patients unable to initiate maintenance therapy within 6 weeks after day 1 of the 
last cycle of combination therapy should discontinue protocol treatment. 
 
5.3 
Missed doses 
In general patients should be encouraged to comply with the treatment schedule. 
However, if IV treatment is missed for reasons other than toxicity (patient vacation, 
family emergency, etc.), patients able to resume treatment within 2 weeks should receive 
the full planned number of cycles. If a delay of more than 2 weeks is required, the missed 
IV treatment should be deleted (ie: not made up) and patients should proceed with the 
next cycle as originally scheduled.  
 
During oral maintenance therapy, if a missed dose is discovered within 3 days of the 
scheduled administration time, patients should take that dose immediately. If a missed 
dose is not discovered until more than 3 days after the scheduled administration time, 
that dose should not be made up and the patient should resume treatment the following 
week. 
 
5.4 
Special instructions for patients initiating IV maintenance therapy prior to 
Amendment #5 
Patients who initiate IV rucaparib maintenance therapy prior to approval of Amendment 
#5 should switch to oral maintenance upon local approval of Amendment #5 and when 
oral drug is available.  
• 
Patients, who are at week 17 or higher of IV rucaparib when Amendment #5 is 
approved,  should complete the study on IV rucaparib and not be switched over to 
oral rucaparib.  
 
• 
 All other patients should be switched over when Amendment # 5  is approved.  
However, to avoid disruption of the evaluation schedule, patients should continue 


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IV maintenance rucaparib until the next clinical evaluation (required every 4 weeks 
as per Table 12). If patients required a dose modification during IV maintenance 
therapy, that dose modification should carry over when patients switch to the oral 
formulation. See Table 7 for dose level equivalents. 
• 
Patients switching from IV to oral maintenance should have PK samples obtained 
with the first and fifth week of oral maintenance therapy (see Section 7.4 and 9.3 
for details) 
 
5.5 
Supportive Care 
The use of supportive care including antibiotics, and blood transfusions will be permitted 
as clinically indicated and according to institutional guidelines. 
 
Prophylactic use of white blood cell growth factors (i.e. Neulasta, Neupogen, 
Leukine, or similar agent) is not allowed.  However, white blood cell growth factors 
may be used in accordance with ASCO guidelines if neutropenic fever occurs. 
 
Recombinant erythropoietin or similar compound may NOT be administered for 
anemia due to restrictions on their use in patients being treated with curative intent. 
 
5.6 
Concomitant Medications 
Concomitant aminoglycoside antibiotic use should be avoided during cisplatin therapy 
and until patient has fully recovered (i.e., at least 4 weeks from last dose of cisplatin). 
 
Bisphosphonate use is allowed. 
 
Aprepitant should be used with caution in patients receiving concomitant medicinal 
products, including chemotherapy agents that are primarily metabolized through 
CYP3A4. Inhibition of CYP3A4 by aprepitant could result in elevated plasma 
concentrations of these concomitant medicinal products. The effect of aprepitant on the 
pharmacokinetics of orally administered CYP3A4 substrates is expected to be greater 
than the effect of aprepitant on the pharmacokinetics of intravenously administered 
CYP3A4 substrates. 
 
 
6.0 
DOSE MODIFICATIONS  
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 will 
be used to grade adverse events. 
   
Patients enrolled in this study will be evaluated clinically and with standard laboratory 
tests before and at regular intervals during their participation in this study as specified in 
section 7.0 
 
Patients will be evaluated for adverse events (all grades), serious adverse events, and 
adverse events requiring study drug interruption or discontinuation at each study visit for 
the duration of their participation in the study.   
 


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Patients discontinued from the treatment phase of the study for any reason will be 
evaluated at least 30 days after the last dose of study drug. 
 
Patients who require discontinuation of rucaparib due to adverse event, have a treatment 
interruption of > 21 days due to toxicity, or require a dose reduction below level 0, will 
be removed from the study. 
 
Patients in the safety run-in, or Arm B, who require a cisplatin dose reduction below 
level -2, should proceed to rucaparib maintenance therapy.  
 
6.1 
Dose Levels  
The following dose levels will be used in this protocol 
 
Table 7:  Dose Level Reductions  
Dose level 
Cisplatin 
Rucaparib IV 
Rucaparib
(maintenance 
therapy only) 
+2 
------ 
30 mg 
100 mg 
+1 (safety run-in cohort 2 and Arm B        
starting dose) 
 
24 mg 
60 mg 
0 (safety run-in cohort 1 starting dose) 
75 mg/m2
16 mg 
40 mg 
-1 
56 mg/m2
 
 
-2 
37 mg/m2
 
 
NOTE: All patients should initiate rucaparib maintenance therapy at dose level +2. 
 
 


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Table 8:  Dose Modifications for Toxicity Cycles 1-4 – Safety Run-in Cohorts, Arms A and B 
Event 
Cisplatin 
Rucaparib
Neutropenia (based on Day 1 CBC, no change required for interval neutropenia unless 
accompanied by fever) 
> 1.5 K/mm3 
No change 
No change 
< 1.5 K/mm3
Hold until > 1.5 K/mm3, resume 
based on timing of recovery: 
< 1 week – no change 
>1 but < 3 weeks - reduce dose 1 
level for subsequent cycles 
> 3 weeks – discontinue therapy 
Hold until > 1.5 K/mm3, resume at 
the same dose upon recovery 
Neutropenic Fever 
ANC < 1000 and 
fever > 38.5 
Interrupt until resolved (ANC 
>1000, fever <38.5), resume 
according to number of episodes: 
1st  - no change, growth factor use 
mandatory for subsequent cycles. If 
growth factors were already used, 
reduce dose one level for all 
subsequent cycles. 
2nd - reduce dose one level 
3rd  - discontinue therapy 
Interrupt until resolved (ANC 
>1000, fever <38.5), resume 
according to number of episodes: 
1st   - no change 
2nd - reduce dose one level 
3rd - discontinue therapy 
Thrombocytopenia (based on Day 1 CBC, no change required for interval thrombocytopenia) 
 >100,000/mm3 
No change 
No change 
 
75-99,999/mm3 
Hold until >100,000, resume based 
on timing of recovery: 
< 1 week – no change 
>1 but < 3 weeks - reduce dose 1 
level for subsequent cycles 
> 3 weeks – discontinue therapy 
Hold until > 100,000/mm3, resume 
at the same dose upon recovery 
<75,000 
Hold until >100,000, Resume with 1 
level dose reduction for subsequent 
cycles. If > 3 weeks delay is 
required, discontinue therapy 
Hold until > 100,000/mm3, resume 
at same dose upon recovery 
Anemia 
Symptomatic 
anemia 
No change. Transfuse as clinically indicated. NOTE: ESAs are not allowed 
due to restrictions on their use in the curative setting 
Hepatic 
> Grade 3 
Delay until recovered to < Grade 2, 
then resume at a one dose level 
reduction. If unable to resume 
therapy within 3 weeks, discontinue 
therapy 
 
 
 
Delay until able to resume cisplatin, 
then resume at same dose 
Nausea/Vomiting 


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Grade > 3 in spite 
of maximal 
antiemetics 
Reduce dose one level for all 
subsequent cycles 
No change 
Renal 
Creatinine < 1.5 x 
ULN 
No change 
No change 
> 1.5 but < 2.0 x 
ULN 
Reduce dose one level and increase 
hydration 
No change 
> 2.0 ULN 
Delay until recovered to < 2.0 ULN, 
then resume with one dose level 
reduction and increased hydration 
Delay until able to resume cisplatin, 
then resume at same dose 
Neurotoxicity on Day 1 
< Grade 1 
No change 
No change 
> Grade 2 
Delay until recovered to Grade 1, 
then resume with one dose level 
reduction. If unable to resume 
therapy within 3 weeks, discontinue 
therapy 
Delay until able to resume cisplatin, 
then resume at same dose 
Hearing Loss 
Grade 2 
Cisplatin is well known to cause 
high-frequency hearing loss. 
Continued use of the drug does not 
always result in hearing loss, 
although it may do so. If grade 2 or 
worse hearing loss is noted, the 
patient should be presented with a 
discussion of the relative risks of 
hearing loss versus the potential 
benefit of continuing cisplatin 
therapy, and a decision made on the 
continuation of cisplatin. 
No change 
> Grade 3 
Discontinue Cisplatin 
No change 
Other clinically significant toxicities 
Grade 2 
No change 
No change 
> Grade 3 
Delay until recovered to < Grade 2, 
then resume at a one dose level 
reduction. If unable to resume 
therapy within 3 weeks, discontinue 
therapy 
Delay until able to resume cisplatin, 
then resume at same dose 


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Table 9:  Dose Modification for Toxicity – Maintenance Therapy (Safety Run-in Cohorts 
and Arm B only) 
 
Event 
Rucaparib
Hematologic 
Grade 1-2 
No change 
Grade 3 
Hold therapy. If recovery to Grade < 2 within 
14 days, resume with a one level dose 
reduction.  
Grade 4 
Discontinue therapy 
Non-Hematologic 
Grade 1-2  
No change 
Grade 3 
Hold therapy. If recovery to Grade < 1 within 
14 days, resume with a one level dose 
reduction.  
Grade 4 
Discontinue therapy 
  


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7.0  
SAFETY 
 
Safety Run-In Cohorts 1 and 2 
 
 
 
 
 
 
      
Maintenance Rucaparib 
 
Screening
Cycle 1-2
Cycles 3-4
Weekly
Every 4 
weeks 
Post-
treatment 
Follow
-up 
 
-30 
days 
-14 
days 
D11
+/-3 
days 
 
D2
D3
D8
+/-3 
days 
D15
+/-3 
days 
D1
+/-3 
days 
D2
D3
+/-3 
days 
+/-3 
days 
30-60 days 
from last 
treatment 
+/- 1 
month
REQUIRED 
ASSESSMENTS
 
 
 
 
 
 
 
 
 
 
Medical history 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Height
X
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination
X
 
X
 
 
 
 
X
 
 
 
X
X
X8
BP, weight
X
 
X
 
 
 
 
X
 
 
X
 
X
X8
ECOG performance status
X 
 
X
 
 
 
 
X
 
 
 
X
X
X8
Blood Chemistries2
 
X
X
 
 
X
X
X
 
 
 
X
X
 
Calculated creatinine 
clearance
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
Platelets, ANC & Hgb
 
X
X
 
 
X
X
X
 
 
 
X
X
 
Breast imaging 
 
 
 
 
 
 
 
 
 
 
 
 
 
yearly
Electrocardiogram
3
X
 
 X 
 
 
 
 
X 
 
 
 
 
 
 
MUGA or ECHO
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy or serum 
HCG4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event and 
concomitant medication 
assessment
X 
 
X 
 
 
X 
X 
X 
 
 
 
X
X
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
Rucaparib
 
 
X
X
X
 
 
X
X
X
X
 
 
 
Cisplatin
 
 
X
 
 
 
 
X
 
 
 
 
 
 
Table 10 – continued on the next page


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 Safety Run-In Cohorts 1 and 2 
 
 
 
 
 
 
 
Maintenance Rucaparib 
 
Screening
Cycle 1-2
Cycles 3-4
Weekly
Every 4 
weeks 
Post-
treatment 
Follow
-up 
 
-30 
days 
-14 
days 
D11
+/-3 
days 
 
D2
D3
D8
+/-3 
days 
D15
+/-3 
days 
D1
+/-3 
days 
D2
D3
+/-3 
days 
+/-3 
days 
30-60 days 
from last 
treatment 
+/- 1 
month
CORRELATIVE 
STUDIES
 
 
 
 
 
 
 
 
 
 
 
Tumor from diagnosis -
Optional
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor from definitive 
surgery - Mandatory
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomic DNA – 
Optional5 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
PK – Mandatory 
 
 
 
 
X6
 
 
 
 
 
X7
 
 
 
1. Screening values obtained within 7 days of Day 1 do not need to be repeated prior to cycle 1 day 1. 
2. Serum chemistries (creatinine, glucose, total protein, blood urea nitrogen [BUN], total carbon    dioxide [CO2], albumin, total bilirubin, alkaline 
phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) and electrolytes (total calcium, chloride, potassium, sodium). 
3. ECG at baseline and prior to each cycle for the first 4 cycles. Additional ECG monitoring should be considered in patients who develop clinical 
significant electrolyte abnormalities during cisplatin therapy at the discretion of the treating physician. 
4. Only in women of child bearing potential. 
5. If the genomic sample collection is missed at cycle1 day 1, it can be collected at any time point during the study. 
6. Mandatory PK samples are to be done pre-dose and 5 minutes (+/-5 minutes) prior to the end of study drug infusion, on cycle1 day 3 and cycle2 
day3.  
7. Week 1 and week 5 only. 
8. Every 4 months throughout years1-2, then every 6 months for years 3-5. 


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Randomized Phase II – Arm A 
 
Screening
Cycles 1-4
Post-treatment
Follow-up
 
-30 days
-14 days
D11 (+/-3 days)
30-60 days from last treatment
+/-1 month
REQUIRED ASSESSMENTS
 
 
 
 
 
Medical history 
X
 
 
 
 
Height
X
 
 
 
 
Physical examination
X
 
X
X
X6
BP, weight
X
 
X
X
X6
ECOG performance status
X 
 
X
X
X6
Blood Chemistries2
 
X
X
X
 
Calculated creatinine clearance
 
X
X 
X
 
Platelets, ANC & Hgb
 
X
X
X
 
Breast imaging 
 
 
 
 
yearly
Electrocardiogram
3
X
 
X 
 
 
MUGA or Echocardiogram
X 
 
 
 
 
Urine pregnancy or serum HCG4 
 
X
 
 
 
Adverse event and concomitant 
medication assessment
X 
 
X 
X 
 
TREATMENT 
 
 
 
 
 
Cisplatin
 
 
X
 
 
CORRELATIVE STUDIES 
 
 
 
 
 
Tumor from diagnosis -Optional
X
 
 
 
 
Tumor from definitive surgery - 
Mandatory
X 
 
 
 
 
Genomic DNA - Optional
 
 
X5 
 
 
 
 
 
 
 
 
1. Screening values obtained within 7 days of Day 1 do not need to be repeated prior to cycle 1 day 1. 
2. Serum chemistries (creatinine, glucose, total protein, blood urea nitrogen [BUN], total carbon    dioxide [CO2], albumin, total bilirubin, alkaline 
phosphatase, and aspartate transaminase [AST] and alanine transaminase [ALT]) and electrolytes (total calcium, chloride, potassium, sodium). 
3. ECG will be done at baseline and prior to cycle 3. Additional ECG monitoring should be considered in patients who develop clinical significant 
electrolyte abnormalities during cisplatin therapy at the discretion of the treating physician. 
4. Only in women of child bearing potential 
5. If the genomic sample collection is missed at cycle1 day1, it can be collected at any time point during the study. 
6. Every 4 months throughout years 1-2, then every 6 months for years 3-5. 


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Randomized Phase II - Arm B       
IV Maintenance Rucaparib 
1. Screening values obtained within 7 days of Day 1 do not need to be repeated prior to cycle 1 day 1. 
2. Serum chemistries (creatinine, glucose, total protein, blood urea nitrogen [BUN], total carbon    dioxide 
[CO2], albumin, total bilirubin, alkaline phosphatase, and aspartate transaminase [AST] and alanine 
transaminase [ALT]) and electrolytes (total calcium, chloride, potassium, sodium). 
3. ECG to be done at baseline and prior to cycle 3. Additional ECG monitoring should be considered in 
patients who develop clinical significant electrolyte abnormalities during cisplatin therapy at the discretion 
of the treating physician. 
4. Only in women of child bearing potential. 
5. If the genomic sample collection is missed at cycle1 day1, it can be collected at any time point during the 
study. 
 
Screening
Cycle 1-4
Weekly
Every 4 
weeks 
Post-
treatment 
Follow-
up 
 
-30 
days
-14 
days 
D11
+/-3 
days 
 
D
2 
D
3 
 
+/-3 days
+/-3 days
30-60 days 
from last 
treatment 
+/- 1 
month 
REQUIRED 
ASSESSMENTS
 
 
 
 
 
 
 
 
 
 
Medical history
X
 
 
 
 
 
 
 
 
 
Height
X
 
 
 
 
 
 
 
 
Physical examination 
X
 
X
 
 
 
X
X
X8
BP, weight
X
 
X
 
 
X
 
X
X8
ECOG performance status
X 
 
X
 
 
 
X
X
X8
Blood Chemistries2 
 
X
X
 
 
 
X
X
 
Calculated creatinine 
clearance
 
X 
X 
 
 
 
 
 
 
Platelets, ANC & Hgb 
 
X
X
 
 
 
X
X
 
Breast imaging
 
 
 
 
 
 
 
 
yearly
Electrocardiogram3 
X
 
X 
 
 
 
 
 
 
MUGA or Echocardiogram
X 
 
 
 
 
 
 
 
 
Urine pregnancy or serum 
HCG4 
 
X 
 
 
 
 
 
 
 
Adverse event and 
concomitant medication 
assessment
X 
 
X 
 
 
 
X
X
 
TREATMENT
 
 
 
 
 
 
 
 
 
 
Rucaparib
 
 
X
X
X
 
X
 
 
 
Cisplatin
 
 
X
 
 
 
 
 
 
CORRELATIVE STUDIES
 
 
 
 
 
 
 
 
 
Tumor from diagnosis -
Optional
X 
 
 
 
 
 
 
 
 
 
Tumor from definitive surgery 
- Mandatory
X 
 
 
 
 
 
 
 
 
Genomic DNA – Optional5 
 
 
X 
 
 
 
 
 
 
PK – Mandatory
 
 
 
 
X
6
X7
 
 
 


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6. Mandatory PK samples are to be done pre-dose and 5 minutes (+/- 5 minutes) prior to the end of study 
drug infusion, on cycle 1 day 3 and cycle 2 day 3.  
7. Week 1 and week 5 only. 
8.  Every 4 months throughout years 1-2, then every 6 months for years 3-5. 
 

 
 


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Randomized Phase II - Arm B       
Oral Maintenance Rucaparib 
1. Screening values obtained within 7 days of Day 1 do not need to be repeated prior to cycle 1 day 1. 
2. Serum chemistries (creatinine, glucose, total protein, blood urea nitrogen [BUN], total carbon    dioxide 
[CO2], albumin, total bilirubin, alkaline phosphatase, and aspartate transaminase [AST] and alanine 
transaminase [ALT]) and electrolytes (total calcium, chloride, potassium, sodium). 
3. ECG to be done at baseline and prior to cycle 3. Additional ECG monitoring should be considered in 
patients who develop clinical significant electrolyte abnormalities during cisplatin therapy at the discretion 
of the treating physician. 
4. Only in women of child bearing potential. 
5. If the genomic sample collection is missed at cycle1 day1, it can be collected at any time point during the 
study. 
6. Mandatory PK samples are to be done pre-dose and 5 minutes (+/- 5 minutes) prior to the end of study 
drug infusion, on cycle 1 day 3 and cycle 2 day 3.  
 
Screening
Cycle 1-4
Weekly
Every 4 
weeks 
Post-
treatment 
Follow
-up 
 
-30 
days 
-14 
days 
D11
+/-3 
days 
 
D
2 
D3
 
+/-3 
days 
+/-3 
days 
30-60 days 
from last 
treatment 
+/- 1 
month
REQUIRED 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
Medical history
X
 
 
 
 
 
 
 
 
 
Height
X
 
 
 
 
 
 
 
 
Physical examination
X
 
X
 
 
 
X
X
X8
BP, weight
X
 
X
 
 
 
X 
X
X8
ECOG performance status
X 
 
X
 
 
 
X
X
X8
Blood Chemistries2 
 
X
X
 
 
 
X
X
 
Calculated creatinine 
clearance
 
X 
X 
 
 
 
 
 
 
Platelets, ANC & Hgb
 
X
X
 
 
 
X
X
 
Breast imaging
 
 
 
 
 
 
 
 
yearly
Electrocardiogram3 
X
 
X 
 
 
 
 
 
 
MUGA or Echocardiogram
X 
 
 
 
 
 
 
 
 
Urine pregnancy or serum 
HCG4 
 
X 
 
 
 
 
 
 
 
Adverse event and 
concomitant medication 
assessment
X 
 
X 
 
 
 
X
X
 
TREATMENT
 
 
 
 
 
 
 
 
 
 
Rucaparib
 
 
X
X
X
 
X
 
 
 
Cisplatin
 
 
X
 
 
 
 
 
 
CORRELATIVE STUDIES
 
 
 
 
 
 
 
 
 
Tumor from diagnosis -
Optional
X 
 
 
 
 
 
 
 
 
 
Tumor from definitive surgery 
- Mandatory
X 
 
 
 
 
 
 
 
 
Genomic DNA – Optional5 
 
 
X 
 
 
 
 
 
 
PK – Mandatory 
 
 
 
 
X6
X7
 
 
 


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7. Pre-dose and 2 hours post-dose during week 1 and week 5 only. PK samples should be drawn during the 
first and fifth week of oral maintenance therapy in patients switching from the IV formulation. 
8.  Every 4 months throughout years 1-2, then every 6 months for years 3-5. 
 
 


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7.1  
BASELINE/SCREENING 
 
 7.1.1 
Within 30 days prior to registration for protocol therapy: 
• 
Complete medical history  
• 
Physical examination including:  height, weight, BP 
• 
ECG 
• 
MUGA or Echocardiogram 
• 
Adverse event and concomitant medication 
• 
ECOG performance status 
 
7.1.2 
Within 14 days of registration for protocol therapy: 
• 
Complete metabolic profile (CMP) including: serum chemistries (creatinine, 
glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], 
albumin, total bilirubin, alkaline phosphatase, and aspartate transaminase [AST] 
and alanine transaminase [ALT]) and electrolytes (total calcium, chloride, 
potassium, sodium 
• 
Calculated creatinine clearance 
• 
Platelets, ANC, Hgb 
• 
Urine pregnancy test or serum HCG (for women of child bearing potential)   
 
7.2 
ON TREATMENT 
 
7.2.1 
Day 1 of each cycle (within 3 days prior): 
Note: Cycle 1 Day 1 testing need not be repeated if completed within 7 days of 
starting protocol therapy. 
• 
Physical examination including 
• 
weight, B/P and ECOG performance 
• 
Platelets, ANC, Hgb 
• 
Complete metabolic profile (CMP) including: serum chemistries (creatinine, 
glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], 
albumin, total bilirubin, alkaline phosphatase, and aspartate transaminase [AST] 
and alanine transaminase [ALT]) and electrolytes (total calcium, chloride, 
potassium, sodium 
• 
Calculated creatinine clearance 
• 
ECGs will be done prior to each treatment cycle in the safety-run in cohorts and 
prior to cycle 3 of combined therapy in randomized portion of the study. Additional 
ECG monitoring should be considered at the treating physician’s discretion, in 
patients who develop clinically significant electrolyte abnormalities 
• 
Assessment of adverse events and concomitant medications 
• 
PK levels:  For patients enrolled in the safety-run-in portion of the study and Arm 
B  - Mandatory plasma sample to be collected prior to infusion and 5 min (+/- 5 
minutes) prior to the end of infusion on Cycle 1 Day 3 and Cycle 2 Day 3 
• 
Optional whole blood sample (genomic DNA) to be collected on all patients at 
cycle 1 day1. 
• 
Correlative studies: (See SPM for collection and shipping instructions). 
•  Optional - tumor tissue submission from diagnosis 


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• 
Mandatory - tumor tissue submission from definitive surgery  
 
 
7.3 
IV MAINTENANCE THERAPY 
• 
During maintenance therapy patient will have weekly BP and weight along with 
study drug 
• 
Every 4 weeks they need: 
 
Physical examination  
 
ECOG Performance status 
 
Platelets, ANC, Hgb 
 
Complete metabolic profile (CMP) including: serum chemistries (creatinine, 
glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], 
albumin, total bilirubin, alkaline phosphatase, and aspartate transaminase 
[AST] and alanine transaminase [ALT]) and electrolytes (total calcium, 
chloride, potassium, sodium 
 
Assessment of adverse events and concomitant medications 
• 
PK levels: Plasma to be collected prior to infusion and 5 min (+/- 5 minutes) prior 
to the end of infusion during Week 1 and Week 5 
 
7.4 
ORAL MAINTENANCE THERAPY 
• 
During maintenance therapy patient will administer the study drug weekly. Patients 
should be instructed to take the drug in clinic on week 1 and week 5 so PK samples 
can be obtained. All other doses are self-administered at home.  
• 
Every 4 weeks they need: 
 
Physical examination  
 
ECOG Performance status 
 
Platelets, ANC, Hgb 
 
Complete metabolic profile (CMP) including: serum chemistries (creatinine, 
glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], 
albumin, total bilirubin, alkaline phosphatase, and aspartate transaminase 
[AST] and alanine transaminase [ALT]) and electrolytes (total calcium, 
chloride, potassium, sodium 
 
Assessment of adverse events and concomitant medications 
• 
PK levels: Plasma to be collected prior to administration and 2 hours post-dose (+/- 
5 minutes) during Week 1 and Week 5 only. PK samples should be drawn during the 
first and fifth week of oral maintenance therapy in patients switching from the IV 
formulation. 
 
7.5 
TREATMENT DISCONTINUATION 
A patient will be discontinued from the treatment under the following circumstances: 
• 
If there is evidence of progressive disease.  
• 
If the attending physician thinks a change of therapy would be in the best interest of 
the patient. 
• 
If the patient requests discontinuation. 
• 
If the drug(s) exhibit(s) unacceptable adverse event. Patients will be followed until 
the resolution of these adverse events. 
• 
If a patient becomes pregnant. 


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• 
Patients can stop participating at any time. However, if they decide to stop 
participating in the study, patients will continue to be followed for progression and 
survival unless the patient has also withdrawn consent for further follow-up.  
 
7.6 
POST TREATMENT EVALUATIONS: ~30 days -60 days from last treatment 
• 
Physical examination  
• 
weight, BP 
• 
 ECOG performance 
• 
Platelets, ANC, Hgb 
• 
Complete metabolic profile (CMP) including: serum chemistries (creatinine, 
glucose, total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], 
albumin, total bilirubin, alkaline phosphatase, and aspartate transaminase [AST] 
and alanine transaminase [ALT]) and electrolytes (total calcium, chloride, 
potassium, sodium 
• 
Assessment of adverse events and concomitant medications 
 
 
7.7 
FOLLOW-UP: 
• 
Patients will be monitored by their treating physicians for the development of 
either local (chest wall, axillary, or supraclavicular nodes) or distal recurrent 
disease at least once every 4 months for the first two years, then at least every 
6 months during years 3-5 after randomization.  
• 
Suggested guidelines for surveillance of breast cancer survivors are available 
through the National Comprehensive Cancer Network (www.nccn.org).  
• 
Routine blood work or radiology in the absence of symptoms suggestive of 
recurrent disease is not recommended.  
• 
Remaining breast tissue (contralateral breast and ipsilateral breast in patients 
treated with breast conserving surgery) should be imaged annually according 
to standard screening guidelines.  
 
 
8.0 
CRITERIA FOR DISEASE EVALUATION 
 
The primary efficacy endpoint of this trial is disease-free survival (DFS) in patients 
confirmed (by central testing) to have triple negative tumors or known BRCA1/2 
mutation. DFS is defined as the duration of time from randomization to time of an DFS 
event, defined as local failure (invasive), regional failure, distant failure, contralateral 
breast cancer (invasive or non-invasive), any other second cancer (excluding non-
melanomatous skin cancer or cervical cancer in situ), or death from any cause. The 
diagnosis of local or distant recurrence should ideally be pathologically confirmed, 
however if biopsy if not possible, radiology confirmation by CT, MRI, or PET scan is 
acceptable. 
 
 
 
 


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9.0 
BIOLOGICAL CORRELATIVES 
 
9.1 
Central Pathology Reassessment  
Analysis by an American Society of Clinical Oncology (ASCO) and College of 
American Pathology (CAP) expert panel suggests that approximately 20% of ER, PR, 
and HER2 tests performed in community laboratories are inaccurate with a fairly equal 
distribution of false positive and false negative results. While the ASCO/CAP guidelines 
seek to improve test quality and reliability, the impact of these recently published25-28 
guidelines is not yet fully known29,30.  As such, a retrospective central reassessment of 
histological subtype, tumor grade, ER, PR, and HER2 will be performed by Dr. Sunil 
Badve for quality assurance and to confirm tumor phenotype. Tissue Microarrays (TMA) 
will be constructed to facilitate potential future correlative studies including genetic 
assessment of DNA damage repair pathways and potential gene expression profiles that 
might predict sensitivity to PARP inhibition. 
 
Formalin-fixed paraffin-embedded (FFPE) tissue from biopsy at the time of initial 
diagnosis (optional) and from the residual disease removed at the time of definitive 
surgery (mandatory) should be sent within 30 days of randomization (or registration for 
patients enrolled to the safety run-in). 
 
NOTE: Patients will be asked to consent to allow banking of their tumor samples for 
future correlative studies. Only tumor samples from consenting patients will be included 
in the TMAs. 
 
Detailed instructions on sample collection, processing and shipping are outlined in the 
Study Procedures Manual. 
 
9.2 
Genomic DNA – Optional 
It has become increasingly clear that therapeutic heterogeneity may arise from 
differences in the tumor (e.g. p53 expression or defects in DNA repair) and/or 
differences in the host (e.g. single nucleotide polymorphisms). Although a candidate 
gene approach is a high yield strategy for biomarker discovery, the variability seen in 
most disease processes is highly dependent on complex gene-gene interactions. Recently, 
advances in technical platforms and bioinformatics have made genome wide association 
studies (GWAS) feasible. This comprehensive approach has led to some important 
discoveries including identification of genes, SNPs, and haplotypes associated with 
breast cancer, lung cancer, colon cancer, prostate cancer, myocardial infarction, and 
type-2 diabetes. Thus, GWAS has become a powerful platform for biomarker discovery. 
DNA samples from patients enrolled in this trial will be an incredibly valuable resource 
for potential future correlative studies using these emerging genomic and 
pharmacogenomic technologies.  
 
Whole blood will be collected for assessment of potential genomic determinants of 
response and toxicity.  
 


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NOTE: Patients will be asked to consent to allow banking of their DNA for future 
correlative studies. Only whole blood samples from consenting patients should be 
submitted. 
 
Detailed instructions on sample collection, processing and shipping are outlined in the 
Study Procedures Manual. 
 
9.3 
Rucaparib Pharmacokinetics (Safety Run-in Cohorts and Arm B patients only) – 
Mandatory 
Extensive pharmacokinetics (PK) is being conducted in several ongoing rucaparib trials 
and thus detailed PK sampling is not planned in this trial. However, limited PK sampling 
will be conducted to complement the other ongoing efforts. Plasma samples will be 
obtained prior to infusion and 5minutes (+/- 5 minutes) prior to the end of infusion on 
Day 3 of cycles 1 and 2 during combination therapy and weeks 1 and 5 of IV 
maintenance therapy. Plasma samples will be obtained prior to administration and 2 
hours (+/- 5 minutes) post dose during week 1 and week 5 of oral maintenance therapy in 
all patients (including those who initiated maintenance therapy with the IV formulation).  
For all collections, the start and end of rucaparib infusion as well as actual time of all PK 
sample collections should be recorded in the source documents.  PK samples will be 
assayed for rucaparib (CO-338/AG-014699/PF-01367388) using a validated analytical 
method. Detailed instructions on sample collection, processing and shipping are outlined 
in the Study Procedures Manual. 
 
 
10.0 
CTM INFORMATION & ADVERSE EVENTS MANAGEMENT 
 
10.1  
Rucaparib (CO-338/AG-014699/PF-01367388) 
 
10.1.1 
Mechanism of Action: Inhibits PARP 
 
10.1.2 
Availability: IV drug will be provide by Clovis via the Hoosier Oncology Group. 
rucaparib investigational drug product will be supplied as rucaparib Lyophilized Powder 
for Injection, 12 mg/vial (as free base), in 10 mL/20 mm, Type I amber glass vials.  The 
composition of rucaparib drug product consists of rucaparib (phosphate salt), mannitol, 
water for injection (WFI), and nitrogen.  The resulting drug product is an off-white to 
yellow cake. 
 
Availability: Oral drug will be provide by Clovis via the Hoosier Oncology Group. 
rucaparib investigational drug product will be supplied as rucaparib immediate release,film 
coated tablets, 40 mg and 60 mg (as free base), in HDPE containers with child resistant 
closures.  The composition of rucaparib drug product consists of rucaparib (camsylate 
salt), microcrystalline cellulose, sodium starch glycolate, dicalcium phosphate, and 
magnesium stearate.  The cosmetic white film coating, Opadry II, contains HPMC 2910, 
hypromellose 6cP, macrogol/PEG3350, triacetin, titanium dioxide, and lactose 
monohydrate.  40 mg rucaparib tablets are 9.5 mm round convex in shape, while 60 mg 
tablets are 15.4 mm x 8 mm oval in shape.   


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10.1.3 
Storage and Reconstitution: Vials of rucaparib Lyophilized Powder for Injection, 
12 mg/vial (as free base), must be stored at room temperature (15°C to 30°C) and 
protected from light.  
 
Each rucaparib drug product vial is to be reconstituted with 6 mL sterile WFI to yield a 
2 mg/mL (as free base) clear yellow solution.  Once 6 mL of SWFI is injected into the 
vial through the stopper, vigorously shake the vial for at least 30 seconds to allow 
complete drug dissolution in the vial.  The reconstituted solution should be clear and free 
of particles.  Segregate and store any rejected vials separately at controlled room 
temperature (15 to 30°C) and notify sponsor immediately.  The reconstituted rucaparib 
drug product must be used within 24 hours and stored at controlled room temperature 
(15°C to 30°C).  Do not refrigerate reconstituted product. 
 
Bottles of rucaparib 40 mg and 60 mg (as free base) immediate release film coated tablets, 
must be stored at room temperature (15°C to 30°C) 
. 
10.1.4 
IV administration: The reconstituted solution will be mixed in an infusion bag 
containing D5W.  Drug should be administered as listed in table 1 of the protocol, as an 
intravenous infusion.  Infusion equipment including infusion bags and tubing must be 
compatible with rucaparib.  Products meeting compatibility requirements will be listed in 
the study documentation prior to the enrollment of the first patient. 
Chemotherapy will be administered approximately one hour after the end of rucaparib 
administration. 
Oral administration: Patients should take rucaparib fasting (at least 1 hour before OR at 
least 2 hours after eating) 
10.1.5 
Side Effects:  
In general rucaparib has been well tolerated in early clinical trials; dose limiting toxicity has not 
been identified at doses that effectively inhibit PARP. Most adverse events were reversible and 
short in duration. Most hematologic toxicity was related to concurrently administered 
chemotherapy and was not obviously increased with combined therapy. No cardiac toxicity 
(changes in electrocardiogram or left ventricular ejection fraction) with repeated dosing. The 
main adverse event associated only with rucaparib is mild injection site reaction. 
 
ADD ORAL here if needed 
 
10.2 
Cisplatin Other: Platinol (NSC-119875); Cis-diamminedichloroplatinum 
 
10.2.1  Classification:  Alkylating agent 
 
10.2.2 
Action: 
Cisplatin forms covalent bonds with nucleophilic sites on guanine present in all DNA. As 
cisplatin is a bifunctional agent, it is able to bind to 2 sites in a DNA strand. This results 
in the formation of inter- and intra- chain cross-linkings, which interferes with cellular 
transcription and replication. Regulatory mechanisms detect the abnormal DNA and so 


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activate a chain of responses to try and correct it. This, ultimately, causes cell death 
(apoptosis). 
 
10.2.3 
Availability: 
 
Cisplatin is commercially available. 
 
 
10.2.4 
Storage: 
 
Cisplatin Injection is a sterile, multi-dose vial without preservatives. Store at 15° to 25°C 
(59° to 77°F). Note: Do not refrigerate. Protect unopened container from light. The 
cisplatin remaining in the amber vial following initial entry is stable for 28 days 
protected from light or for 7 days under fluorescent room light. 
 
10.2.5 
Reconstitution: 
 
The aqueous solution should be used intravenously only and should be administered by 
IV. Cisplatin is a cytotoxic chemotherapeutic agent. Appropriate precautions for 
hazardous drug handling should be taken during handling, preparation, administration 
and disposal of this agent. As with other potentially toxic compounds, caution should be 
exercised in handling the aqueous solution. Skin reactions associated with accidental 
exposure to cisplatin may occur. The use of gloves is recommended. If cisplatin contacts 
the skin or mucosa, immediately and thoroughly wash the skin with soap and water and 
flush the mucosa with water. 
10.2.6 
Administration: 
 
Cisplatin will be administered IV according to institutional guidelines. 
Hydration for cisplatin can be administered at the discretion of the treating physician and   
according to institutional standards. However, the following regimen is suggested: 
 
Table 10: Pre-dose: Hydration guidelines 
 
Instructions 
Normal Saline 
at 350 mL/hour x 1000 mL 
Mannitol bolus, 
immediately prior to 
cisplatin 
12.5 g IV piggyback in 25 mL D5W 
x1 through 1.2 micron in-line filter 
 
 Table 11: Post-dose: Hydration guidelines 
 
Instructions 
Normal Saline 
at 350 mL/hour x 1000 mL 
 
10.2.7 
Side Effects: 
Nephrotoxicity: Dose related and cumulative renal insufficiency is the major dose-limiting 
toxicity. Renal toxicity has been noted in 28-36% of patients treated with a single dose of 50 
mg/m2. It is first noted during the second week after a dose and is manifested by elevations in 
BUN and creatinine, serum uric acid, and/or a decrease in creatinine clearance. 
Note: Renal toxicity becomes more prolonged and severe with repeated courses of the drug. 
Renal function must return to normal before another dose of cisplatin can be given. 
 


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10.2.8 
Ototoxicity: Ototoxicity has been observed in up to 31% of patients treated with a single dose 
of cisplatin 50 mg/m2, and is manifested by tinnitus and/or hearing loss in the high frequency 
range (4,000 to 8,000 Hz). Decreased ability to hear normal conversational tones may occur 
occasionally. Deafness after the initial dose of cisplatin has been reported rarely. Ototoxic 
effects may be more severe in children receiving cisplatin. Hearing loss can be unilateral or 
bilateral and tends to become more frequent and severe with repeated doses. Ototoxicity may 
be enhanced with prior or simultaneous cranial irradiation. It is unclear whether cisplatin-
induced ototoxicity is reversible. Ototoxic effects may be related to the peak plasma 
concentration of cisplatin. Vestibular toxicity has also been reported. Ototoxicity may become 
more severe in patients being treated with other drugs with nephrotoxic potential. Patients 
should be questioned regarding any history of hearing deficit. 
 
10.2.9 
Hematologic: Myelosuppression occurs in 25% to 30% of patients treated with cisplatin. The 
nadirs in circulating platelets and leukocytes occur between days 18 to 23 (range 7.5 to 45) 
with most patients recovering by day 39 (range 13 to 62). Leukopenia and thrombocytopenia 
are more pronounced at higher doses (>50 mg/m2). Anemia (decrease of 2 g hemoglobin/100 
mL) occurs at approximately the same frequency and with the same timing as leukopenia and 
thrombocytopenia. Fever and infections have also been reported in patients with neutropenia. 
In addition to anemia secondary to myelosuppression, a Coombs’ positive hemolytic anemia 
has been reported. In the presence of cisplatin hemolytic anemia, a further course of treatment 
may be accompanied by increased hemolysis, and this risk should be weighed by the Treating 
Physician. 
 
The development of acute leukemia coincident with the use of cisplatin has rarely been 
reported in humans. In these reports, cisplatin was generally given in combination with other 
leukemogenic agents. 
 
10.2.10 Gastrointestinal: Marked nausea and vomiting occur in almost all patients treated with 
cisplatin, and are occasionally so severe that the drug must be discontinued. Nausea and 
vomiting usually begin within 1 to 4 hours after treatment and last for 24 hours. Various 
degrees of vomiting, nausea and/or anorexia may persist for up to 1 week after treatment. 
Delayed nausea and vomiting (begins or persists 24 hours or more after chemotherapy) has 
occurred in patients attaining complete emetic control on the day of cisplatin therapy. Diarrhea 
has also been reported. 
 
10.2.11 Other Toxicities: Vascular toxicities coincident with the use of cisplatin in combination with 
other antineoplastic agents have been reported rarely. The events are clinically heterogeneous 
and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy 
(HUS), or cerebral arteritis. Various mechanisms have been proposed for these vascular 
complications. There are also reports of Raynaud’s phenomenon occurring in patients treated 
with the combination of bleomycin, vinblastine with or without cisplatin. It has been suggested 
that hypomagnesemia developing coincident with the use of cisplatin may be an added, 
although not essential, factor associated with this event. However, it is currently unknown if 
the cause of Raynaud’s phenomenon in these cases is the disease, underlying vascular 
compromise, bleomycin, vinblastine, hypomagnesemia, or a combination of any of these 
factors. 
 


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10.2.12 Serum Electrolyte Disturbances: Hypomagnesemia, hypocalcemia, hyponatremia, 
hypokalemia, and hypophosphatemia have been reported to occur in patients treated with 
cisplatin and are probably related to renal tubular damage. Tetany has occasionally been 
reported in those patients with hypocalcemia and hypomagnesemia. Generally, administering 
supplemental electrolytes and discontinuing cisplatin restore normal serum electrolyte levels. 
Inappropriate antidiuretic hormone syndrome has also been reported. 
 
10.2.13 Hyperuricemia: Hyperuricemia has been reported to occur at approximately the same 
frequency as the increases in BUN and serum creatinine. It is more pronounced after doses 
greater than 50 mg/m2, and peak levels of uric acid generally occur between 3 to 5 days after 
the dose. Allopurinol therapy for hyperuricemia effectively reduces uric acid levels. 
 
10.2.14 Neurotoxicity: Neurotoxicity, usually characterized by peripheral neuropathies, has been 
reported. The neuropathies usually occur after prolonged therapy (4 to 7 months); however, 
neurologic symptoms have been reported to occur after a single dose. Although symptoms and 
signs of cisplatin neuropathy usually develop during treatment, symptoms of neuropathy may 
begin 3 to 8 weeks after the last dose of cisplatin, although this is rare. Cisplatin therapy 
should be discontinued when the symptoms are first observed. The neuropathy, however, may 
progress further even after stopping treatment. Preliminary evidence suggests peripheral 
neuropathy may be irreversible in some patients. Lhermitte’s sign, dorsal column myelopathy, 
and autonomic neuropathy have also been reported. Loss of taste and seizures have also been 
reported. 
Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of 
sudden onset and short duration, have been reported and were usually associated in patients 
receiving a relatively high cumulative dose of cisplatin and with a relatively advanced 
symptomatic stage of peripheral neuropathy. 
 
10.2.15 Ocular Toxicity: Optic neuritis, papilledema, and cerebral blindness have been reported 
infrequently in patients receiving standard recommended doses of cisplatin. Improvement 
and/or total recovery usually occurs after discontinuing cisplatin. Steroids with or without 
mannitol have been used; however, efficacy has not been established. 
 
10.2.16 Blurred vision and altered color perception have been reported after the use of regimens with 
higher doses of cisplatin or greater dose frequencies than those recommended in the package 
insert. The altered color perception manifests as a loss of color discrimination, particularly in 
the blue-yellow axis. The only finding on funduscopic exam is irregular retinal pigmentation 
of the macular area. 
 
10.2.17 Anaphylactic-like Reactions: Anaphylactic- like reactions have been occasionally reported in 
patients previously exposed to cisplatin. The reactions consist of facial edema, wheezing, 
tachycardia, and hypotension within a few minutes of drug administration. Reactions may be 
controlled by IV epinephrine with corticosteriods and/or antihistamines as indicated. Patients 
receiving cisplatin should be observed carefully for possible anaphylactic- like reactions and 
supportive equipment and medication should be available to treat such a complication. 
 
10.2.18 Hepatotoxicity: Transient elevations of liver enzymes, especially SGOT, as well as bilirubin, 
have been reported to be associated with cisplatin administration at the recommended doses. 
 


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10.2.19 Other Events: Other toxicities reported to occur infrequently are cardiac abnormalities, 
hiccups, elevated serum amylase, and rash. Alopecia, malaise, and asthenia have been reported 
as part of postmarketing surveillance. 
 
Local soft tissue toxicity has rarely been reported following extravasation of cisplatin. Severity 
of the local tissue toxicity appears to be related to the concentration of the cisplatin solution. 
Infusion of solutions with a cisplatin concentration greater than 0.5 mg/mL may result in tissue 
cellulitis, fibrosis, and necrosis. 
 
10.2.20 Pregnancy: Cisplatin can cause fetal harm when administered to a pregnant woman. Cisplatin 
is mutagenic in bacteria and produces chromosome aberrations in animal cells in tissue culture. 
In mice, cisplatin is teratogenic and embryotoxic. If this drug is used during pregnancy or if 
the patient becomes pregnant while taking this drug, the patient should be apprised of the 
potential hazard to the fetus. Patients should be advised to avoid becoming pregnant. 
 
10.2.21 Nursing Mothers. Cisplatin has been reported to be found in human milk, patients receiving 
cisplatin should not breastfeed. 
 
 
11.0 
REPORTING ADVERSE EVENTS & SERIOUS ADVERSE EVENTS 
 
11.1  
Definitions of Adverse Events 
 
11.1.1 
Adverse Event (AE) 
 
Any untoward medical occurrence in a patient or clinical trial subject administered an 
investigational product and which does not necessarily have a causal relationship with 
the treatment.  An adverse event (AE) can, therefore, be any unfavorable and unintended 
sign (including an abnormal finding), symptom, or disease temporally associated with 
the use of an investigational product, whether or not related to the investigational 
product. 
 
11.1.2 
Serious Adverse Event (SAE) 
 
A serious adverse event is any untoward medical occurrence resulting in one or more of 
the following: 
• 
Results in death 
• 
Is life-threatening (defined as an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but,  based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may 
require intervention (e.g., medical, surgical) to prevent one of the other serious 
outcomes listed in the definition above).  Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 


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bronchospasm; blood dyscrasias or convulsions not resulting in hospitalization; or 
the development of drug dependency or drug abuse. 
 
11.1.3 
Unexpected Adverse Event 
An adverse event not mentioned in the Investigator's Brochure or package insert or the 
specificity or severity of which is not consistent with the Investigator's Brochure or 
package insert. 
 
11.2 
Adverse Event (AE) Reporting 
 
Adverse events (AEs) will be recorded from the time of consent and for at least 30 days 
after treatment discontinuation, regardless of whether or not the event(s) are considered 
related to trial medications.  All AEs considered related to trial medication will be 
followed until resolution, return to baseline, or deemed clinically insignificant, even if 
this occurs post-trial. 
 
11.3 
Serious Adverse Event (SAE) Reporting 
 
11.3.1 
Study Center (Site) Requirements for Reporting SAEs 
Investigators and other site personnel must report any SAEs occurring during the course 
of the study within one business day of discovery of the event.  This includes events both 
related and unrelated to the investigational product.   
 
The definition of "related" being that there is a reasonable possibility the drug caused the 
adverse experience. 
 
Table 12: Relationship of adverse event to the investigational agent 
Unrelated 
The Adverse Event is clearly not related to the investigational agent(s) 
Unlikely 
The Adverse Event is doubtfully related to the investigational agent(s) 
Possible 
The Adverse Event  may be related to the investigational agent(s) 
Probable 
The Adverse Event is likely related to the investigational agent(s) 
Definite 
The Adverse Event is clearly related to the investigational agent(s) 
 
The completed SAE Report Form (see Study Procedure Manual) must be faxed to 
Hoosier Oncology Group within 1 business day of discovery of the event.   The 
investigator is responsible for informing the IRB and/or the Regulatory Authority of the 
SAE as per local requirements. 
 
 
 
11.3.2 
Death and Immediately Life-Threatening Events  
Any death and immediately life-threatening event from any cause while a patient is 
receiving trial treatment on this protocol or up to 30 days after the last dose of trial 
treatment, or any death and immediately life-threatening event occurring more than 30 
days after trial treatment has ended but which is felt to be treatment related must be 
reported within one business day of discovery of the event.  All deaths must be reported 


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primarily for the purposes of SAE reporting; however, deaths due unequivocally to 
progression are not SAEs.   
 
Your local IRB should be notified and their reporting procedure followed.  The 
completed SAE Reporting Form should be faxed to Hoosier Oncology Group within one 
business day of discovery of the event. 
 
11.3.3 
HOG Requirements for Reporting SAEs 
The Hoosier Oncology Group will report all SAEs that occur on subjects receiving 
rucaparib (from the time of first dose until 30 days post discontinuation) to Clovis within 
one business day of receipt of the SAE Reporting Form and to regulatory authorities 
(FDA) per federal guidelines.   
 
The Hoosier Oncology Group will fax a MedWatch Report to: 
BioSoteria, Inc 
Fax #  +1-800-708-3370 or 1-510-225-3980 
  
 
11.4 
IND Safety Reports Unrelated to This Trial 
IND safety reports not occurring on this trial but involving the study intervention 
(outside SAEs) received from outside sources will be reviewed by the Sponsor 
Investigator and will be forwarded to participating sites for submission to their 
Institutional Review Boards per their guidelines.   
 
 
12.0 
STATISTICAL CONSIDERATIONS 
 
Table 13: Data Sets for Protocol Endpoints 
Data Set/Endpoint 
Criteria 
Disposition 
All subjects registered into the study 
General safety 
All subjects receiving at least one dose of any drug 
Efficacy 
All subjects with at least one disease evaluation 
Patients will be included in the analysis for the treatment to which they were 
randomized. 
 
12.1 
Sample Size Justification 
The primary endpoint for this trial is 2 year DFS. In order to detect an improvement of 
the fraction of patients free from disease at 2-year from 40% in the control arm to 63.2% 
in the rucaparib arm (corresponding to an HR=0.5), 38 events are needed to have 80% 
power to detect a difference in DFS using a one-side log-rank test with 0.10 level of 
significance (calculation done using nQuery Advisor 7.0 and assuming exponential 
survival).  In order to observe 38 events we need to accrue about 102 patients, with an 
accrual time of about 13-18 months and an overall study duration around 25-30 months.  
In addition, 6 patients will be needed at the lower dose (cohort 1). Assuming ~20% will 
not be confirmed to have TNBC on central review; the total sample size will be increased 
to 135 to ensure 102 in the primary analysis (using cohort 2 and the randomized patients) 
and 6 in the safety analysis for cohort 1.  


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12.2 
 Patient Characteristics 
Patient characteristics will be summarized by treatment group for demographics, baseline 
disease characteristics, and medical history.  The two treatment groups will be compared 
using standard methods such as t-tests and chi-square tests. 
 
12.3 
Interim Safety Analyses 
The first 12 patients (6 in cohort 1 and 6 in cohort 2) will be assigned to the rucaparib arm 
for an initial safety run-in. A safety analysis will be done after all six patients in each 
cohort have completed cycle 2.  All toxicities will be tabulated.  The study will move 
forward to cohort 2 if  1 of 6 in cohort 1 experience a DLT (as defined in Section 5.1).  
If > 2 of 6 in cohort 1 experience a DLT, the study will be suspended and an amendment 
to explore alternate dosing schemes will be considered. Similarly, if  1 of 6 in cohort 2 
experience a DLT (as defined in Section 5.1), the randomized portion will commence.  If 
> 2 of 6 in cohort 2 experience a DLT, the study will be suspended and an amendment to 
proceed with the randomized portion with the cohort 1 dose will be considered. 
 
Once the decision is made to move forward with the randomized portion, a second safety 
analysis will be conducted after the first 40 patients (~20 from each group) have been 
randomized and completed 2 cycles of treatment.  Toxicity counts and rates will be 
tabulated by treatment arm in a blinded fashion. The study will be terminated if the 
probability that the DLT rate equals 20% or less in either arm drops below .10. Accrual 
will continue during the interim analysis. The results of the analysis will be submitted to 
the CTMC for external review. 
 
12.4 
Analysis of Primary Objective   
The comparison of DFS between the two groups will be made using an unstratified 
Kaplan-Meier analysis with a log-rank test to test for differences using the patients in 
safety run-in cohort 2 and the randomized portion of the study.  A specific comparison of 
2-year DFS will be made using a two-sample test based on the complementary log-log 
transformation as suggested in Klein, et al32.  As supportive analysis, a stratified log-rank 
test will be done using the stratified randomization factors neoadjuvant anthracycline 
versus not and lymph node involvement at time of definitive surgery versus not. In 
addition, sensitivity analyses using Cox regression may be carried out to identify 
prognostic factors and provide adjusted estimates of the treatment group differences in 
DFS. 
 
12.5 
Analysis of Secondary Objectives 
As support for the primary objective, overall DFS and 2-year DFS will be compared 
using the same techniques above using only the subjects in the randomized part of the 
study.  One-year DFS will be tested using the test described above for 2-year DFS. 
Safety and tolerability variables will be tabulated separately for the two groups. 
Incidences of selected adverse events from the two treatment arms may be compared 
using Fisher’s Exact tests on an exploratory basis. OS will be compared between 
treatment groups using the same methodology as DFS. PK levels will be described using 
summary statistics. In addition, characteristics of tumor specimens, and genomic DNA 
will be correlated with PARP inhibition, recurrence and toxicity. Continuous measures 
will be correlated with binary variables (e.g. recurrence and toxicity) using maximal chi-


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square tests and continuous variables (e.g. PARP inhibition) using Pearson or Spearman 
correlations. Binary variables such as tumor and genomic characteristics will be 
correlated recurrence and toxicity using chi-square or Fisher’s Exact test. All of the 
analyses with the PK and correlative data are exploratory and are designed to 
complement efforts in other trials with this agent. 
 
 
13.0 
TRIAL MANAGEMENT 
 
13.1 
Quality Controls and Quality Assurance 
 
 
 
13.1.1 Study Monitoring/Auditing 
Monitoring/Auditing visits to the trial sites will be made periodically during the trial, to 
ensure all aspects of the protocol are followed. Source documents will be reviewed for 
verification of agreement with data as submitted via the data collection system. The 
investigator/institution guarantee access to source documents by HOG or its designee and 
appropriate regulatory agencies.  
 
The trial site may also be subject to quality assurance audit by Pfizer or its designee as well 
as inspection by appropriate regulatory agencies.  
 
It is important for the investigator and their relevant personnel to be available during the 
monitoring/auditing visits and for sufficient time to be devoted to the process. 
 
13.1.2  Data and Safety Monitoring Plan 
HOG data safety monitoring activities include: 
• 
Review of clinical trial conducted for progress and safety 
• 
Review of all adverse events requiring expedited reporting as defined in the 
protocol 
• 
Review of reports generated by data quality control review process  
• 
Notification of the Sponsor Investigator of recommended action 
• 
Notification of sites coordinated by the HOG of adverse events requiring expedited 
reporting and subsequent committee recommendations for study modifications 
 
13.1.3 
Data/Safety Monitoring and Reporting Guidelines 
The HOG will compile data summary reports for this trial and submit these reports 
monthly to the Sponsor-investigator.  The HOG will submit data summary reports 
quarterly to the Indiana University Melvin and Bren Simon Cancer Center (IUSCC) 
Clinical Trial Monitoring Committee (CTMC) for review.  
 
13.2  
 Data Handling and Record Keeping 
 
13.2.1 
Case Report Forms 
An electronic case report form (eCRF) is required and must be completed for each 
included patient.  The completed dataset is the sole property of HOG and should not be 


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made available in any form to third parties, except for authorized representatives of 
appropriate Health/Regulatory Authorities, without written permission from HOG. 
 
13.2.2 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HOG, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records; e.g., hospital records), all original signed informed consent 
forms, copies of all eCRF’s, and detailed records of drug disposition.  To comply with 
international regulations, the records should be retained by the investigator in compliance 
with regulations. 
 
During data entry, range and missing data checks will be performed on-line.  The checks 
to be performed will be documented in the Data Monitoring Plan for the study.  A 
summary report (QC Report) of these checks together with any queries resulting from 
manual review of the eCRF’s will be generated for each site and transmitted to the site 
and the site monitor.  Corrections will be made by the study site personnel.  This will be 
done on an ongoing basis. 
 
13.3 
Changes to the Protocol 
Study procedures will not be changed without the mutual agreement of the Sponsor 
Investigator, Hoosier Oncology Group, and Clovis. 
 
If it is necessary for the study protocol to be amended, the amendment or a new version 
of the study protocol (amended protocol) will be generated by the Hoosier Oncology 
Group and must be approved by each IRB, Clovis, and if applicable, also the local 
regulatory authority.  Local requirements must be followed. 
 
If a protocol amendment requires a change to the Written Informed Consent Form, then 
the IRB must be notified.  Approval of the revised Written Informed Consent Form by 
the IRB is required before the revised form is used.  
 
The principal investigator is responsible for the distribution of these documents to his or 
her IRB, and to the staff at his or her center.  The distribution of these documents to the 
regulatory authority will be handled according to local practice. 
 
Clovis’s willingness to supply study drug is predicated upon the review of the protocol.  
The Hoosier Oncology Group agrees to provide written notice to Clovis of any 
modifications to the protocol or informed consent. 
 
13.4  
Ethics 
 
13.4.1 
Ethics Review 
 
The final study protocol, including the final version of the Written Informed Consent 
Form, must be approved or given a favorable opinion in writing by an IRB.  The 
investigator must submit written approval to the HOG office before he or she can enroll 
any patient into the study.   
 


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The principal investigator is responsible for informing the IRB of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB must approve all 
advertising used to recruit patients for the study.  The protocol must be re-approved by 
the IRB annually, as local regulations require.  
 
Progress reports and notifications of serious unexpected adverse drug reactions will be 
provided to the IRB according to local regulations and guidelines. 
 
The investigator is also responsible for providing the IRB with reports of any serious 
adverse drug reactions from any other study conducted with the investigational product.  
Clovis will provide this information to the Sponsor Investigator.  These reports will be 
reviewed by the Sponsor Investigator and those considered unexpected and possibly 
related to protocol therapy plus all deaths within 30 days of discontinuing treatment will 
be forwarded to participating sites for submission to their Institutional Review Boards 
per their guidelines.  All other events will be held and submitted to the sites for 
continuing review. 
 
13.4.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki, which are consistent with ICH/Good Clinical Practice, and 
applicable regulatory requirements. 
 
13.5  
Written Informed Consent 
The investigator will ensure the patient is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Patients 
must also be notified they are free to discontinue from the study at any time.  The patient 
should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
 
The patient’s signed and dated informed consent must be obtained before conducting 
any procedure specifically for the study.  The investigator must store the original, signed 
Written Informed Consent Form.  A copy of the signed Written Informed Consent Form 
must be given to the patient. 
 
 


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