Conditions: Hormone-Resistant Prostate Cancer Metastatic Prostate Carcinoma Recurrent Prostate Carcinoma Stage IV Prostate Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
In this study, patients who have metastatic prostate cancer that does not respond to hormone treatment and who have mutations in certain cancer-related genes will be treated with docetaxel and carboplatin chemotherapy.

Detailed description:
This is a phase 2 study of the combination of docetaxel and carboplatin in patients with germline inactivation of genes in the homologous recombination pathway, including BRCA1, BRCA2, and Ataxia Telangiectasia Mutated (ATM).

PRIMARY OBJECTIVE To assess rate of 50% Prostate Specific Androgen (PSA) decline to docetaxel and carboplatin

Arms:
arm 1: Docetaxel 60 mg/m2 will be administered on Day 1 of each 21-day cycle. Carboplatin Area Under the Curve (AUC) 5 will be administered on Day 1 of each 21-day cycle.

Docetaxel and carboplatin should be administered per institutional guidelines. Treatment will be repeated until disease progression or unacceptable toxicity.

Interventions: intervention 1: Carboplatin intervention 2: Docetaxel
Intervention descriptions: intervention 1: Chemotherapy intervention 2: Chemotherapy

Protocol document:
Prot_SAP_001.pdf: 
Study Title 
A Phase 2 Study of Docetaxel and Carboplatin for treatment of patients with metastatic, 
castration resistant prostate cancer and germline or somatic DNA repair deficiency    
Study Number POPCAP1 
Product Name Docetaxel and Carboplatin 
MIRB 00947 
Funding Agency  Prostate Cancer Foundation 
Principal Investigator  R. Bruce Montgomery, MD 
Version  6.0, 7/26/2019 
Human Subjects Protocol 
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Abstract 
This is a phase II study of the combination of docetaxel and carboplatin in patients with 
inactivation of genes in the homologous recombination pathway, including BRCA2, BRCA1, 
ATM, or a signature of homologous recombination deficiency (HRD).  At the VA Puget Sound 
only, up to 5 patients with each of the following mutations may be enrolled: ATM, CDK12, 
BARD!, BRIP1, CHEK1, CHEK2, RAD51C, RAD51D, MRE11, ATR, FANOM, and SOP 
mutations (without CHD1 loss). If 2 patients with the same mutation do not achieve a PSA50 
response before enrollment completes, we will terminate enrollment for this mutation for futility 
and it will not be considered predictive.  
Patients will be treated with docetaxel (60 mg/m2) and carboplatin (AUC 5) every 21 days until 
complete response, progression, unacceptable toxicity, or investigator discretion. Progression 
will be determined by PSA, CT chest/abdomen/pelvis and bone scan per Prostate Cancer 
Working Group 3 (PCWG3) criteria. 
The primary endpoint for the trial will be the maximal PSA response rate on 
docetaxel/carboplatin. This study will employ an admissible two-stage design. We expect the 
response rate with docetaxel/carbolatin to be 40% and consider the treatment as futile if PSA 
response rate is < 20%. In the first stage, 18 patients will be accrued. If there are 4 or fewer 
responses in these 18 patients, the study will be terminated. If more than 4 patients respond, 
then stage two begins and 17 additional patients will be accrued for a total of 35 at all sites who 
have similar studies. We will reject the null hypothesis that the treatment is futile and consider 
this treatment warrants further evaluation if 10 or more responses are observed in 35 patients. 
Patients must complete two cycles of chemotherapy to be considered evaluable. This design 
provides 80% power at the 5% level if the true response rate is 40%.  
We plan to treat up to 20 patients at the VA Puget Sound Health Care System, and at this site 
we have implemented a Pre-Screening procedure that will allow for testing of patients for both 
certain patterns of DNA damage. Because we anticipate a 70% genetic screening failure rate, we 
will need to consent up to 67 patients in order to find 20 who are eligible for treatment.  
 
 
 
 
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List of Abbreviations 
ADR 
 
Adverse drug reaction 
ADT 
 
Androgen deprivation therapy 
AE 
 
Adverse event 
ALT 
 
Alanine aminotransferase (SGPT) 
ANC 
 
Absolute neutrophil count 
AR 
 
Androgen receptor 
AST 
 
Aspartate aminotransferase (SGOT) 
ATM 
 
Ataxia Telangectasia Mutated 
AUC 
 
Area under the curve (concentration vs time) 
C 
 
Celsius 
CBC 
 
Complete blood count 
CLIA  
Clinical Laboratory Improvement Amendments 
CR 
 
Complete response 
CRPC  
Castration Resistant Prostate Cancer 
ctDNA  
Circulating tumor DNA 
CrCl 
 
Creatinine clearance 
CPK 
 
Creatinine phosphokinase 
CRF 
 
Case Report Form 
CT 
 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
 
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group (ECOG) Performance Status 
F 
 
Fahrenheit 
FDA 
 
Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 
GCSF/ G-CSF Granulocyte stimulating factor 
GLP 
 
Good Laboratory Practice 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GnRH  
Gonadotropin-releasing hormone 
Hct 
 
Hematocrit 
Hgb 
 
Hemoglobin 
HIPAA  
Health Information Portability and Accountability Act 
HR 
 
Hazard ratio 
HRD 
 
Homologous recombination deficiency 
ICF 
 
Informed consent form 
ICH 
 
International Conference on Harmonisation 
ISO 
 
Information Security Officer  
 
IND 
 
Investigational New Drug  
INR 
 
International normalized ratio 
IRB 
 
Institutional Review Board 
LDH 
 
Lactic dehydrogenase 
LLN 
 
Lower limit of normal 
LN 
 
Lymph node 
MedDRA 
Medical Dictionary for Regulatory Activities 
mCRPC 
metastatic Castration Resistant Prostate Cancer 
MRI 
 
Magnetic resonance imaging 
mTOR  
mammalian target of rapamycin 
NCCN  
National Comprehensive Cancer Network 
NCI 
 
National Cancer Institute 
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NYHA  
New York Heart Association 
OS 
 
Overall survival 
PARPi  
poly ADP ribose polymerase inhibitor 
PCF 
 
Prostate Cancer Foundation 
PCWG3 
Prostate Cancer Working Group 3 
PD 
 
Progressive disease 
PFS 
 
Progression free survival 
PR 
 
Partial response 
PSA 
 
Prostate specific antigen 
PSA50  
Greater than 50% PSA decline 
PT 
 
Prothrombin time 
QT 
 
Time from the start of the Q wave to the end of the T wave in the heart 
RANKL 
Receptor activator of nuclear factor kappa B ligand 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
 
Serious adverse event 
SAFE  
Safe Access File Exchange 
SCCA  
Seattle Cancer Care Alliance 
SU2C  
Stand Up to Cancer 
SD 
 
Stable disease 
SOC 
 
System Organ Class 
SRS 
 
Special reporting situations 
SUSAR 
Suspected unexpected adverse event reporting 
ULN 
 
Upper limit of normal 
UW 
 
University of Washington 
UWMC 
University of Washington Medical Center 
VAMC  
Veterans Administration Medical Center 
VHA 
 
Veterans Health Administration 
VIReC  
Veterans Administration Information Resource Center 
WBC  
White blood cell (count) 
 
 
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Contents 
1.0 
Study Personnel ................................................................................................................ 7 
2.0 
Introduction ....................................................................................................................... 7 
2.1 
Therapy for metastatic, castration resistant prostate cancer (mCRPC) .......................... 7 
2.2  
Sensitivity and resistance of CRPC to DNA damaging agents ....................................... 8 
2.3  
BRCA2 and DNA damage repair pathway genes in mCRPC ......................................... 9 
2.4  
Response to DNA damaging agents in tumors with biallelic inactivation of BRCA2 ..... 10 
2.4.1 
Additional mutation cohorts ...................................................................................... 11 
2.5  
Response to DNA damaging agents in tumors with a signature of homologous 
recombination deficiency in the absence of a mutation in a DNA repair gene (VA Puget Sound 
only) 11 
2.6 
Docetaxel and Carboplatin .............................................................................................. 12 
2.6.1 
Drug toxicity ............................................................................................................. 12 
2.6.2  
Dosing ...................................................................................................................... 14 
2.6.3 
Supply, Packaging and Storage ............................................................................ 14 
2.6.4 
Dose Modifications................................................................................................ 14 
2.7. Concomitant and supportive therapies ............................................................................. 15 
2.7.1 
 Antiemetics .......................................................................................................... 15 
2.7.2 
 Growth Factors .................................................................................................... 16 
2.7.3 
 Concomitant Therapy ........................................................................................... 16 
2.7.4 
 Restrictions .......................................................................................................... 16 
3.0 Objectives ............................................................................................................................ 16 
3.1 
Primary Objective......................................................................................................... 16 
3.2 
Exploratory Objectives (Phase 2) ................................................................................. 16 
4.0 
Resources and Personnel ............................................................................................... 17 
5.0 
Study Procedures ............................................................................................................ 17 
5.1  
Study Design ............................................................................................................... 17 
5.1.2  
Genitourinary Repository (VA Puget Sound only) ................................................. 17 
5.2  
Recruitment Methods ................................................................................................... 18 
5.3  
Informed Consent Procedures ..................................................................................... 19 
5.4  
Inclusion/Exclusion Criteria .......................................................................................... 19 
5.5  
Study Evaluations ........................................................................................................ 22 
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5.5.1  
Study Visit Overview ............................................................................................. 22 
5.5.2  
Pre-Screening Period (VA Puget Sound only) ....................................................... 23 
5.5.3 
Screening Period .................................................................................................. 23 
5.5.4  
Treatment Period .................................................................................................. 24 
5.5.5 
Study Discontinuation Visit.................................................................................... 24 
5.6  
Data Analysis ............................................................................................................... 25 
5.6.1 PLANNED STATISTICAL METHODS ........................................................................ 25 
5.7  
Withdrawal of Subjects ................................................................................................ 26 
5.8  
Safety Assessments .................................................................................................... 27 
6.0 
6.0 Reporting ................................................................................................................... 27 
6.1  
Definition of Adverse Event (AE) .................................................................................. 27 
6.2  
Adverse Drug Reaction (ADR) ..................................................................................... 28 
6.3  
Definition of a Serious Adverse Event .......................................................................... 28 
6.4  
Reporting Procedures for Adverse Events ................................................................... 29 
6.4.1  
Serious Adverse Events (on-site SAEs) ................................................................ 30 
6.4.2 
Reporting to IRB ................................................................................................... 30 
6.4.3 
Medical Monitor .................................................................................................... 30 
7.0 
Privacy and Confidentiality .............................................................................................. 30 
8.0 
Communication Plan ....................................................................................................... 31 
9.0 Information Security and Data Storage/Movement ............................................................... 31 
10.0  
References .................................................................................................................. 32 
11.0 
Appendices ..................................................................................................................... 35 
Appendix 1: 
Schedule of events ........................................................................................ 35 
Appendix 2: 
Adverse Events .............................................................................................. 36 
Appendix 3: 
Progression and response criteria.................................................................. 38 
Appendix 4: 
ECOG Grading Scale ..................................................................................... 44 
 
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Protocol Title:  A Phase 2 Study of Docetaxel and Carboplatin for treatment of patients with 
metastatic, castration resistant prostate cancer and germline or somatic DNA repair 
deficiency    
1.0 
Study Personnel 
NAME 
PAGER 
EMAIL 
AFFILIATION 
EMPLOYEE 
PI: Bruce Montgomery, MD  
206-559-5058 
Robert.Montgomery@med.va.gov 
VA Puget 
Sound HCS, 
UW, SCCA 
Attending 
Physician 
Matthew Rettig, MD, PI at 
VA Greater LA HCS 
310.478.3711 
x44761 
Matthew.Rettig@va.gov 
VA Greater 
LA HCS, 
UCLA 
Chief of 
Hematology-
Oncology 
Ajjai Alva, MD 
(734) 845-
5800 
Ajjai.Alva@va.gov 
VA Ann Arbor 
Healthcare 
System 
Attending 
Physician 
 
2.0 
Introduction 
2.1 
Therapy for metastatic, castration resistant prostate cancer (mCRPC)   
Prostate cancer is the most common cancer among men with approximately 220,000 new cases 
per year in the United States alone. Roughly 10-20% of patients present with metastatic disease, 
and 40% of patients relapse after surgery or radiation therapy for presumed localized disease. 
While androgen-deprivation therapy for advanced prostate cancer is usually initially effective, 
almost all tumors eventually become castration resistant after a median of 18-24 months. The 
currently FDA approved therapies for mCRPC include: docetaxel (Taxotere), the androgen 
receptor (AR) targeting agents abiraterone (Zytiga) and enzalutamide (Xtandi) prior to or after 
docetaxel, radium 223 (Xofigo) for patients declining docetaxel or after docetaxel, sipuleucel-T 
(Provenge) prior to or after docetaxel, and cabazitaxel (Jevtana).  Thus, there are many new 
treatment options for men with mCRPC.  One major challenge for the field is to identify subsets 
of patients whose cancer biology is distinct and may disproportionally benefit from treatment 
regimens that would otherwise not be considered.   
 
 
In current clinical practice the vast majority of patients receive either abiraterone or 
enzalutamide, and often radium 223, prior to docetaxel in the mCRPC setting.  The second 
generation AR-targeting agents abiraterone and enzalutamide are FDA-approved prior to 
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docetaxel in patients with mCRPC.  No prospective studies have been performed with docetaxel 
after either agent, and these are unlikely to be carried out given the cost and lack of industry 
sponsor. Single institution series suggest that treatment of prostate cancer with abiraterone prior 
to docetaxel reduces PSA response rates and progression free survival (PFS) to docetaxel 1. 
These results compare to the phase III registration studies of docetaxel (TAX-327) in which 
PSA50 was 45-50%, PFS 6 months and median OS of 18-19 months.2,3 
Together, these suggest that in the current treatment environment docetaxel is significantly less 
efficacious than has been reported in the registry studies, highlighting the need for approaches to 
improve docetaxel efficacy.  
Regimen 
Indication 
PSA50 
PFS  
OS 
Reference 
Docetaxel 
mCRPC 1st line 
45% 
NA 
18.9 mos 
Tannock 
Docetaxel 
mCRPC 1st line 
50% 
6 mos 
18 mos 
Petrylak 
Docetaxel after Abi 
mCRPC 1st line 
26%  
4.6 mos 
12.5 mos 
Mezynski 
Docetaxel after Abi 
mCRPC 1st line 
38 vs. 63% 
4.4 mos 
NA 
Schweizer 
 
2.2  
Sensitivity and resistance of CRPC to DNA damaging agents 
The first chemotherapeutic agent FDA approved for the treatment of CRPC was the DNA-
damaging anthracycline, mitoxantrone.4 Subsequent studies of the use of Satraplatin, a platinum 
agent in phase III randomized studies as second line chemotherapy (including after docetaxel) 
demonstrated a significant improvement in progression free survival (HR 0.67, PFS 11 weeks, 
PSA50 25%) 5.  Based on this evidence, investigators hypothesized that combining the DNA 
damaging agent carboplatin with docetaxel could improve efficacy. A CALGB phase II study of 
the combination of docetaxel and carboplatin with estramustine induced a PSA50 response rate 
of 68% with progression free survival of 8 months 6.  Estramustine is no longer considered 
because not only did it fail to improve response or survival compared to docetaxel alone, but it 
also added significant toxicity. Later studies indicated that combination therapy with a DNA 
damaging platinum and docetaxel improved response in previously treated tumors mCRPC 5.  In 
patients with tumors refractory to docetaxel, the addition of carboplatin has been reported to 
result in a PSA50 rate of 18% and PFS of 3 months 7. These results provide evidence that 
combining the DNA damaging agent carboplatin with docetaxel could improve efficacy, 
particularly in the right tumor context, such as known sensitivity to DNA-damaging agents such 
as platinums and anthracyclines.   
 
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Activity of carboplatin with docetaxel in prostate cancer 
Regimen 
 
Indication 
PSA50 
PFS  
OS 
Reference 
Docetaxel/carboplatin 
mCRPC 2nd 
line 
18% 
3 mos 
12 mos 
Ross 
Docetaxel/EMP 
carboplatin 
mCRPC 1st 
line 
68% 
8 mos 
19 mos 
Oh 
Platinum compounds, such as carboplatin and cisplatin, are believed to exert their anti-tumor 
effects through crosslinking of DNA, which in turn inhibits DNA synthesis and repair.  As a result, 
tumors with defects in DNA repair, and in particular those with mutations in homologous 
recombination genes such as components of the BRCA1/2-Fanconi anemia pathway are 
particularly sensitive to platinum agents and poly-ADP-ribose polymerase inhibitors (PARPi).  
The relationship between BRCA1/2-Fanconi anemia pathway and platinum sensitivity is well-
described in breast and ovarian cancers 8,9.  
The relationship between DNA-damaging cytotoxic chemotherapies such as platinums and 
anthracyclines and modest response in earlier prostate cancer trials suggests that an as-yet 
unidentified subset of patients benefitted most from treatment due to specific tumor biology.  We 
hypothesize that this is a subset of patients with defects in homologous recombination DNA 
damage repair pathway genes. 
2.3  
BRCA2 and DNA damage repair pathway genes in mCRPC  
Recent efforts have been underway to perform molecular profiling of metastatic, castration 
resistant prostate cancer as part of the SU2C Prostate Dream Team research studies in an 
attempt to better characterize the molecular subtypes of mCRPC.  Indeed, current analyses have 
revealed approximately 33% of CRPC metastatic tumors contain biallelic inactivation of BRCA1, 
BRCA2 or ATM10.  In approximately half of these cases, inactivation results from heterozygous 
copy loss in combination with a germline mutation, whereas in the other half of tumors 
inactivation results from somatic biallelic inactivation. The majority of mutations identified, both in 
the germline deleterious variants and purely somatic loss are in the BRCA2 gene, but mutations 
have also been identified in BRCA1, ATM, CHEK2, RAD51D, and PALB2 (BRCA1/2-Fanconi 
anemia pathway genes)10-12. Thus, the 20-30% of patients with mCRPC whose tumors harbor 
biallelic inactivation of BRCA1/2, ATM and other DNA repair enzymes may be the subset with 
increased sensitivity to treatment with DNA-damaging agents such as carboplatin, satraplatin 
and mitoxantrone in the earlier studies of unselected patients with mCRPC described above.  
The frequency of pathogenic germline variants in patients with mCRPC represents a significant 
enrichment compared to the frequency of germline DNA repair variants, generally estimated at 1-
2%12-14.  The increased frequency in germline pathogenic variants in patients with advanced 
disease likely results from the aggressiveness of these tumors15,16.  The relevance of identifying 
germline carriers of these genes among men with advanced prostate cancer is that essentially all 
of the primary and metastatic tumors from these patients contain biallelic inactivation of the DNA 
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repair gene of interest, and these are therefore considered founder mutations and present in 
essentially all malignant cells 11, and Montgomery unpublished. This is similar to findings in 
breast cancers, which develop in women with deleterious germline BRCA1 and BRCA2 variants, 
in whom essentially all tumors have loss of heterozygosity of the other allele 17,18. Hence, in the 
vast majority of tumors, both breast and prostate cancer develop in germline carriers harbor 
biallelic inactivation for the gene of interest.    
2.4  
Response to DNA damaging agents in tumors with biallelic 
inactivation of BRCA2 
We have identified three patients from UW/SCCA whose tumors contain biallelic inactivation in 
one of these three genes using either UW-Oncoplex or UWMC sequencing and have been 
successfully treated with regimens containing DNA damaging agents, either docetaxel with 
carboplatin (60 mg/m2 and AUC 5 every 21 days, 2 patients) or doxorubicin with carboplatin (1 
patient).  Two of the patients were treated with first-line docetaxel, one of whom was primarily 
refractory to docetaxel.  All three patients experienced significant PSA responses.   
• 
Patient 1 developed liver metastasis, had a limited response docetaxel, and no response 
to abiraterone and enzalutamide, and was ultimately treated with two prolonged cycles of 
docetaxel and carboplatin.   
• 
Patient 2 was treated docetaxel/carboplatin with complete response in his metastatic liver 
disease and subsequently treated with “maintenance” carboplatin and achieved two years 
of progression free survival.    
• 
Patient 3 was refractory to abiraterone and docetaxel and was treated with doxorubicin 
and carboplatin by his local oncologist based on the knowledge of his BRCA2 sequencing 
results and has achieved a greater than 50% PSA decline (PSA50).  
In summary, 3 of 3 patients with tumors containing biallelic BRCA2 inactivation achieved 
dramatic and sometimes very prolonged clinical responses to DNA damaging agents despite 
poor prognostic features such as liver metastases and failure of first-line docetaxel and second 
line hormonal agents. One case series of germline BRCA mutations carriers (unselected for 
biallelic loss) included a germline BRCA2 carrier with prostate cancer treated with 
docetaxel/carboplatin who survived for 37 months19. Our experience and the literature in 
malignancies other than prostate cancer suggest the possibility that 1 in 5 metastatic castration 
resistant prostate cancer tumors containing biallelic inactivation of BRCA1, BRCA2 or ATM and 
will be exquisitely sensitive to DNA damaging agents such as carboplatin and doxorubicin. The 
combination of taxane with platinum is proposed as the intervention based on several factors. 
First, docetaxel has been shown to be effective against adenocarcinoma of the prostate and is a 
standard of care intervention. Second, in phase II studies the combination of docetaxel and 
carboplatin is at least equally as effective as docetaxel against mCRPC which is not stratified by 
DNA repair deficiency. Third, the experience in the treatment of serous ovarian cancers, in which 
50% of patients’ tumors have inactivation of DNA repair genes demonstrates superiority of 
taxane plus platinum over either agent alone. 
 
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2.4.1 Additional mutation cohorts 
In order to improve recruitment and keep up with the latest research in precision oncology 
research, we will allow up to 5 patients with ATM, CDK12, BARD!, BRIP1, CHEK1, CHEK2, 
RAD51C, RAD51D, MRE11, ATR, FANOM, and SOP mutations (without CHD1 loss) each. If 2 
patients do not achieve a PSA50 response before enrollment completes, we will terminate 
enrollment for this alteration for futility and this aberration will not be considered predictive. 
2.5  
Response to DNA damaging agents in tumors with a signature of 
homologous recombination deficiency in the absence of a mutation in a 
DNA repair gene (VA Puget Sound only) 
It has been observed in breast and ovarian cancer that some tumors which do not contain 
obvious mutations in DNA repair pathway genes respond exceptionally well to platinum or 
PARPi.  Analysis of gene expression and patterns of DNA instability have revealed that many of 
these tumors contain a pattern of DNA damage which resembles tumors which contain a BRCA 
gene mutation or alteration 19,20.  This may occur through methylation of promotors for BRCA1 or 
BRCA2 and subsequent decrease in expression or through alterations of other genes in the DNA 
repair pathway 21,22.  In breast and ovarian cancer the use of signatures measuring the 
“BRCAness” phenotype (more accurately termed “BRCAlessness”) can find patients both with 
and without a BRCA alteration 23 and predict responses to platinum agents and PARPi 24-26.  
Sensitivity to platinum and PARPi occurs in a subset of patients with prostate cancer whose 
tumors do not contain BRCA mutations.   
In an ongoing study of docetaxel and carboplatin with the mTOR inhibitor sirolimus at UWMC 
and SCCA (NCT02565901), we have treated 17 patients with docetaxel refractory metastatic 
prostate cancers.  In that cohort, 4 patients have remained on therapy for over 40 weeks, 2 for 
over 70 weeks and 1 ongoing at over 90 weeks (predicted time to progression based on prior 
studies is 9 weeks).  These patients have had targeted next generation sequencing performed 
on their metastatic tumors and none have alterations of any genes known to regulate DNA 
repair.  We have also performed analysis of the metastasis biopsy DNA from patients who 
underwent sequencing as a component of the SU2C/PCF study which defined the current 
landscape of metastatic prostate cancer (Robinson).  In this analysis, 423 of the total of 650 
metastasis biopsies could be assessed for the presence of a signature for BRCAness.  There 
were 61 Homologous Recombination Deficiency signature positive tumors which did not contain 
an alteration in any known DNA repair gene, which represents 14% of all patients who had 
assessable tumor (De Sarkar and Nelson unpublished).  The signature analysis suggests that 
the largest metastasis biopsy cohort ever assembled in prostate cancer demonstrates a 
substantial subset of patients whose cancers do not contain a DNA repair mutation or loss (such 
as BRCA) but whose cancers are predicted to respond to platinum or PARPi. As a component of 
the current study we will test the hypothesis that a BRCAness signature (as assessed by the 
CLIA level assay Oncoplex) will predict for response to carboplatin based chemotherapy in men 
with mCRPC. 
In this study we propose to prospectively assess response to the combination of docetaxel and 
carboplatin in patients with mCRPC who have 1) germline pathogenic variant homologous 
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recombination genes 2) tumors which contain biallelic inactivation of BRCA1, BRCA2, ATM, 
PALB2 and RAD51D or other genes involved in homologous recombination, or 3) tumors which 
contain a signature for homologous recombination deficiency and have progressed after any 
succession of front-line agents.   
Patients will be identified through any of the following; 
 
1) Germline sequencing, and/or 
2) Tumor sequencing using a CLIA level assay (e.g. Foundation One, Oncoplex).  
3) Tumor sequencing for HRD signature using the CLIA level assay Oncoplex (HRD 
signature will only be performed using Oncoplex).   
 
The focus of the study is to determine if prostate cancers that contain DNA repair deficiency 
through germline or other mechanisms of inactivation are sensitive to DNA damaging agents. 
Although the biology clearly predicts that this will be the case, the sum of the data to support 
activity of platinum agents in DNA repair deficient tumors comes from the single case report cited 
previously.  In addition, in order to justify future standard of care germline screening of the 
population of men with metastatic prostate cancer, there must be a readily available therapeutic 
intervention which has been shown to be effective in deficient tumors.  Even a small study 
evaluating response of DNA repair deficient prostate cancer could have significant implications 
for screening and for future studies assessing the efficacy of platinum vs. more expensive agents 
such as PARP inhibitors.  Such a study would also justify additional efforts to improve outcomes 
for this subgroup of patients including chemotherapy followed by maintenance therapy with 
PARP inhibitors, more intensive regimens of DNA damaging agents (anthracyclines with 
platinum) and/or platinum based therapy at initiation of ADT for men with de novo metastatic 
prostate cancer.  
VA Puget Sound patients who have metastatic prostate cancer and tissue that can be 
sequenced but do not have qualifying mutations may sign a Pre-Screening consent form so that 
the tissue may be sent for HRD signature analysis. See section 5.5.2 for details.  
2.6 
Docetaxel and Carboplatin 
Docetaxel (Taxotere) and carboplatin (Paraplatin) are synthetic antineoplastic agents extensively 
used in the treatment of solid tumors.  Commercial sources will be used for this study.  
2.6.1 Drug toxicity 
  Toxicity of docetaxel includes:  
• 
Allergic Reaction:  Hypotension, urticaria, and hypersensitivity are reported.  
Premedication with dexamethasone is required. 
• 
Hematologic:  Taxanes, including docetaxel alone and in combination with other 
antineoplastic agents, have been associated with neutropenia, anemia and 
thrombocytopenia.  
• 
Neurologic:  Neuropathy is reported in over 10% of patients 
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• 
Dermatologic: Alopecia (56% to 76%), dermatological reaction (20% to 48%; severe: 
≤5%), nail disease (11% to 41%) 
• 
Endocrine & metabolic: Fluid retention (13% to 60%; severe: 7% to 9%; dose dependent) 
• 
Gastrointestinal: Stomatitis (19% to 53%; severe 1% to 8%), diarrhea (23% to 43%; 
severe: 5% to 6%), nausea (34% to 42%), vomiting (22% to 23%)  
• 
Hepatic: Increased serum transaminases (4% to 19%).  If bilirubin > ULN, or if AST 
and/or ALT > 1.5 × ULN concomitant with alkaline phosphatase > 2.5 × ULN docetaxel 
should not be administered.  
• 
Neuromuscular & skeletal: Weakness, myalgia and arthralgia are reported in greater than 
10% of patients.  
• 
Ophthalmic: Epiphora (associated with canalicular stenosis ≤1% with every 3-week 
administration)  
Toxicity of carboplatin includes: 
• 
Endocrine & metabolic: Hyponatremia (29% to 47%), hypomagnesemia (29% to 43%), 
hypocalcemia (22% to 31%), hypokalemia (20% to 28%) 
• 
Gastrointestinal: Vomiting (65% to 81%), abdominal pain (17%), nausea (without 
vomiting: 10% to 15%) 
• 
Hematologic & oncologic: Bone marrow depression (dose related and dose limiting; nadir 
at ~21 days with single-agent therapy), anemia (3/4: 21%), leukopenia (grades 3/4: 15% 
to 26%), neutropenia (grades 3/4: 16% to 21%), thrombocytopenia (grades 3/4: 25% to 
35%)  
• 
Hypersensitivity: Hypersensitivity (2% to 16%) 
• 
Renal: Decreased creatinine clearance (27%), increased blood urea nitrogen (14% to 
22%) 
• 
Central nervous system: Peripheral neuropathy (4% to 6%), neurotoxicity (5%) 
• 
Dermatologic: Alopecia (2% to 3%) 
Please refer to the package insert for docetaxel and carboplatin for all risks and precautions. The 
following are risks when docetaxel and carboplatin have been used in combination. 
 
Grade 3 
Grade 4 
Anemia 
6% 
0 
Neutropenia 
56% 
6% 
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Thrombocytopenia 
6% 
0 
Febrile neutropenia 
3% 
0 
Infection  
6% 
0 
Hyperglycemia 
6% 
0 
Pain 
6% 
0 
Renal insufficiency 
3% 
0 
Ross et al. 
2.6.2  Dosing 
Please refer to the docetaxel and carboplatin package inserts for complete preparation and 
administration. Dosing will be administered per institutional protocol. The starting doses for the 
study medications are as follows:  
• 
Docetaxel 60 mg/m2 will be administered on Day 1 of each 21-day cycle. 
• 
Carboplatin AUC 5 will be administered on Day 1 of each 21-day cycle. 
2.6.3 Supply, Packaging and Storage 
Docetaxel and carboplatin are stored, prepared, and administered per institutional protocol.  
2.6.4 Dose Modifications 
2.6.4.1  
Dose modifications for hematologic toxicity 
On day 1 of a cycle 
Dose 
ANC ≥1.5 x109 cells /L and platelet count ≥100 
x 109 /L 
100% 
ANC <1.5 x109 cells /L and platelet count <100 
x 109 /L  
Delay docetaxel and carboplatin. Repeat CBC 
weekly. If ANC resolves to ≥1.5 x109 cells /L 
AND platelet count to ≥100 x 109/L, resume 
docetaxel and carboplatin at 100% of starting 
dose. 
At any time during a cycle 
Grade 3 febrile neutropenia (defined as an 
ANC <1.0 x 109 cells/L) and a single 
Temperature of >38.3°C or a sustained 
temperature of ≥38°C for more than one 
hour)  
Delay treatment until improvement of symptoms 
and resolution of the ANC to ≥1.5 x109 cells /L 
and platelet count to ≥100 x 109 /L. 
Documented infection with Grade 3 
neutropenia (defined as an ANC <1.0 x 109 
cells/L) 
Decrease BOTH docetaxel and carboplatin to 
80% of starting dose for all subsequent cycles. 
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Grade 4 neutropenia (defined as an ANC 
<0.5 x 109 cells/L lasting more than 5 days) 
With recurrence of any of these toxicities, 
consider removal from chemotherapy or addition 
of growth factor support 
 
2.6.4.2  
Dose Modifications for Hepatic Toxicity 
AST/ALT > 2 x ULN OR AP  > 2x ULN 
(unless due to bone disease) OR bilirubin > 
WNL 
Delay treatment until recovery 
 
2.6.4.3  
Dose modifications for gastrointestinal toxicity 
For Grade 4 nausea and vomiting despite maximal antiemetic therapy, delay docetaxel and 
carboplatin until symptoms have resolved to ≤Grade 2. When symptoms have resolved to ≤
Grade 2, continue docetaxel and carboplatin at 100% of the current dose. If Grade 4 nausea and 
vomiting recur despite maximal antiemetic therapy, the patient should be removed from 
chemotherapy. 
2.6.4.4  
Dose modifications for docetaxel or carboplatin toxicity  
For patients who respond to combined study treatment of docetaxel and carboplatin (by PSA 
and/or radiographically assessed stable disease, partial response or complete response at first 
restaging in 3 months) treatment will continue until disease progression or unacceptable 
toxicities. If there is clinical response and toxicity (such as fatigue or neuropathy), doses of either 
docetaxel and/or carboplatin may be reduced (up to 25%) and/or held (up to 8 weeks) per 
investigator discretion to improve tolerability and allow the patient to continue treatment.  
For patients who respond to combined study treatment of docetaxel and carboplatin (by PSA 
and/or radiographically assessed stable disease, partial response or complete response at first 
restaging in 3 months), the docetaxel may be discontinued in the event of limiting toxicities from 
docetaxel and patient may continue on single agent carboplatin. If there is clinical response and 
cumulative toxicities to single agent carboplatin, doses may be reduced (up to 25%) and/or held 
(up to 6 weeks) per investigator discretion to improve tolerability and allow the patient to continue 
treatment. 
2.6.4.5  
Rationale for study design 
The combination of docetaxel and carboplatin has activity as first and second line therapy for 
patients with CRPC.  In the small number of patients at the UWMC/FHCRC for whom tumor 
sequencing has revealed biallelic inactivation, 3 out of 3 patients have responded to a 
carboplatin-containing regimen. Because the combination of docetaxel and carboplatin has been 
previously tested, has known efficacy and toxicity data for patients with CRPC, it is the most 
appropriate regimen for testing in this study. 
2.7. Concomitant and supportive therapies 
2.7.1  
Antiemetics 
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Dose modifications for nausea and vomiting should not be made until patients are on adequate 
doses of antiemetics. Docetaxel and carboplatin are classified as moderately emetogenic 
chemotherapeutic agents, with a frequency of emesis of 30-60%. Institutional guidelines for 
moderately emetogenic chemotherapy should be followed. 
2.7.2  
Growth Factors 
Filgrastim (G-CSF), pegfilgrastim, sargramostim (GM-CSF), and other growth factors may be 
utilized at the discretion of the investigator. All growth factors must be recorded as concomitant 
medication. NCCN guidelines for use of growth factors and prophylactic antibiotics will be 
followed based on patient risks of neutropenia and infection27. 
2.7.3  
Concomitant Therapy 
Concurrent enrollment in another clinical investigational drug or device study is prohibited. 
Supportive care medications are permitted with their use following institutional guidelines. 
Ongoing castration with GnRH analogue or surgical castration is required. Ongoing use of bone 
targeting agents (e.g. bisphosphonates, RANKL inhibitor) is allowed if initiated >4 weeks prior to 
initiation of study treatment. No other systemic antineoplastic is allowed. Palliative radiation to a 
single site is allowed at the discretion of the investigators.  
2.7.4  
Restrictions 
The concurrent administration of other anticancer therapy, including cytotoxic or immunotherapy, 
is prohibited. Use of other investigational drug therapy for any reason is prohibited. The decision 
to administer a prohibited drug/treatment will be made by the investigator based on the 
consideration of the safety of study participant. 
3.0 Objectives 
3.1 
Primary Objective  
• 
To assess rate of 50% PSA decline to docetaxel and carboplatin. 
3.2 
Exploratory Objectives (Phase 2) 
• 
To assess PSA response duration to docetaxel and carboplatin 
• 
To assess response of measurable disease  
• 
To assess time to progression of bone lesions or measurable disease (RECIST) 
• 
To assess response to docetaxel and carboplatin in patients with germline or somatic 
alterations of DNA repair pathway genes (such as BRCA1, BRCA2, ATM) or with a 
signature of homologous recombination deficiency   
• 
 To correlate the presence of DNA repair pathway mutations and copy number alterations 
in cell free DNA  
 
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4.0 
Resources and Personnel 
Name 
Role 
PHI Recruit Procedures ICF 
Analysis 
Bruce Montgomery, MD* PI 
Yes Yes 
Yes 
Yes Yes 
Matthew Rettig, MD 
PI LA 
No 
No 
No 
No 
Yes 
Ajjai Alva, MD 
PI Ann Arbor No 
No 
No 
No 
Yes 
 
* Please see Study Staff Page for all other study personnel.  
Dr. Montgomery will be running this study and recruiting patients from the VA Puget Sound 
Health Care System. Dr Matthew Rettig has a similar study at the VA Greater Los Angeles 
Health Care System, and Dr. Alva has a variation of this study at the VA Ann Arbor Health Care 
System. None of the other sites will be performing analysis based on signatures of homologous 
recombination deficiency. The PIs will analyze a combined subset of data from all sites. This 
subset of data shared between sites will consist of the minimum data necessary to accomplish 
study goals. All studies will be run independently aside from data sharing. 
5.0 
Study Procedures 
5.1  
Study Design 
This is an open-label study with a single phase II component.  
Patients will remain on treatment until any of the following occur: 
• 
unacceptable toxicity 
• 
documented progression by radiographic imaging  
• 
completion of 10 cycles of therapy (Note: Additional cycles permitted at the investigator’s 
discretion if patients are responding and there is no evidence of cardiomyopathy or other 
toxicities).  
• 
achievement of complete response (CR) per RECIST 1.1 criteria  
 
RECIST 1.1: (See Appendix).   Baseline CT or MRI of the abdomen/pelvis and chest film or 
chest CT will be performed during screening and every 3 cycles (9 weeks), or as clinically 
indicated. 
Bone Scan: Baseline bone scan will be performed during screening and every 3 cycles (9 
weeks), or as clinically indicated. 
5.1.2  Genitourinary Repository (VA Puget Sound only) 
All subjects will be invited to consent to the Genitourinary Repository (MIRB 00757) at the time of 
consenting to this study. Cell Free DNA will only be collected from subjects who consent to the 
Repository because all blood samples will be stored in the Repository. Repository subjects will 
also be invited to donate pre and post treatment biopsies of metastatic lesions if any are 
amenable to the procedure, but biopsies are optional. Banked data, blood, and tissue will be 
stored indefinitely per the repository guidelines.  
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5.2  
Recruitment Methods 
Study subjects will be recruited from the VA Puget Sound Health Care System, the VA Ann 
Arbor, and the VA Greater Los Angeles Health Care System.  
At the VA Puget Sound, eligible patients will be identified during routine review of the 
urology/oncology clinic. Their providers will give a brief introduction to the study, and if the 
patients are interested, they will be referred to the Investigators or study coordinator for a more 
detailed discussion and consenting. When presenting a research study to a patient the 
investigator will present multiple care options when it comes to research studies (these options 
are also described within the ‘alternatives to participation’ section of the consent form). The 
physician will discuss benefits and risks of each of the patients’ options (research and non-
research). The patient will then determine which of these care options they are interested in. This 
also prevents undue coercion because the provider is discussing all available options with the 
patient for their cancer care with no emphasis being placed on which option the patient should 
choose. No subject will be coerced in any way during the consenting process or during the study. 
Patients will be informed that participation in research studies is voluntary. Subjects will be 
informed that they do not need to participate in the study, that the subject can change their mind 
and decide to or not to participate at any time without penalty or loss of benefit to which they are 
otherwise entitled, and that the choice to participate or not participate in the study will not affect 
their VA care. Subjects can take the consent form home to discuss with their family, friends, or 
another doctor such as their primary care physician, and may return whenever they like to sign it 
or further discuss the study.  
A total of 18-35 subjects will be enrolled in the study, up to 20 of whom will be enrolled at the VA 
Puget Sound. Due to the anticipated pre-screening failure rate, we anticipate consenting up to 67 
patients in order to find 20 who qualify for treatment. This study will not use any advertising 
materials. Subjects will not be paid.  
 
Eligibility:  
Patients with mCRPC following 
any line of prior treatment AND  
identified by tumor NGS to have 
biallelic inactivation of:  
1. BRCA1/2 
2. ATM or other 
homologous DNA 
repair gene 
3. Signature for HRD 
Docetaxel  
60mg/m2 q21days 
+ 
Carboplatin  
AUC 5 q21days 
Primary objective:  
Rate of PSA50 
Exploratory:  
-PSA response duration 
-TT radiographic prog. 
-Correlate presence of tumor 
mutations in ctDNA 
P
R
O
G
R
E
S
S
I
O
N 
 
ctDNA 
ctDNA 
After study, 
Consider 
Mitoxantrone 
 or  
Carboplatin 
+Etoposide 
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5.3  
Informed Consent Procedures 
Study personnel who have been delegated to obtain informed consent will approach interested 
subjects during their clinic visit and will give them a brief verbal overview of the study. Those who 
are interested will be taken to a private room with their companions (if they wish), and the study 
personnel will review the whole ICF with them, answering any questions or concerns that may 
arise. Once all questions have been answered, the subject will sign the ICF and HIPAA under 
the supervision of the study personnel, who will also sign. Subjects may also take the ICF home 
for discussion with their physician or significant others, but must return to the VA Puget Sound to 
review, ask questions, and sign the ICF and HIPAA in the presence of qualified study personnel 
prior to any study-related procedures.  
We will be requesting a waiver of informed consent and HIPAA for screening so that we can 
identify eligible subjects when we review the lists of patients coming into the genitourinary 
oncology clinic. Written informed consent will be obtained from all subjects prior to any study 
procedures by study personnel (investigators and coordinators) who have been trained in the VA 
human subjects protections requirements and in the process of obtaining and documenting 
informed consent. All current study personnel have extensive experience obtaining and 
documenting informed consent. Any new study personnel who have not had such experience will 
be trained in several stages, including verbal instruction, shadowing consenting visits, VA 
training modules, and observation by qualified personnel.  
Consent will be documented by the signed Informed Consent Form (ICF) and by a Research 
Screening/Enrollment Note in the patient’s medical record. A copy of the signed form will be 
provided to the subject. No study procedures will be performed until after the ICF and HIPAA 
have been signed. All subjects must be able to give consent without the help of a legally 
authorized representative, and those with impaired decision-making capability or those who 
cannot read will not be included on this study.  
Study personnel obtaining informed consent will check that: 
• 
The most recent ICF and HIPAA forms are being used 
• 
All pages have the IRB approval stamp 
• 
All pages are present 
• 
Names, signatures, and dates are correct and none have been missed 
• 
Any errors have been properly corrected with one line through them and an initial and 
date 
• 
A copy of the signed ICF and HIPAA is given to the subject 
• 
An enrollment note is present in the patient’s medical record or as a hard copy 
• 
A copy of the ICF has been sent to the RCO within 3 days 
 
5.4  
Inclusion/Exclusion Criteria 
Patients meeting the following inclusion criteria will be eligible to participate in this study: 
1. Signed informed consent form (ICF) providing agreement to adhere to the dosing 
schedule, report for all trial visits and authorization, use and release of health and 
research trial information. 
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2. Age > 18 years 
3. Known prostate cancer  
4. Ongoing gonadal androgen deprivation therapy with gonadotropin-releasing hormone 
(GnRH) analogues, antagonists or orchiectomy.  Patients who have not had an 
orchiectomy must be maintained on effective GnRH analogue/antagonist therapy. 
5. Castration resistant prostate cancer as defined by serum testosterone < 50ng/ml and one 
of the following: 
• 
PSA level of at least 2 ng/ml that has risen on at least 2 successive occasions at least 
1 week apart. 
• 
Evaluable disease progression by modified RECIST (Response Evaluation Criteria in 
Solid Tumors). 
• 
Progression of metastatic bone disease on bone scan with > 2 new lesions. 
6. Prior therapy with abiraterone acetate, enzalutamide, or docetaxel.  There is no limit to 
the number of prior treatment regimens. 
7. Presence of metastatic disease on scans. 
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2. 
9. Life expectancy >12 weeks. 
10. No prior malignancy is allowed except: 
• 
Adequately treated basal cell or squamous cell skin cancer or 
• 
In situ carcinoma of any site or 
• 
Other adequately treated malignancy for which the patient has been disease-free 
for at least one year (any prior chemotherapy is allowed). 
11. Patients must have adequate organ and marrow function as defined below obtained 
within 14 days prior to initiating therapy: 
• 
Absolute neutrophil count >1.5 x 109 cells/L 
• 
Hgb > 9.0 g/dL 
• 
Platelets >100,000 x 109/L 
• 
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total 
bilirubin levels < 1.5 x ULN 
12. 
Presence of inactivation of BRCA1, BRCA2, or ATM genes OR one of the following: 
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• 
Patients with clearly deleterious mutations of other genes involved in homologous DNA 
repair may be included at the investigator's discretion. 
• 
Patients with homozygous inactivation of genes involved in homologous recombination 
from primary or metastatic tumor as assessed by a CLIA level assay for DNA sequencing 
may be included.  
• 
Patients with a signature of homologous recombination deficiency ("BRCAness") in 
primary or metastatic tissue may be included (VA Puget Sound only).  
Up to 5 patients with each of the following mutations may be enrolled: ATM, CDK12, BARD!, 
BRIP1, CHEK1, CHEK2, RAD51C, RAD51D, MRE11, ATR, FANOM, and SOP mutations 
(without CHD1 loss). If 2 patients with the same mutation do not achieve a PSA50 response 
before enrollment completes, we will terminate enrollment for this mutation for futility and it will 
not be considered predictive (VA Puget Sound only). 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study: 
1. Currently receiving active therapy for other neoplastic disorders. 
2. Histologic evidence of small cell carcinoma (morphology alone – immunohistochemical 
evidence of neuroendocrine differentiation without morphologic evidence is not 
exclusionary). 
3. Prior treatment with platinum-based chemotherapy for prostate cancer. 
4. Known parenchymal brain metastasis. 
5. Active or symptomatic viral hepatitis or chronic liver disease. 
6. Clinically significant heart disease as evidenced by myocardial infarction, or arterial 
thrombotic events in the past 6 months, severe or unstable angina, or New York Heart 
Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of 
< 35 % at baseline, if done. 
7. Treatment with an investigational therapeutic within 30 days of Cycle 1.  
8. Patients with dementia/psychiatric illness/social situations limiting compliance with study 
requirements or understanding and/or giving of informed consent are not eligible 
9. Any medical conditions, which, in the opinion of the investigators, would jeopardize either 
the patient or the integrity of the data obtained are not eligible. 
 
 
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5.5  
Study Evaluations 
5.5.1  Study Visit Overview 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant's malignancy. See Appendix 1 for Schedule of 
Events.  
Medical History 
Medical history, such as previous treatments, procedures, and conditions will be collected during 
the screening period. 
Physical Examination 
Physical examination includes HEENT (head, eyes, ears, nose, and throat), chest, cardiac, 
abdominal, extremities, neurologic, and lymph node examinations. 
Vital Signs 
Vital signs include blood pressure, heart rate and temperature on day of treatment. Weight will 
be recorded at every chemotherapy visit. Height will be recorded at initial clinic visit only. 
 
Imaging 
CT or MRI of the abdomen/pelvis will be performed during screening and every 3 cycles (9 
weeks), or as clinically indicated. A chest film or chest CT will be performed if clinically indicated.  
 
Bone Scan: Baseline bone scan will be performed during screening and every 3 cycles (9 
weeks), or as clinically indicated. 
 
Clinical Safety Laboratory Tests 
Clinical safety laboratory tests will be assessed as VA standard of practice. At a minimum, a 
complete blood count (CBC) and complete serum chemistry will be performed within 3 days of 
the first day of each cycle and thereafter as clinically indicated.  
Table 9. List of Clinical Safety Laboratory Tests 
Hematology: 
• 
Hematocrit (Hct) 
• 
Hemoglobin (Hgb) 
• 
Platelet count   
• 
Red blood cell (RBC) count  
• 
White blood cell (WBC) count with 
differential  
 
Liver Functions: 
• 
Alanine aminotransferase (ALT; SGPT) 
• 
Aspartate aminotransferase (AST; SGOT) 
• 
Alkaline phosphatase (ALK-P) 
• 
Total bilirubin 
Serum Chemistry: 
• 
Blood urea nitrogen (BUN) 
• 
Carbon dioxide (CO2) 
• 
Chloride (Cl) 
• 
Creatinine 
• 
Glucose 
• 
Potassium (K) 
• 
Sodium (Na) 
 
*Additional laboratory tests: 
Add Prothrombin Time (PT/INR) test per 
institutional guidelines for patients who are taking 
Coumadin while on study.  
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Research Labs 
Please refer to the laboratory manual for details. 
Sample Collection, Storage, and Shipping 
The relevant VAMC clinical laboratories will analyze all hematology, blood chemistry samples 
collected for the study. Samples will be analyzed at a facility meeting Good Laboratory Practice 
(GLP) requirements and/or using methods documented in a methods validation report 
5.5.2  Pre-Screening Period (VA Puget Sound only) 
Patients who have metastatic prostate cancer but do not have previous tests that confirm the 
presence of qualifying DNA mutations may sign a Pre-Screening consent form giving the study 
team permission to send blood or archival tumor tissue for CLIA level assay for genetic 
mutations and/or signature analysis to determine whether the patient has a hallmark of DNA 
repair deficiency ("BRCAness" or “genomic scarring”). The archival tumor sample may come 
from either clinically archived samples or from samples stored in the Genitourinary Repository 
(MIRB 00757) if available. The samples will be analyzed using the Oncoplex assay (UW CLIA 
certified assay) for the presence of a signature of homologous recombination deficiency.  
Patients whose pre-screening genetic tests are positive for genomic scarring will be invited to 
sign the Main Study Consent Form and enter the Screening Period. Patients who already have 
results showing that they have qualifying mutations do not need to complete Pre-Screening. 
They will sign the Main Study Consent Form and enter Screening directly.  
5.5.3 Screening Period  
Screening procedures to be completed within 30 days prior to the start of study treatment for 
patients who have qualifying mutations or DNA damage patterns. Baseline evaluations will be 
done within 30 days prior to start of therapy with the exception of laboratory tests, which should 
be completed within 14 days prior to initiating therapy. All screening should be complete prior to 
initiating therapy. 
• 
Informed consent 
• 
Medical history and demographics 
• 
Concurrent illness 
• 
Physical examination, including weight and height 
• 
Vital signs including blood pressure, heart rate, temperature. 
• 
Assessment of ECOG Performance Status 
• 
Blood collection within 14 days prior to initiating therapy for: 
o CBC (WBC with differential count, RBC, hemoglobin, hematocrit, platelets) 
o Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin), 
o Serum chemistries (sodium, potassium, chloride, carbon dioxide, creatinine, BUN, 
glucose) 
o Add prothrombin time (PT/INR) per institutional guidelines for patients who are 
taking coumadin while on study 
o PSA 
o Cell free DNA blood sample 
• 
Bone scan 
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• 
CT or MRI of the abdomen/pelvis 
• 
Chest film or chest CT if indicated 
• 
Concomitant medications.  Obtain a complete and thorough listing of all prescription and 
nonprescription (over the counter) medications currently taken including pain 
medications.  
• 
Obtain the sequencing report (UW Oncoplex, Foundation One, etc) wherein BRCA1/2, 
ATM mutation or HRD signature is reported and investigator to review for suitability to 
study. Patients who do not already have qualifying sequencing results must complete 
Pre-Screening first.  
 
5.5.4  Treatment Period 
Day 1 
Study assessments and medications should be administered ±4 days of the protocol-specified 
date, unless otherwise noted. Cycles are 21 days long.  
On Day 1 (± 4 days) of each cycle the following procedures will occur: 
• 
Vital signs (blood pressure, heart rate, temperature and weight)  
• 
Review adverse events and changes in concomitant medications 
• 
Blood collection for:  
o CBC (WBC with differential count, RBC, hemoglobin, hematocrit, platelets) 
o Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin) 
o Serum chemistries (sodium, potassium, chloride, carbon dioxide, creatinine, BUN, 
glucose) 
o Add prothrombin time (PT/INR) per institutional guidelines for patients who are 
taking coumadin while on study 
o Cell free DNA collection 
• 
Treatment with docetaxel & carboplatin 
 
• 
CT or MRI of the abdomen/pelvis and Chest film or chest CT will be repeated every 3 
months, or as clinically indicated. 
• 
Bone scan - if bone lesions are present at baseline, then bone scans will be performed 
every 3 months, at development of progression by RECIST or as clinically indicated. 
 
5.5.5 Study Discontinuation Visit 
This visit should occur within 28 days (± 7 days) of last dose of study medication if possible. 
• 
Physical exam 
• 
Vital Signs 
• 
ECOG performance status 
• 
Blood collection for:  
o CBC (WBC with differential count, RBC, hemoglobin, hematocrit, platelets) 
o Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin) 
o Serum chemistries (sodium, potassium, chloride, carbon dioxide, creatinine, BUN, 
glucose) 
o Add prothrombin time (PT/INR) per institutional guidelines for patients who are 
taking coumadin while on study 
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o PSA 
o Cell free DNA collection 
• 
Adverse Events 
 
5.6  
Data Analysis 
Criteria for Evaluation 
Antitumor effects:    
• 
The percentage of patients achieving ≥50% reduction in PSA according to PCWG3 
criteria 
• 
The percentage of patients achieving ≥90% reduction in PSA according to the PCWG3 
criteria 
• 
The percentage of patients achieving ≥30% reduction in measurable disease by RECIST. 
• 
Median time to tumor progression by PCWG3 criteria 
 
Statistical Methods: 
This is a phase II open-label, single-arm study in patients with mCRPC who have progressed on 
abiraterone acetate, enzalutamide, or docetaxel.  Patients will be treated docetaxel/carboplatin 
every three weeks concomitant maintenance of castrate levels of serum testosterone by GnRH 
analogue or surgical castration. Therapy will continue until disease progression, unacceptable 
toxicity, complete response, or patient withdraws consent.   
The primary endpoint for the trial will be the maximal PSA response rate or docetaxel/ 
carboplatin. Patients must complete two cycles of chemotherapy to be considered evaluable. 
This study will employ an admissible two-stage design. We expect the response rate with 
docetaxel/carboplatin to be 40% and consider the treatment as futile if PSA response rate is < 
20%. In the first stage, 18 patients will be accrued. If there are 4 or fewer responses in these 18 
patients, the study will be terminated.  If more than 4 patients respond, then stage two begins 
and 17 additional patients will be accrued for a total of 35. We will reject the null hypothesis that 
the treatment is futile and consider this treatment warrants further evaluation if 10 or more 
responses are observed in 35 patients. This design provides 80% power at the 5% level if the 
true response rate is 40%.  
Study Endpoints:  
ctDNA will be collected as per standard operating protocol (appendix). 
5.6.1 PLANNED STATISTICAL METHODS 
Determination of Sample Size 
The primary endpoint for the trial will be the maximal PSA response rate on 
docetaxel/carboplatin. This study will employ an admissible two-stage design. We expect 
the response rate with docetaxel/carbolatin to be 40% and consider the treatment as 
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futile if PSA response rate is < 20%. In the first stage, 18 patients will be accrued. If there 
are 4 or fewer responses in these 18 patients, the study will be terminated.  If more than 
4 patients respond, then stage two begins and 17 additional patients will be accrued for a 
total of 35. We will reject the null hypothesis that the treatment is futile and consider this 
treatment warrants further evaluation if 10 or more responses are observed in 35 
patients. Patients must complete two cycles of chemotherapy to be considered evaluable; 
we expect a 5% drop out rate, so we plan to enroll 35 patients in total. This design 
provides 80% power at the 5% level if the true response rate is 40%.  
The Investigators at all sites will analyze the limited data sets from all sites after phase 1 
and at the end of the study.  
Analysis Populations 
All patients who receive at least one dose of study drug will be included in the analysis. 
 
Demographics and Baseline Characteristics 
Demographic variables will include age, race, height, and weight. Baseline disease 
characteristics will include clinical stage, date of diagnosis, histology. 
5.7  
Withdrawal of Subjects 
 
Criteria for Discontinuation of Study 
• 
The patient develops an unacceptable toxicity  
• 
Radiographic disease progression per RECIST 1.1 or PCWG3 criteria 
• 
Clinical disease progression as assessed by the investigator  
• 
The patient develops a concurrent illness that is a contraindication to receiving further 
treatment. 
• 
The patient elects to discontinue treatment or withdraws consent. 
• 
At the discretion of the Investigator. 
 
Withdrawal from Study 
The investigator may withdraw a patient from any phase of the study for any of the following 
reasons. 
• 
Patient meets criteria for discontinuation of treatment. 
• 
Patient receives prohibited medications (i.e., concurrent administration of other 
anticancer therapy, immunotherapy or investigational drug therapy given for any reason 
during study treatment Phase).  
• 
Patient withdraws consent. In this event, the reason(s) for withdrawal must be 
documented and clarification if withdrawal of consent includes follow-up phase for 
progression data collection. If a subject terminates the study early, an Early Termination 
visit will be performed 
 
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5.8  
Safety Assessments 
All participants receiving investigational agents will be evaluated for safety. The safety 
parameters include all laboratory tests and hematological abnormalities, physical examination 
findings, and spontaneous reports of adverse events reported to the investigator by participants. 
All toxicities encountered during the study will be evaluated according to the NCI criteria 
specified in the protocol and reported according to the following sections.  
Safety assessments will include:  
• 
Adverse events including laboratory adverse events will be graded according to the NCI 
CTCAE, version 4.0.  
• 
Laboratory tests (CBC with differential, platelets, LFT’s, chemistry)  
• 
Vital Signs (blood pressure, heart rate, temperature and weight)  
• 
Physical exam  
• 
ECOG performance status  
 
6.0 
6.0 Reporting 
6.1  
Definition of Adverse Event (AE)  
An adverse event is defined in the International Conference on Harmonisation (ICH) Guideline 
for Good Clinical Practice as “Any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have to 
have a causal relationship with this treatment” (ICH E6:1.2). An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, diagnosis 
or disease temporally associated with the use of a medicinal product, whether or not related to 
the medicinal product. For the purposes of this study, temporal association is defined as the time 
between the subject’s informed consent signature through 28 days after the final dose of study 
medication.  
AEs further include worsening of a pre-existing medical condition (e.g., diabetes, migraine 
headaches, gout, hypertension, etc.) which has increased in severity, frequency or duration, or is 
associated with significantly worsened outcomes.  
The investigator or a medically licensed designee must pursue and obtain information adequate 
to determine the following: Grade (CTCAE v4.0), Causality (relationship to study medication) and 
Outcome. The investigator’s assessment of Grade, any Intervention (medication, procedure, 
etc.), Causality and Outcome will be indicated by signature of the PI or designated physician. For 
adverse events with a causal relationship to the investigational product, follow-up by the 
investigator is required until the event or its sequelae resolve or stabilize at a level acceptable to 
the investigator, or his/her designated representative.  
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Attribution is defined as the determination of whether an adverse event is related to a medical 
treatment or procedure. Attribution categories are as follows:  
•  Unrelated: The adverse event is clearly NOT related to therapy 
•  Unlikely: The adverse event is doubtfully related to therapy 
•  Possible: The adverse event may be related to therapy 
•  Probable: The adverse event is likely related to therapy 
•  Definite: The adverse event is clearly related to therapy  
6.2  
Adverse Drug Reaction (ADR)  
A noxious and unintended response to any dose of the drug (or biological) product for which 
there is a reasonable possibility that the product caused the response. ‘‘Reasonable possibility’’ 
means there is evidence to suggest a causal relationship between the drug and the adverse 
event.  
Suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event (21 CFR 312.23).  
Suspected Unexpected Adverse Event Reaction (SUSAR) is defined as an AE that is not 
consistent in nature, severity, or frequency with the product information documented in the 
current package insert or in the protocol, consent form, and/or prior reports.  
If the investigator or designee determines that an AE meets the criteria for classification as a 
Serious Adverse Event (SAE) or Suspected Unexpected Adverse Event Reaction (SUSAR), s/he 
will notify the IRB, and FDA according to site reporting policies (see section 6.4).  
Interventions for pretreatment conditions (e.g., elective cosmetic surgery) or medical procedures 
that were planned before study enrollment are not considered adverse events.  
6.3  
Definition of a Serious Adverse Event  
An adverse event or suspected adverse reaction is considered ‘‘serious’’ if, in the view of the 
investigator or a medically licensed designee, it results in any of the following outcomes:  
• 
Death;  
• 
a life-threatening adverse event;  
o 
An adverse event or suspected adverse reaction is considered ‘‘life-threatening’’ if 
its occurrence places the patient or subject at immediate risk of death. This 
definition does not include an adverse event or suspected adverse reaction that, 
had it occurred in a more severe form, might have caused death 
• 
inpatient hospitalization or prolongation of existing hospitalization;  
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• 
a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions;  
• 
a congenital anomaly/birth defect;  
• 
is a suspected transmission of infectious agents by a medicinal product.  
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.  
A hospitalization meeting the definition for “serious” is any in-patient hospital admission that 
includes a minimum of an overnight stay in a health care facility. Interventions for pretreatment 
conditions (e.g., elective cosmetic surgery) or medical procedures that were planned before 
study enrollment are not considered SAE/SUSARs for the purposes of this study. Inpatient 
admission does not include admissions to rehabilitation facilities, hospice facilities, skilled 
nursing facilities, nursing homes, routine emergency room admissions, same day surgery (as 
outpatient/same day/ambulatory procedures) or social admission (e.g., subject has no place to 
sleep).  
6.4  
Reporting Procedures for Adverse Events  
The investigator is responsible for ensuring that adverse events observed by the investigator or 
reported by subjects are collected and recorded in the CRF. All unexpected observed or 
volunteered adverse events will be recorded on the adverse event page(s) of the case report 
form (CRF) throughout the study period, from the signing of the informed consent through 28 
days after the final dose of study treatment.  
All AEs that are related to the study medication (listed in the prescribing information for the study 
drugs) of CTCAE v4.0 grade 3 or 4 will be recorded and reported per VA guidelines, but non-
serious AEs grade ≤ 2 that are expected and related to the study medication will only be 
recorded if the Investigator determines that they are clinically significant. Source documents may 
include the subjects’ medical records, patient diaries or study-specific worksheets. Recording for 
all events should be done in a concise manner using standard, acceptable medical terms.  
The adverse event recorded should not be a procedure or a clinical measurement (i.e. a 
laboratory value or vital sign) but should reflect the reason for the procedure or the diagnosis 
based on the abnormal measurement.  
Preexisting conditions that worsen in severity or frequency during the study should also be 
recorded (a preexisting condition that does not worsen is not an adverse event). Further, a 
procedure or surgery is not an adverse event; rather, the event leading to the procedure or 
surgery is considered an adverse event. Any event requiring unplanned in-patient hospitalization 
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that occurs during the course of a subject’s participation in a trial must be reported as an SAE, as 
previously stated.  
If, in the investigator’s judgment, a clinically significant worsening from baseline is observed in 
any laboratory or other test parameter (e.g. electrocardiogram (ECG), angiogram), physical 
exam finding, or vital sign, a corresponding clinical adverse event should be recorded.  
If a specific medical diagnosis has been made, that diagnosis or syndrome should be recorded 
as the adverse event, whenever possible. However, a complete description of the signs, 
symptoms and investigations which led to the diagnosis should be provided. For example, if 
clinically significant elevations of liver function tests are known to be secondary to hepatitis, 
“hepatitis” and not “elevated liver function tests” should be recorded. If the cause is not known, 
the abnormal test or finding should be recorded as an adverse event, using appropriate medical 
terminology (e.g., thrombocytopenia, peripheral edema, QT prolongation).  
For all adverse events, sufficient information should be obtained by the investigator to determine 
the causality of the adverse event (e.g., study drug, other illness, progressive malignancy, etc.). 
The relationship of the adverse event to the investigational product will be assessed by means of 
the question, “Is there a reasonable possibility that the event may have been caused by the 
investigational product?” The investigator should respond to this question with either Yes or No. 
6.4.1  Serious Adverse Events (on-site SAEs) 
New SAEs will be collected and recorded throughout the study period, from the signing of the 
informed consent through 28 days after the final dose of study treatment. Ongoing SAE/SUSARs 
with a causal relationship to the investigational product will be followed until the event or its 
sequelae resolve or stabilize at a level acceptable to the investigator or designee.  
6.4.2 Reporting to IRB  
AEs, SAEs, deviations, and problems should be reported per VA and local regulations. The 
requirements for the VA Puget Sound are listed here.  
Local research deaths that are both unanticipated and related to research must be reported 
orally to the HRPP director immediately. Written notification must be sent within 5 business days.  
Local SAES/Serious problems that are both unanticipated and related to research must be 
reported in writing to the IRB within 5 days.  
Events/problems that do not meet immediate reporting criteria should be reported to the IRB at 
the time of continuing review.  
6.4.3 Medical Monitor 
Dr. Wu, Chief of Oncology at the VA Puget Sound HCS will review safety and toxicity data (if 
any) for subjects at all sites every 6 months, or as necessary.  
7.0 
Privacy and Confidentiality 
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The collection and processing of personal data from subjects enrolled in this study will be limited 
to those data that are necessary to fulfill the study objectives. These data must be collected and 
processed with adequate precautions to ensure confidentiality and compliance with applicable 
data privacy protection laws and regulations. Appropriate technical and organizational measures 
to protect the personal data against unauthorized disclosures or access, accidental or unlawful 
destruction, or accidental loss or alteration must be put in place. Study personnel whose 
responsibilities require access to personal data agree to keep the identity of subjects 
confidential. 
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IRB review, and 
regulatory inspection. The consent also addresses the transfer of the data to other entities. 
The subject has the right to request through the investigator access to his personal data and the 
right to request rectification of any data that are not correct or complete. Reasonable steps will 
be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations. 
All study personnel will be trained in GCPs, HIPAA, and research regulations. Data will be stored 
in secure databases, on secure servers, or in locked cabinets in locked offices.   
8.0 
Communication Plan 
The site investigators at VA Puget Sound, VA Ann Arbor, and VA West Los Angeles will monitor 
study progress at both sites, including response and toxicities through regular teleconferences 
and email communication. The toxicities of docetaxel and carboplatin have been described in 
multiple phase I/II studies, and grade 3 or 4 toxicities are rare as per protocol. Because the drugs 
are being administered per standard of care and the toxicity profile has been described, it is felt 
that detailed toxicity monitoring is not critical. Monthly teleconferences are already in place 
between the sites and the sponsor, Prostate Cancer Foundation, to monitor study performance 
as a whole and this will continue for duration of study.  During this call investigators will 
communicate unexpected toxicities at each site and determine cumulative toxicity across the 
study.     
9.0 Information Security and Data Storage/Movement 
After consenting, data regarding the patient’s medical history and cancer treatment will be 
collected from patients and from CPRS. It will be stored on paper and electronically. Paper PHI 
will be stored together with study data in charts kept in locked cabinets in locked offices 
belonging to study personnel. Electronic data will be stored on secure VA servers accessible 
only to study personnel through secure, password-protected VA computers or VA web portals. 
All personnel who have access to study data agree to keep it confidential, and site personnel 
have all been trained in VA privacy policies. The Master Patient List will be kept separate from 
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study data. All study personnel will abide by GCPs, the HIPAA privacy law, and all other 
applicable laws and regulations.  
Data necessary for analysis of study results will be shared with researchers at other VAs who are 
affiliated with this study for analysis via secure portal (VA’s VIReC RedCap system), secure fax, 
tracked mail, email, Safe Access File Exchange (SAFE), Virtru, or other method approved by the 
ISSO.  
Study data will be archived and destroyed per VHA records control requirements.  
Some genomic and medical data may be shared with NIH databases such as the National 
Institutes of Health (NIH) Genomic Data Repository, GenBank, and National Cancer Foundation 
(NCF). The data will not contain any names, addresses, or personally identifiable information that 
could be used to identify individuals. These databases are available to help researchers 
understand different diseases. These databases contain DNA code and medical information from 
participants who have various diseases.  
As part of this study, we may release DNA and disease information about our patients into 
relevant genetic databases in order to help researchers understand the relationship between 
DNA and diseases.  
The DNA code in a genetic database cannot be used by itself to identify any specific person. A 
researcher who already has DNA code for one person could use information from a genetic 
database to learn more about that person. Once we release information to a genetic database, 
we no longer have any control over the use of this information 
10.0  References 
1. 
Mezynski J, Pezaro C, Bianchini D, et al. Antitumour activity of docetaxel following 
treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance? Ann 
Oncol 2012;23:2943-7. 
2. 
Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with 
mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 
2004;351:1513-20. 
3. 
Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus 
prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12. 
4. 
Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus 
prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian 
randomized trial with palliative end points. J Clin Oncol 1996;14:1756-64. 
5. 
Sternberg CN, Petrylak DP, Sartor O, et al. Multinational, double-blind, phase III study of 
prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer 
progressing after prior chemotherapy: the SPARC trial. J Clin Oncol 2009;27:5431-8. 
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6. 
Oh WK, Halabi S, Kelly WK, et al. A phase II study of estramustine, docetaxel, and 
carboplatin with granulocyte-colony-stimulating factor support in patients with hormone-refractory 
prostate carcinoma: Cancer and Leukemia Group B 99813. Cancer 2003;98:2592-8. 
7. 
Kumar A, White TA, MacKenzie AP, et al. Exome sequencing identifies a spectrum of 
mutation frequencies in advanced and lethal prostate cancers. Proc Natl Acad Sci U S A 
2011;108:17087-92. 
8. 
Byrski T, Huzarski T, Dent R, et al. Response to neoadjuvant therapy with cisplatin in 
BRCA1-positive breast cancer patients. Breast Cancer Res Treat 2009;115:359-63. 
9. 
Tan DS, Rothermundt C, Thomas K, et al. "BRCAness" syndrome in ovarian cancer: a 
case-control study describing the clinical features and outcome of patients with epithelial ovarian 
cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 2008;26:5530-6. 
10. 
Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic 
Prostate Cancer. N Engl J Med 2015;373:1697-708. 
11. 
Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced 
prostate cancer. Cell 2015;161:1215-28. 
12. 
Pritchard CC, Mateo J, Walsh M, et al. Inherited DNA-Repair Gene Mutations in Men with 
Metastatic Prostate Cancer. N Engl J Med 2016;1056/NEJMoa1603144. 
13. 
Gallagher DJ, Gaudet MM, Pal P, et al. Germline BRCA mutations denote a 
clinicopathologic subset of prostate cancer. Clin Cancer Res 2010;16:2115-21. 
14. 
Kote-Jarai Z, Leongamornlert D, Saunders E, et al. BRCA2 is a moderate penetrance 
gene contributing to young-onset prostate cancer: implications for genetic testing in prostate 
cancer patients. Br J Cancer 2011;105:1230-4. 
15. 
Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher 
risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J 
Clin Oncol 2013;31:1748-57. 
16. 
Akbari MR, Wallis CJ, Toi A, et al. The impact of a BRCA2 mutation on mortality from 
screen-detected prostate cancer. Br J Cancer 2014;111:1238-40. 
17. 
Gudmundsson J, Johannesdottir G, Bergthorsson JT, et al. Different tumor types from 
BRCA2 carriers show wild-type chromosome deletions on 13q12-q13. Cancer Res 
1995;55:4830-2. 
18. 
Neuhausen SL, Marshall CJ. Loss of heterozygosity in familial tumors from three BRCA1-
linked kindreds. Cancer Res 1994;54:6069-72. 
19. 
Gallagher DJ, Cronin AM, Milowsky MI, et al. Germline BRCA mutation does not prevent 
response to taxane-based therapy for the treatment of castration-resistant prostate cancer. BJU 
Int 2012;109:713-9. 
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20. 
Crawford J. Prevention and treatment of chemotherapy-induced neutropenia. Clin Adv 
Hematol Oncol 2013;11:514-7. 
21. 
Esteller M, Silva JM, Dominguez G, et al. Promoter hypermethylation and BRCA1 
inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 2000;92:564-9. 
22. 
Chalasani P, Livingston R. Differential chemotherapeutic sensitivity for breast tumors with 
"BRCAness": a review. Oncologist 2013;18:909-16. 
23. 
Davies H, Glodzik D, Morganella S, et al. HRDetect is a predictor of BRCA1 and BRCA2 
deficiency based on mutational signatures. Nat Med 2017;23:517-25. 
24. 
Zhao EY, Shen Y, Pleasance E, et al. Homologous Recombination Deficiency and 
Platinum-Based Therapy Outcomes in Advanced Breast Cancer. Clin Cancer Res 2017;23:7521-
30. 
25. 
Isakoff SJ, Mayer EL, He L, et al. TBCRC009: A Multicenter Phase II Clinical Trial of 
Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer. 
J Clin Oncol 2015;33:1902-9. 
26. 
Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade 
ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. 
Lancet Oncol 2017;18:75-87. 
27. 
Crawford J. Prevention and treatment of chemotherapy-induced neutropenia. Clin Adv 
Hematol Oncol 2013;11:514-7. 
 
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11.0 Appendices 
Appendix 1: 
Schedule of events 
 
Procedure 
Pre-Screening8 
Screening     
(within 30 
days prior to 
Day 1)1 
 
Day 1 of 
Every 
Cycle2 
Termination 
visit5 
Informed Consent  
 X (Pre-Screen) 
X (Main) 
 
 
Medical History  
 
X 
 
 
Physical exam 
 
X 
 
X 
Vital Signs 
 
X 
X 
X 
ECOG performance status 
 
X 
 
X 
CBC (w/ platelets & differentials) 
 
X 
X 
X 
Serum chemistry & electrolytes3 
 
X 
X 
X 
Hepatic function4 
 
X 
X 
X 
PSA 
 
X 
 
X 
CT or MRI of pelvis/abdomen6 
 
X 
 
 
Bone scan7 
 
X 
 
 
Chest film or chest CT6 
 
X 
 
 
Docetaxel and carboplatin 
 
 
X 
 
Adverse Events 
 
 
X 
X 
Concomitant Medications 
 
X 
X 
 
Cell free DNA collection 
 
X 
X 
X 
DNA sequencing for signature 
analysis 
X8 
 
 
 
 
1. Baseline evaluations will be done within 30 days prior to start of therapy. With the exception of laboratory tests, 
which should be completed within 14 days prior to initiating therapy. All screening should be complete prior to initiating 
therapy.  
2. All study assessments and medications should be administered ±4 days of the protocol-specified date, unless 
otherwise noted. Cycles are 21 days long. 
3. Chemistry & electrolyte labs include: BUN, CO2, chloride, creatinine, glucose, potassium, sodium. Add Prothrombin 
Time (PT/INR) test per institutional guidelines for patients who are taking Coumadin while on study.  
4. Hepatic function includes AST, ALT, alkaline phosphatase and total bilirubin. 
5. Termination visit to occur within 28 days (± 7 days) of last dose of study medication if possible. 
6. CT or MRI of the abdomen/pelvis will be performed during screening and every 3 cycles (9 weeks), or as clinically 
indicated. A chest film or chest CT will be performed if clinically indicated.  
7. Bone Scan: Baseline bone scan will be performed during screening and every 3 cycles (9 weeks), or as clinically 
indicated. 
8. Pre-Screening and signature analysis only available at the VA Puget Sound. This may be performed at any time 
prior to Screening. 
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Appendix 2: 
Adverse Events 
Definitions 
 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
medicinal product and which does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not related to the medicinal product. 
 
Adverse Drug Reaction (ADR) 
A noxious and unintended response to any dose of the drug (or biological) product for which 
there is a reasonable possibility that the product cause the response.  ‘‘Reasonable possibility’’ 
means there is evidence to suggest a causal relationship between the drug and the adverse 
event.  Suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any adverse event caused by a drug. 
 
Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered ‘‘serious’’ if, in the view of the 
investigator, it results in any of the following outcomes:  
• 
Death,  
• 
a life-threatening adverse event,  
• 
Life-threatening adverse event or life-threatening suspected adverse reaction.  
• 
An adverse event or suspected adverse reaction is considered ‘‘life-threatening’’ if, in the 
view of the investigator, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
• 
inpatient hospitalization or prolongation of existing hospitalization,  
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or  
• 
a congenital anomaly/birth defect.  
• 
is a suspected transmission of infectious agents by a medicinal product 
 
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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
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Appendix 3: 
Progression and response criteria  
Antitumor Effect– Solid Tumors 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Changes in only 
the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST 
1.1 criteria. 
Definitions 
Evaluable for toxicity. All participants who receive at least one dose of study treatment will be 
evaluable for toxicity from the time of their first treatment. 
Evaluable for objective response. Only those participants who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response. These participants will have their response classified 
according to the definitions stated below. (Note: Participants who exhibit objective disease 
progression or die prior to the end of cycle 1 will also be considered evaluable. 
Disease Parameters 
Measurable disease (Target Lesions)  
Lesions that can be accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 10 mm (this requirement based on a CT slice thickness of ≤ 5 mm; for slice 
thicknesses > 5 mm, measurable lesions must have a longest diameter ≥ 2 times the slice 
thickness). 
A lymph node will be considered pathologically enlarged and measurable if its short axis is ≥ 15 
mm; the short axis should be measured and followed throughout. Nodes with a short axis ≥ 10 
mm and < 15 mm will be considered pathologically enlarged but nonmeasurable (see below). 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft-tissue components will be 
considered measurable if the soft-tissue component can be evaluated by cross-sectional imaging 
(i.e., CT scan) and meets the general definition of measurability. 
Simple cysts will not be considered malignant lesions,and will be neither measurable nor 
nonmeasurable. Cystic lesions believed to be metastases may be considered measurable if they 
meet the general definition of measurability, but noncystic lesions are preferred as target lesions. 
A lesion located in a previously irradiated area, or in an area previously subjected to any 
locoregional therapy, will be considered measurable only if there has been a documented 
increase in lesion size subsequent to prior treatment but prior to study entry. 
 
 
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Non-measurable disease (Non-target Lesions) 
All other lesions including small lesions (longest diameter < 10 mm or pathological lymph nodes 
with a short axis of ≥ 10 mm and < 15 mm) and truly nonmeasurable lesions. 
Lesions considered to be truly nonmeasurable include the following: bone lesions; ascites; 
pleural/pericardial effusion; inflammatory breast disease; lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques. Blastic bone lesions are nonmeasurable. 
1. Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or digital 
measurement tool. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the anti-tumor effect of a treatment. 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes). For the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable. 
Conventional CT and MRI. These techniques should be performed with cuts of 10 mm or less 
in slice thickness contiguously. Spiral CT should be performed using a 5mm contiguous 
reconstruction algorithm. This applies to tumors of the chest, abdomen, and pelvis. Head and 
neck tumors and those of extremities usually require specific protocols. 
2. Response Criteria 
Overall tumor response, as defined in Table 11, will be based on an integration of the evaluation 
of target, non-target, and new lesions, as described below: 
2.1. Evaluation of Target Lesions 
Complete Response (CR):  
The disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes 
reduced to < 10 mm. 
Partial Response (PR):  
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At least a 30% decrease in the sum of the diameters of target lesions (including the short axes of 
any target lymph nodes), taking as reference the baseline sum diameter. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum diameter since the treatment started 
Progressive Disease (PD):   
At least a 20% increase in the sum of the diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm. (Note: the appearance of one or more new lesions is also considered progression.) 
Not Evaluable (NE):  
A target lesion present at baseline which is subsequently not measured or which is unable to be 
evaluated, leading to an inability to determine the status of that particular tumor for the time point 
in question. This category also includes scans that are not performed at this time point to 
evaluate the target lesion(s). The reason(s) explaining the absence of the evaluation or 
nonevaluable nature of the lesion(s) should be specified at the time of the assessment (eg, early 
death due to malignant disease; early death due to toxicity; tumor assessments not repeated or 
incomplete; other [specify]). 
Note: If tumor response data is missing, an overall assessment cannot be done. However, if 
there is missing or unevaluable data for non-target lesions, but data is available for all target 
lesions, the overall response for that time point will be assigned based on the sum LD of all 
target lesions. Additionally, the assessment of CR cannot be made if there is missing or 
unevaluable data for non-target lesions. In this case, the overall assessment would be PR. 
2.2. Evaluation of Non-Target Lesions 
Complete Response (CR):  
The disappearance of all non-target lesions, the normalization of the tumor marker level (if tumor 
markers are measured and are initially above the upper limit of normal, those must normalize for 
a patient to be considered in complete clinical response). All lymph nodes must be < 10 mm 
(short axis). 
Incomplete Response/Stable Disease (SD):  
The persistence of one or more non-target lesions and/or the maintenance of the tumor marker 
level above normal limits. 
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Progressive Disease (PD):  
The appearance of one or more new lesions and/or unequivocal progression of existing non-
target lesions. PD may be declared on the basis of “unequivocal progression” in cases where the 
overall tumor burden increases significantly enough to require a change in therapy; in most 
cases, a modest increase in the size of one or more non-target lesions is not sufficient to qualify 
(especially in the presence of SD or PR in target disease). 
Unknown (UN):  
A nontarget lesion present at baseline which is subsequently not measured or which is unable to 
be evaluated, leading to an inability to determine the status of that particular tumor for the time 
point in question.  
This category also includes scans that are not performed at this time point to evaluate the 
nontarget lesion(s). The reason(s) explaining the absence of the evaluation or nonevaluable 
nature of the lesion(s) should be specified at the time of the assessment (e.g., early death, 
malignant disease; early death, toxicity; tumor assessments not repeated or incomplete; other.) 
Note: Although a clear progression of "non-target" lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression status 
should be confirmed at a later time by review of the Principal Investigator (or Protocol Chair). 
Additionally, the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment is mandatory to differentiate between stable or progressive disease 
status. 
3. Evaluation of Best Overall Response 
Each response parameter (target, non-target, and new lesions) will be reported independently at 
each radiologic read. The investigator will make a determination of overall response based on 
the evaluation of target, non-target, and new lesions, as shown in Table 11 and Table 12. 
Table 10. Time Point Response: Patients with Target (± Non-Target) Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not Evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
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SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluateda 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
a In general, if only a subset of lesion measurements are taken at a given assessment time point, the 
patient as a whole is considered not evaluable for that time point, unless a convincing argument can be 
made that the contribution of the individual missing lesion(s) would not change the assigned time point 
response. 
Abbreviations: CR = complete response; NE = nonevaluable or inevaluable; PD = progressive disease; PR 
= partial response; SD = stable disease 
Table 11. Time Point Response: Patients with Non-Target Disease Only 
Non-target Lesions 
New  Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a Non-CR/non-PD is preferred over stable disease for non-target disease since SD is increasingly used as 
an endpoint for assessment of efficacy in some trials. Thus, it is not advised to assign the category of SD 
when no lesions can be measured. 
Abbreviations: CR = complete response; NE = nonevaluable or inevaluable; PD = progressive disease 
4. Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrence or PD is objectively documented, taking as reference for PD the smallest 
measurements recorded since the treatment started. 
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that recurrent disease is objectively 
documented. 
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Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started. 
5. Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to time 
of objective disease progression. 
9. Bone Scan Progression per PCWG3 
The criteria for radiographic progression by bone scan are based on the recommendations of the 
PCWG3.  The evaluation of radiographic bone lesion response will be performed by bone scan 
only. Of note, progressive disease determination for bone scan disease requires a confirmatory 
scan as outlined below. 
Prior to the Week 12 assessment, a patient will be considered to have progressed if the bone 
scan shows ≥ 2 new lesions compared with baseline and confirmed ≥ 6 weeks later by a second 
bone scan showing ≥ 2 additional new lesions (total of ≥ 4 new lesions compared with baseline). 
After the Week 12 assessment, a patient will be considered to have progressed if the bone scan 
shows ≥ 2 new lesions compared with baseline and confirmed ≥ 6 weeks later by a second bone 
scan.  
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 Appendix 4: 
ECOG Grading Scale 
 
ECOG Performance Status Scale 
 
GRADE SCALE 
0 
Fully active, able to carry out all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out work activities. Up and about 
more than 50% of waking hours.  
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.  
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
 
 
 
 
 
 
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