Conditions: Castration Levels of Testosterone Castration-Resistant Prostate Carcinoma Metastatic Prostate Carcinoma Prostate Carcinoma Metastatic in the Bone PSA Progression Stage IV Prostate Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
This pilot clinical trial studies docetaxel and carboplatin in treating patients with castration resistant prostate cancer that has spread from the primary site (place where it started) to other places in the body (metastatic) and contains inactivated genes in the BRCA 1/2 pathway. Drugs used in chemotherapy, such as docetaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description:
OUTLINE:

Patients receive docetaxel intravenously (IV) over 30-60 minutes and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 10 courses in the absence of disease progression or unacceptable toxicity.

Arms:
arm 1: Patients receive docetaxel IV over 30-60 minutes and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 10 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Carboplatin intervention 2: Docetaxel intervention 3: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
 
 
Official Title: 
A Pilot Study of Docetaxel and Carboplatin for treatment 
of patients with metastatic, castration resistant prostate 
cancer containing biallelic inactivation of genes in the 
BRCA1/2 pathway 
NCT number: 
NCT02598895 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
June 8, 2022 
 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
1 
Clinical Study Protocol 
Study 
Title: 
A Pilot Study of Docetaxel and Carboplatin for treatment of patients with metastatic, 
castration resistant prostate cancer containing biallelic inactivation of genes in the BRCA1/2 
pathway 
Study Number: 
9381 
Study Phase: 
Pilot 
Product Name: 
Docetaxel and Carboplatin 
IND Number: 
not applicable 
Indication: 
Treatment of metastatic, castration resistant prostate cancer containing biallelic 
mutations of genes in the BRCA1/2 pathway 
Study sites 
University of Washington, Fred Hutchinson Cancer Center 
Investigators 
Principal investigator:  
Heather Cheng, M.D., Ph.D. 
Co-Investigators: 
Robert Bruce Montgomery, M.D. 
Andrew Hsieh, M.D. 
Elahe Mostaghel, M.D., Ph.D. 
Peter Nelson, M.D. 
Michael Schweizer, M.D. 
Evan Yu, M.D. 
James Drechsler PA-C 
Tanisha Mojica, ARNP Katie 
Nega, ARNP 
Protocol version 
Current Version Date: 04.22.2022 
IRO REC'D MAY 17 2022
FHCRC IRB Approval  
JUN 08 2022 
Document Released Date


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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STUDY 
OBJECTI
VES: 
Primary Objective: 
To determine the PSA response to docetaxel and carboplatin in the treatment of 
patients with metastatic CRPC containing biallelic inactivation of the
homologous DNA repair (BRCA1/2) pathway, including BRCA1, BRCA2 and
ATM.
Secondary Objectives: 

To assess maximal PSA response to docetaxel and carboplatin

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 1.1) 
 To correlate the presence of DNA repair pathway mutations in circulating tumor
cells (CTC) and cell free DNA with the presence of mutations in tumor 
biopsy. 
METHODS: 
This is a pilot study of the combination of docetaxel and carboplatin in patients whose tumors are found to 
contain biallelic inactivation of genes in the BRCA1/2 pathway, including BRCA2, BRCA1 and ATM. 
Patients will be treated with docetaxel (60 mg/m2) and carboplatin (AUC 5) every 21 days until progression or 
unacceptable toxicity. Progression will be determined by PSA, CT chest/abdomen/pelvis and bone scan per 
Prostate Cancer Working Group 2 (PCWG2) criteria. 
Number of Patients: 14 or more 
Inclusion 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
2.
Male age > 18 years 
3.
Histologically or cytologically confirmed adenocarcinoma of the prostate (excluding neuroendocrine 
differentiation and small cell histology) 
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 < 50 ng/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 1.1 (Response Evaluation Criteria in Solid Tumors)

Progression of metastatic bone disease on bone scan with > 2 new lesions
6.
Presence of metastatic disease on bone or CT scan
7.
Prior therapy with abiraterone, enzalutamide and/or docetaxel. There is no limit to the number of prior treatment
regimens.
8.
Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1
9.
Presence of biallelic inactivation of BRCA1, BRCA2, ATM (see section 1.1)


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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and/or Patients with clearly deleterious mutations of other genes involved in homologous DNA repair 
may be included at the investigator’s discretion. 
 
Exclusion Criteria: 
 
Patients meeting any of the following exclusion criteria are NOT eligible: 
 
1. Currently receiving active therapy for other neoplastic disorders will not be eligible. 
2. Histologic evidence of neuroendocrine or small cell carcinoma of the prostate will not be eligible. 
3. Known parenchymal brain metastasis 
4. Active or symptomatic viral hepatitis or chronic liver disease 
5.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 
6. Treatment with an investigational therapeutic within 30 days of Cycle 1. 
7.Presence of dementia, psychiatric illness, and/or social situations limiting compliance with study 
requirements or understanding and/or giving of informed consent. 
8.Any condition(s), medical or otherwise, which, in the opinion of the investigators, would jeopardize either the 
patient or the integrity of the data obtained. 
 
CRITERIA FOR EVALUATION 
 
Anti-Tumor Effects: 
 
The percentage of patients achieving ≥50% reduction in PSA according to PCWG2 criteria. 
 
The percentage of patients achieving ≥90% reduction in PSA according to PCWG2 criteria. 
 
The percentage of patients achieving ≥30% reduction in measurable disease by RECIST 1.1. 
 
Median time to tumor progression by PCWG2 criteria. 
 
STATISTICAL METHODS: 
Efficacy: 
The proportion of patients with PSA decline by 50% from baseline (PSA50) will be evaluated. The primary 
efficacy endpoint is the percent of patients achieving PSA50 with docetaxel and carboplatin. The historical 
comparison is a PSA50 of 26%. The target response rate is 60%. The study will follow an optimal two-stage 
Simon design (Simon, 1989) where the null hypothesis that the true PSA response rate (PSA decline by 50% 
from baseline) is 0.26 will be tested against a one-sided alternative. 
 
We will use a Simon minimax 2-stage design, which will allow early stopping for futility after the first stage if the 
response rate is low. Our null and alternative hypotheses are H0: p≤26% vs. H1: p≥60%. The minimax 2-stage design 
for these parameters requires a first stage enrolling 5 patients. If 1 of the first 5 patients achieves a PSA50 response, H0 
cannot be rejected. If ≥1 of 5 patients respond, enrollment in that cohort continues until 14 patients have completed the 
trial, and the response rate is calculated for all 14 patients. If ≤6 of 14 patients have a PSA50 the null hypothesis cannot 
be rejected. This design will provide 80% power to detect a PSA50 rate of 60% (one-sided α=0.05). This design also 
provides a 60% probability of early stopping if H0 is true, affording protection against treating more patients than 
necessary if the treatment is not effective.


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ....................................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .......................................................... 6 
1 INTRODUCTION ............................................................................................................................ 8 
1.1 Therapy for metastatic, castration resistant prostate cancer (CRPC) ........................................ 8 
1.2 Sensitivity and resistance of CRPC to DNA damaging agents ................................................. 9 
1.3 BRCA2 and DNA damage repair pathway genes in CRPC ................................................... 10 
1.4 Response to DNA damaging agents in tumors with biallelic inactivation of BRCA2.10 1.5
 
Docetaxel and carboplatin ..................................................................................................... 11 
1.5.1 
Drug toxicity ............................................................................................................... 12 
1.5.2 
Supplier ....................................................................................................................... 12 
1.5.3 
Rationale for study design ........................................................................................... 13 
2 STUDY OBJECTIVES ................................................................................................................... 13 
2.1 Primary Objective ................................................................................................................. 13 
2.2 Exploratory Objectives (Phase 2) .......................................................................................... 13 
3 INVESTIGATIONAL PLAN ......................................................................................................... 13 
3.1 Overall study design and plan ................................................................................................ 13 
4 STUDY POPULATION SELECTION ........................................................................................... 14 
4.1 Study Population ................................................................................................................... 14 
4.2 Inclusion Criteria ................................................................................................................... 14 
4.3 Exclusion Criteria ................................................................................................................. 15 
5 STUDY TREATMENT(S) ............................................................................................................. 16 
5.1 Treatments Administered ...................................................................................................... 16 
5.1.1 
Docetaxel and carboplatin ........................................................................................... 16 
5.1.2 
Antiemetics ................................................................................................................. 16 
5.1.3 
Growth Factors ............................................................................................................ 16 
5.1.4 
Concomitant Therapy ................................................................................................... 17 
5.1.5 
Restrictions ................................................................................................................. 17 
5.2 Supply, Packaging and Storage ............................................................................................. 17 
5.2.1 
Docetaxel and carboplatin Supply, Packaging, Storage ............................................... 17 
5.3 Investigational Product Retention and Accountability at Study Site ....................................... 17 
5.3.1 
Dose modifications for hematologic toxicity ................................................................ 17 
5.3.2 
Dose modifications for gastrointestinal toxicity ........................................................... 18 
6 STUDY PROCEDURES ................................................................................................................ 19 
6.1 Informed Consent .................................................................................................................. 19 
6.2 Medical History .................................................................................................................... 19 
6.3 Physical Examination ............................................................................................................ 19 
6.4 Laboratory Tests.................................................................................................................... 19 
6.4.1 
Clinical Safety Laboratory Tests ................................................................................. 19 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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6.4.2 
Research Labs ............................................................................................................. 20 
6.4.3 
Sample Collection, Storage, and Shipping ................................................................... 20 
6.5 Criteria for Evaluation .......................................................................................................... 20 
6.5.1 
Antitumor effects ........................................................................................................ 20 
6.5.2 
Statistical Methods ...................................................................................................... 20 
6.5.3 
Tissue Endpoints .......................................................................................................... 21 
6.6 Safety Assessments ............................................................................................................... 21 
6.7 Safety Data Collection, Recording and Reporting ................................................................. 21 
6.8 Criteria for Discontinuation of Study .................................................................................... 26 
6.9 Withdrawal from Study ......................................................................................................... 26 
6.10 Data Safety Monitoring Plan ................................................................................................. 26 
7 STUDY ACTIVITIES .................................................................................................................... 27 
7.1 Study Visit Overview ............................................................................................................ 27 
7.2 Screening Period ................................................................................................................... 27 
7.3 Treatment Period. ................................................................................................................. 28 
7.3.1 
Day 1 ........................................................................................................................... 28 
8 PLANNED STATISTICAL METHODS ........................................................................................ 28 
8.1 Determination of Sample Size............................................................................................... 28 
8.2 Analysis Populations ............................................................................................................. 29 
8.3 Demographics and Baseline Characteristics .......................................................................... 29 
9 REFERENCE LIST ........................................................................................................................ 30 
10 APPENDICES .............................................................................................................................. 31 
APPENDIX 1 - SCHEDULE OF EVENTS ......................................................................................... 31 
APPENDIX 2 - ADVERSE EVENTS .................................................................................................. 33 
APPENDIX 3 – PROGRESSION AND RESPONSE CRITERIA ....................................................... 34 
APPENDIX 4 – ECOG GRADING SCALE ...................................................................................... 40 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
AST 
Aspartate aminotransferase (SGOT) 
BUN 
Blood urea nitrogen 
C 
Celsius 
CBC 
Complete blood count 
CR 
Complete response 
cfDNA 
Cell free DNA 
CrCl 
Creatinine clearance 
CPK 
Creatinine phosphokinase 
CRF 
Case Report Form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTC 
Circulating Tumor Cells 
ECG 
Electrocardiogram 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
GCSF 
Granulocyte stimulating factor 
GLP 
Good Laboratory Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HIPAA 
Health Information Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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LDH 
Lactic dehydrogenase 
LLN 
Lower limit of normal 
LN 
Lymph node 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
PD 
Progressive disease 
PFS 
Progression free survival 
PR 
Partial response 
PT 
Prothrombin time 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
 Serious adverse event 
SD 
Stable disease 
SOC 
System Organ Class 
SRS 
Special reporting situations SUSAR 
Suspected unexpected adverse event reporting 
ULN 
Upper limit of normal 
WBC 
White blood cell (count) 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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1 
INTRODUCTION 
1.1 
Therapy for metastatic, castration resistant prostate cancer (CRPC) 
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 metastatic CRPC include: docetaxel (Taxotere), the 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 metastatic CRPC. 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 most patients receive either abiraterone or enzalutamide, and 
often radium 223, prior to docetaxel in the metastatic CRPC setting. 
The second-generation AR-targeting agents abiraterone and enzalutamide are FDA-approved prior to 
docetaxel in patients with metastatic CRPC. 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 {Petrylak, 2004 #2233, Tannock, 2004 #2882). 
 
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 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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1.2 
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 {Tannock, 1996 #2883}. 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%) 2. 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 3. 
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 mCRPC2. 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 4. 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. 
 
Activity of carboplatin with docetaxel in prostate cancer 
Docetaxel/carboplatin 
mCRPC 
line 
nd 
18% 
3 mos 
12 mos 
Ross 
 
Docetaxel/EMP 
mCRPC 
1st 
68% 
8 mos 
19 mos 
Oh 
carboplatin 
line 
 
 
 
 
 
 
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 those with mutations in homologous recombination mutations such as 
BRCA1/2-Fanconi anemia pathway genes 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 cancers5,6. 
 
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 believe this is a subset of patients with 
defects in homologous recombination DNA damage repair pathway genes. 
 
1.3 
BRCA2 and DNA damage repair pathway genes in CRPC. 
 
Very recent efforts have been underway to perform molecular profiling of metastatic, castration resistant prostate cancer 
as part of the SU2C Prostate Dream Team research study at UWMC/FRED HUTCHINSON CANCER CENTER 
(CC-IRB # 7917) to better characterize the molecular subtypes of mCRPC. Indeed, current analyses have revealed 
approximately 20% of CRPC metastatic tumors contain biallelic inactivation of BRCA1, BRCA2 or ATM (De 
Bono, unpublished). 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 homozygous copy 
loss. Most mutations identified thus far are in the BRCA2 gene, but mutations have also been identified in BRCA1, 
ATM, and other BRCA1/2-Fanconi anemia pathway genes (De Bono, unpublished data). Thus, the 20% of patients 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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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 in the earlier studies 
of unselected patients with mCRPC described above. 
 
1.4 
Response to DNA damaging agents in tumors with biallelic inactivation of BRCA2. 
We have identified three patients from UW/FRED HUTCHINSON CANCER CENTER who 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 UWMC/FRED HUTCHINSON CANCER CENTER 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 months7. Our experience suggests 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. 
 
Therefore, in this study we propose to prospectively assess response to the combination of 
docetaxel and carboplatin in patients with mCRPC whose tumors contain biallelic inactivation 
of BRCA1, BRCA2 or ATM and have progressed after any succession of front-line agents. 
Sequencing results may be procured through UW-Oncoplex, SU2C or other commercial sequencing 
assays (e.g., Foundation One). If the true rate of response is 80% or higher (the anticipated result) in 
the prospective patient population, a very limited number of patients will be needed to demonstrate 
statistically significant superiority over docetaxel alone after any front-line agents (PSA50 of 26%)1. 
 
Of note, an ovarian cancer study applied massively parallel sequencing of 390 tumors and identified 
germline and somatic mutations not only in BRCA1, BRCA2 and ATM, but also in 10 other homologous 
recombination genes (BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, 
RAD51C and RAD51D) were associated with platinum response and 
survival8. If results from the proposed study are positive, we propose to expand the eligibility to include 
mCRPC with loss of other DNA repair genes. 
 
If this study successfully demonstrates significant responses to DNA damaging agents in this 
meaningful subset of patients with mCRPC, there would be clear rationale for follow up studies aimed 
at further disruption of DNA repair pathway. Potential approaches would include chemotherapy 
followed by maintenance therapy with PARP inhibitors, more intensive regimens of DNA damaging 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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agents (anthracyclines with platinum) and/or immediate alternative effective chemotherapy regimens in 
treatment of an estimated 1 in 5 men with mCRPC. 
1.1 
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. 
 
1.5.1 
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 
 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%), 
1.5.2 Supplier 
 
Commercial supplies of docetaxel and carboplatin will be used.


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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1.5.3 
Rationale for study design 
The combination of docetaxel and carboplatin has activity as first and second line therapy for patients 
with CRPC. In the very 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. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
 To assess rate of 50% PSA decline to docetaxel and carboplatin. 
 
2.2 
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 tumors with mutation of DNA repair 
pathway genes (BRCA1, BRCA2, ATM) 
 To correlate the presence of DNA repair pathway mutations and copy number alterations in 
metastatic tissue versus in circulating tumor cells (CTC) and cell free DNA 
 To correlate changes in CTC number with PSA and radiographic response 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall study design and plan 
This is an open-label study with a single Pilot 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 months, or as clinically indicated.


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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Eligibility: 
Patients with mCRPC following 
any line of prior treatment AND 
identified by tumor NGS to have 
biallelic inactivation of: 
1.    BRCA1/2, n= 14 
2.  ATM or other 
homologous DNA 
repair gene, n=any 
CTCs 
ctDNA 
Docetaxel 
60mg/m2q21days 
+ 
Carboplatin 
AUC 5 q21days 
P 
R 
Primaryobjective: 
Rate of PSA 
50 
 
 Exploratory: 
‐PSA response duration 
‐TT radiographic prog. 
‐Correlate presence of tumor 
mutations in CTCs, ctDNA 
G 
R 
E 
S 
S 
I 
After study, 
Consider 
 
or 
Carboplatin 
+Etoposide 
N 
 
CTCs 
ctDNA 
 
Bone Scan: Baseline bone scan will be performed during screening and every 3 months, or as clinically 
indicated. 
 
 
4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Study subjects will be recruited from the Fred Hutchinson Cancer Center and University of Washington (UW), which 
are separate sites within the same practice and share a single IRB. 
 
Eligible patients will be identified by their medical oncologist, who will discuss the study with the 
patient. If a patient is interested in participating, he will be appropriately counseled and informed consent 
will be obtained by one of the investigators. A total of 14 or more subjects will be enrolled in the study. 
 
4.2 
Inclusion 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. 
2. Age > 18 years. 
3. Histologically or cytologically confirmed carcinoma of the prostate (excluding neuroendocrine 
differentiation or squamous cell histology). 
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 rising PSA when serum testosterone 
<50ng/ml (note: current testosterone results are not required if the potential subject has not missed 
any GnRH analogue/antagonist doses since their last result was received) 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 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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 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, enzalutamide and/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 ≤ 1. 
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 registration: 
 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. Patients must have clear and documented evidence of biallelic inactivation BRCA1, BRCA2 or ATM 
by sequencing, for example UW-Oncoplex, SU2C, or Foundation One testing. 
and/or 
Patients with clearly deleterious mutations of other genes involved in homologous DNA repair (e.g., 
PALB2, BRIP1, etc.) by sequencing via UW-Oncoplex, SU2C, or Foundation One testing may be 
included at the investigator’s discretion. 
 
4.3 
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 neuroendocrine or small cell carcinoma of the prostate. 
3. Known parenchymal brain metastasis. 
4. Active or symptomatic viral hepatitis or chronic liver disease. 
5. 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. 
6. Treatment with an investigational therapeutic within 30 days of Cycle 1. 
7. Patients with dementia/psychiatric illness/social situations limiting compliance with study 
requirements or understanding and/or giving of informed consent are not eligible 
8. 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.


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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5 
STUDY TREATMENT(S) 
5.1 
Treatments Administered 
5.1.1 
Docetaxel and carboplatin 
Please refer to the docetaxel and carboplatin package inserts for complete preparation and administration. 
Docetaxel and carboplatin should be administered over approximately 30-60 minutes per institutional 
standard. 
 
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. 
 
5.1.1.1 
Docetaxel and carboplatin risks and precautions 
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% 
Thrombocytopenia 
6% 
0 
Febrile neutropenia 
3% 
0 
Infection 
6% 
0 
Hyperglycemia 
6% 
0 
Pain 
6% 
0 
Renal insufficiency 
3% 
0 
Ross et al. 
5.1.2 
Antiemetics 
 
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. 
 
5.1.3 
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 infection9.


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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5.1.4 
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. 
 
5.1.5 
Restrictions 
 
The concurrent administration of other anticancer therapy, including cytotoxic or immunotherapy, is 
prohibited therapy. 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. 
5.2 
Supply, Packaging and Storage 
5.2.1 
Docetaxel and carboplatin Supply, Packaging, Storage 
Docetaxel and carboplatin are stored and administered per institutional protocol. 
 
5.3 
Investigational Product Retention and Accountability at Study Site 
5.3.1 
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/or 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 
 
If treatment is delayed by more than 6 weeks, the 
patient should be removed from chemotherapy 
treatment. 
 
(*If ANC and/or platelet count are outside of 
the range listed above but still considered 
within an acceptable range for standard of 
care range, the PI may determine that 
dosing may still occur at PI discretion.) 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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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) 
 
Documented infection with Grade 3 
neutropenia (defined as an ANC <1.0 x 109 
cells/L) 
 
Grade 4 neutropenia (defined as an ANC<0.5 x 109 
cells/L lasting more than 5 days) 
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. 
 
 
Decrease BOTH docetaxel and carboplatin to 80% 
of starting dose for all subsequent cycles. 
 
With recurrence of any of these toxicities, consider 
removal from chemotherapy 
 
Dose Modifications for Hepatic Toxicity 
AST/ALT > 2-5 x ULN and 
AP < 2x ULN and bilirubin WNL 
Delay treatment until recovery 
AST/ALT > 2-5 x ULN and AP > 2.5-5 x ULN 
and 
bilirubin WNL 
Delay treatment until recovery 
AST/ALT > 5 x ULN and AP 
> 5 x ULN and bilirubin WNL 
Delay treatment until recovery 
 
5.3.2 
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. 
 
5.3.3 
Dose modifications for cumulative docetaxel or carboplatin toxicity 
 
For all patients who respond to combined study treatment of docetaxel and carboplatin (as assessed by PSA, restaging 
scans, and/or clinical improvement), treatment will continue until disease progression or unacceptable toxicities. To 
improve tolerability and allow the patient to continue in the event of treatment response, the regimen may be 
modified per investigator discretion treatment in the following ways: If there are cumulative toxicities (such as 
fatigue, myelosuppression, or neuropathy), doses of either docetaxel and/or carboplatin may be reduced (up to 
25%) and/or held (up to 6 weeks) OR 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).


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
Written Informed Consent and Authorization must be obtained from the patient in accordance with local 
practice and regulations. The study will be discussed with the patient, and a patient wishing to participate 
must give written informed consent and Authorization for Use and Release of Health and Research Study 
Information prior to any study-related procedures or change in treatment. 
 
A signed, Institutional Review Board/Ethics Committee (IRB) approved, informed consent must be 
obtained from patients before any study specific procedures can occur. Confirmation of the patient’s 
informed consent and the informed consent process must also be documented in the patient’s medical 
record. 
 
A copy of the fully signed informed consents will be given to the patient. 
 
6.2 
Medical History 
Medical history, such as previous treatments, procedures, and conditions will be collected during the 
screening period. 
 
6.3 
Physical Examination 
The investigator or qualified designee will perform a complete physical exam during the screening 
period. Clinically significant abnormal findings should be recorded as medical history. A full physical 
exam should be performed during screening and at EOT. Otherwise, directed physical exams are 
permissible.  
 
6.4 
Laboratory Tests 
6.4.1 
Clinical Safety Laboratory Tests 
Clinical safety laboratory tests will be assessed as UWMC/FRED HUTCHINSON CANCER CENTER 
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. 
 
Clinical safety labs will include the following: 
 
Table 9. List of Clinical Safety Laboratory Tests 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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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: 
Albumin (ALB) 
Blood urea nitrogen (BUN) 
Calcium (Ca) 
Carbon dioxide 
(CO2) Chloride 
(Cl) Creatinine 
Glucose 
Potassium 
(K) Sodium 
(Na) 
 
*Additional laboratory tests: 
Baseline Prothrombin Time (PT/INR) 
test for patients who are taking 
Coumadin while on study. Further 
monitoring per discretion of treating 
physician. 
 
 
 
 
 
6.4.2 
Research Labs 
Please refer to the laboratory manual for details. 
 
6.4.3 
Sample Collection, Storage, and Shipping 
 
The Fred Hutchinson Cancer Center and University of Washington 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. 
 
6.5 
Criteria for Evaluation 
6.5.1 
Antitumor effects: 
 
 The percentage of patients achieving ≥50% reduction in PSA according to PCWG2 criteria. 
 The percentage of patients achieving ≥90% reduction in PSA according to the PCWG2 criteria. 
 The percentage of patients achieving ≥30% reduction in measurable disease by RECIST. 
 Median time to tumor progression by PCWG2 criteria 
 
6.5.2 
Statistical Methods: 
 
The proportion of patients with PSA decline by 50% from baseline (PSA50) will be evaluated. The 
primary efficacy endpoint is the percent of patients achieving PSA50 with docetaxel and  
carboplatin. The historical comparison is a PSA50 of 26%. The target response rate is 60%.


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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study will follow an optimal two-stage Simon design (Simon, 1989) where the null hypothesis that the 
true PSA response rate (PSA decline by 50% from baseline) is 0.26 will be tested against a one-sided 
alternative. 
 
We will use a Simon minimax 2-stage design, which will allow early stopping for futility after the first 
stage if the response rate is low. Our null and alternative hypotheses are H0: p≤26% vs. H1: p≥60%. The 
minimax 2-stage design for these parameters requires a first stage enrolling 5 patients. If 1 of the first 5 
patients achieves a PSA50 response, H0 cannot be rejected. If ≥1 of 5 patients respond, enrollment in 
that cohort continues until 14 patients have completed the trial, and the response rate is calculated for all 
14 patients. If ≤6 of 14 patients have a PSA50 the null hypothesis cannot be rejected. This design will 
provide 80% power to detect a PSA50 rate of 60% (one-sided α=0.05). This design also provides a 60% 
probability of early stopping if H0 is true, affording protection against treating more patients than 
necessary if the treatment is not effective. 
6.5.3 
Tissue Endpoints: 
Circulating tumor cells (CTCs) and cfDNA will be collected as per standard operating protocol (appendix). 
6.6 
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 recorded prior to each course of therapy. Life-threatening toxicities should be reported immediately 
to the Protocol Chair and Institutional Review Board (IRB). 
 
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 
6.7 
Safety Data Collection, Recording and Reporting 
 
All observed or volunteered adverse events regardless of causal relationship to study drug will be recorded on 
the adverse event page(s) of the case report form (CRF).


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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6.7.1 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 GC and/or rapamycin) 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 
on the adverse event CRF. 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. 
 
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 
6.7.2 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). 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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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 
immediately notify the UW/FHCRC Cancer Consortium IRB, and FDA. See Section 6.7.3 for 
definition of SAEs and SUSARs, and 6.7.6 for reporting guidelines. 
 
Interventions for pretreatment conditions (e.g., elective cosmetic surgery) or medical procedures that 
were planned before study enrollment are not considered adverse events. 
 
6.7.3 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; 
Life-threatening adverse event or life-threatening suspected adverse reaction. 
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; 
 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). 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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6.7.6 Reporting Procedures for Adverse Events 
 
The investigator is responsible for ensuring that all grade 3 and above non-serious adverse events (as 
defined in Section 6.7.1 and as further specified below) observed by the investigator or reported by 
subjects are collected and recorded in the CRF. 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 that occurs during 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 these 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. 
 
6.7.7 Reporting Procedures for Serious Adverse Event (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. 
 
6.7.8 Reporting to IRB 
 
All serious adverse events that occur after the subject has signed the informed consent form or during the 
study at the University of Washington or Fred Hutchinson Cancer Center and meet IRB reporting criteria must 
be reported to the Cancer Consortium IRB (CC-IRB, fax 206-667-6831). AEs that are unexpected, possibly 
related to the study drug, and serious or suggest a risk of greater harm from the research then previously 
known will be reported to the IRB within 10 calendar days of the Investigator’s awareness of the event. 
 
The Adverse Event Reporting Form is available online: 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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http://extranet.fhcrc.org/EN/sections/iro/irb/forms/index.html#Reporting (as of Jan2012). 
 
SUSARs will be reported on the Expedited Reporting Form for Unanticipated Problems or 
Noncompliance. Special Reporting Situations (SRS) will be reported to CC-IRB either immediately or 
at annual renewal, upon consultation with IRB staff. The SAE, SUSAR or SRS should be recorded on 
the appropriate case report form (CRF). 
 
Reports of SAEs should be signed and dated by the principal investigator. In the absence of the PI, 
reports should be signed and dated by the individual reporting the event. If s/he is not medically 
licensed, the report should also be signed by a licensed medical practitioner, preferably a sub-
investigator for this protocol. The PI will review and sign the report at the next opportunity. 
 
Each report should contain the following information: 
 
 Protocol number 
 Subject number 
 Disease/histology if applicable 
Date the event occurred 
 Description of the SAE 
 Relationship of the event to treatment or other causality 
 Whether the event was “expected’ 
 Severity of the event 
 Intervention 
 Outcome of the event 
 Detailed text that includes the following information: 
 An explanation of how the SAE was handled 
 
A description of the patient’s condition 
 
Indication whether the subject remains on study 
 
Recommendation whether an amendment will need to be made to the protocol and/or 
the consent form. 
Relevant, redacted medical records should be provided as soon as they become available; autopsy reports 
should be provided for deaths if available. Determination of expectedness will be based on the contents 
of the current Investigator’s Brochure or package insert. 
If a subject is permanently withdrawn from the study because of a serious adverse event, this information 
must be included in the End of Study Case Report Form as well as all SAE/SUSAR reports. 
 
6.7.9 Annual Safety Reports 
 
In addition to the expedited reporting, sponsor shall submit, once a year throughout the clinical trial or 
on request a safety report to the competent authority and Institutional Review Board, considering all 
new available safety information received during the reporting period. 
 
6.8 
Criteria for Discontinuation of Study 
 The patient develops an unacceptable toxicity 
 Disease progression per RECIST 1.1 criteria 
 The patient develops a concurrent illness that is a contraindication to receiving further 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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treatment. 
 The patient elects to discontinue treatment or withdraws consent. 
 At the discretion of the Investigator. 
 
6.9 
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. 
 
6.10 Data Safety Monitoring Plan 
 
Institutional support of trial monitoring will be in accordance with the FHCRC/University of Washington 
Cancer Consortium Institutional Data and Safety Monitoring Plan. Under the provisions of this plan, 
FHCRC Clinical Research Support coordinates data and compliance monitoring conducted by 
consultants, contract research organizations, or FHCRC employees unaffiliated with the conduct of the 
study. Independent monitoring visits occur at specified intervals determined by the assessed risk level of 
the study and the findings of previous visits per the institutional DSMP. 
 
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and Safety 
Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) and the 
FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB). The review 
committees evaluate accrual, adverse events, stopping rules, and adherence to the applicable data and 
safety monitoring plan for studies actively enrolling or treating patients. The IRB reviews the study 
progress and safety information to assess continued acceptability of the risk-benefit ratio for human 
subjects. Approval of committees as applicable is necessary to continue the study. 
 
The trial will comply with the standard guidelines set forth by these regulatory committees and other 
institutional, state, and federal guidelines. 
7 
STUDY ACTIVITIES 
7.1 
Study Visit Overview 
 Expected toxicities, potential risks, and dose modifications are described in Section 5 (Risks and 
Precautions and Dose Reductions). 
 
 No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant's malignancy. 
 
7.2 
Screening Period 
Screening procedures to be completed within 30 days prior to the start of study treatment, 
 
 Informed consent 
 Medical history and demographics 
 Concurrent illness 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
26 
 
 Physical examination, including weight and height 
 Vital signs including blood pressure, heart rate, temperature. 
 Assessment of ECOG Performance Status 
 Clinical laboratory tests: 
 CBC (WBC, absolute neutrophil count, hemoglobin, hematocrit, platelets) 
 Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin), 
 Serum chemistries (albumin, sodium, potassium, carbon dioxide, creatinine, BUN, 
glucose, calcium) 
 PSA 
 Circulating tumor cells (optional) and cell free DNA collection 
 Bone scan 
 CT or MRI of the abdomen/pelvis 
 Chest film or chest CT if indicated 
Concomitant medications listing: 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 is reported 
and investigator to review for suitability to study. 
 
7.3 
Treatment Period 
7.3.1 
Day 1 
 
On Day 1 (± 3 days) of each cycle the following procedures will occur: 
 
 Vital signs (blood pressure, heart rate, temperature, and weight) 
 CBC (WBC with differential count, RBC, hemoglobin, hematocrit, platelets) 
 Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin) 
 Serum chemistries (albumin, sodium, potassium, chloride, carbon dioxide, creatinine, BUN, 
calcium, glucose) 
 PSA will also be collected if it is clinically indicated. 
 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 whichever occurs 
first. 
 
7.4 
Termination Visit/End of Treatment 
 
Termination visit to occur within 28 days (± 7 days) of last dose of study medication if possible. The following 
procedures will occur at this visit: 
 
 Physical examination, including weight and height 
 Vital signs including blood pressure, heart rate, temperature. 
 Assessment of ECOG Performance Status 
 Clinical laboratory tests: 
 CBC (WBC, absolute neutrophil count, hemoglobin, hematocrit, platelets) 
 Liver function tests (AST, ALT, alkaline phosphatase, total bilirubin), 
 Serum chemistries (albumin, sodium, potassium, , carbon dioxide, creatinine, BUN, 
glucose, calcium) 
 PSA 
 Circulating tumor cells (optional) and cell free DNA collection 
 
8 
PLANNED STATISTICAL METHODS 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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8.1 
Determination of Sample Size 
The proportion of patients with PSA decline by 50% from baseline (PSA50) will be evaluated. The 
primary efficacy endpoint is the percent of patients achieving PSA50 with docetaxel and carboplatin. The 
historical comparison is a PSA50 of 26%. The target response rate is 60%. The study will follow an 
optimal two-stage Simon design (Simon, 1989) where the null hypothesis that the true PSA response rate 
(PSA decline by 50% from baseline) is 0.26 will be tested against a one-sided alternative. 
 
We will use a Simon minimax 2-stage design, which will allow early stopping for futility after the first 
stage if the response rate is low. Our null and alternative hypotheses are H0: p≤26% vs. H1: p≥60%. The 
minimax 2-stage design for these parameters requires a first stage enrolling 5 patients. If 1 of the first 5 
patients achieves a PSA50 response, H0 cannot be rejected. If ≥1 of 5 patients respond, enrollment in 
that cohort continues until 14 patients have completed the trial, and the response rate is calculated for all 
14 patients. If ≤6 of 14 patients have a PSA50 the null hypothesis cannot be rejected. This design will 
provide 80% power to detect a PSA50 rate of 60% (one-sided α=0.05). This design also provides a 60% 
probability of early stopping if H0 is true, affording protection against treating more patients than 
necessary if the treatment is not effective. 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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8.2 
Analysis Populations 
All patients who receive at least one dose of study drug will be included in the analysis. 
 
8.3 
Demographics and Baseline Characteristics 
Demographic 
variables will 
include age, 
race, 
height, 
and 
weight. 
Baseline 
disease 
characteristics will include clinical stage, date of diagnosis, histology. 
 
9 
REFERENCE LIST 
 
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? Annals of oncology : official 
journal of the European Society for Medical Oncology / ESMO 2012;23:2943-7. 
2. 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. 
3. 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. 
4. Kumar A, White TA, MacKenzie AP, et al. Exome sequencing identifies a spectrum of 
mutation frequencies in advanced and lethal prostate cancers. Proceedings of the National 
Academy of Sciences of the United States of America 2011;108:17087-92. 
5. Byrski T, Huzarski T, Dent R, et al. Response to neoadjuvant therapy with cisplatin in BRCA1-
positive breast cancer patients. Breast cancer research and treatment 2009;115:359-63. 
6. 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. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 2008;26:5530-6. 
7. 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 
international 2012;109:713-9. 
8. Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous 
recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal 
carcinomas. Clinical cancer research : an official journal of the American Association for Cancer 
Research 2014;20:764-75. 
9. Crawford J. Prevention and treatment of chemotherapy-induced neutropenia. Clinical 
advances in hematology & oncology : H&O 2013;11:514-7.


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
29
 
 
10 APPENDICES
APPENDIX 1 - SCHEDULE OF EVENTS 
 
 
Procedure 
Screening (within 30 
days prior to Day 1)1 
Day 1 of 
Every Cycle2 
 
 
Visit17 
Informed Consent 
X 
 
 
Registration 
X 
 
 
Medical History 
X 
 
 
Physical exam 
X 
 
X 
Vital Signs 
X 
X 
X 
ECOG performance status 
X 
 
X 
CBC (w/ platelets, ANC) 
X 
X 
X 
Serum chemistry & electrolytes 
X 
X 
X 
Hepatic function 
X 
X 
X 
PSA 
X 
X*** 
X 
CT or MRI of pelvis/abdomen 
X 
X** 
X** 
Bone scan 
X 
X** 
X** 
Chest film or chest CT 
X 
X** 
X** 
Docetaxel and carboplatin 
 
X 
 
Adverse Events 
 
X 
X 
 
 
 
X 
 
 
Circulating tumor cells and cell free 
DNA collection* 
X* 
 
X* 
1Baseline 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 registration. All screening should be complete prior to registration. 
2All study assessments and medications should be administered ±3 days of the protocol-specified date, unless otherwise 
noted. For patients taking Coumadin, a baseline PT/INR test should be done (further monitoring per discretion of treating 
physician). Hepatic function includes AST, ALT, alkaline phosphatase and total bilirubin. 
 
17Termination visit to occur within 28 days (± 7 days) of last dose of study medication if possible. 
Chemistry & electrolyte labs include: albumin, BUN, calcium, CO2, chloride, creatinine, glucose, potassium, sodium 
 
*Circulating tumor cells and cell free DNA collection should occur one time prior to treatment and one time at progression. 
Circulating tumor cells are optional. If circulating tumors cells are collected for another study the results may be used. 
**CT or MRI of pelvis/abdomen, bone scan, and chest film or Chest CT are done at screening, every 3 months or as 
clinically indicated, and at progression. 
*** PSA will also be collected in the event that it is clinically indicated. 
 
 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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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 causes 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 
 
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. 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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APPENDIX 3 – PROGRESSION AND RESPONSE CRITERIA 
1. 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. 
 
2. 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. 
 
3. 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 after prior treatment but prior to study entry. 
 
 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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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. 
 
 
4. 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 5 mm 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. 
 
5. 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: 
 


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5.1. 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): 
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 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 (e.g., 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.


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
34 
 
5.2. 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. 
 
Progressive Disease (PD): 
The appearance of one or more new lesions and/or unequivocal progression of 
existing non- target lesions. PD may be declared based on “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 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 later 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. 
6. 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 decide of overall response 
based on the evaluation of target, non-target, and new lesions, as shown in Table 11 and 
Table 12. 


9381 Docetaxel and Carboplatin for mCRPC with BRCA1/2 pathway inactivation 
 
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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 
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 
 
7. 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. 


 
36 
 
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. 
 
8. Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to time of 
objective disease progression. 
 
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.