A Phase 1-2 Study of Sirolimus, Docetaxel and Carboplatin for Treatment of Patients With Metastatic, Castration Resistant Prostate Cancer: (Rapamycin Inhibition of DDSP [RID])
Phase: PHASE1
Conditions: Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Stage IV Prostate Cancer AJCC v7, Metastatic Malignant Neoplasm in the Bone
Sponsor: University of Washington



 
 
 
A Phase 1-2 Study of Sirolimus, Docetaxel and Carboplatin for Treatment of Patients with Metastatic, Castration Resistant Prostate Cancer: 
(Rapamycin inhibition of DDSP [RID]) 
 
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Protocol version 
6.0; 7/01/2019 
STUDY 
OBJECTIVES: 
Phase 1: 
Primary Objective: Phase 1 
• To determine the recommended phase 2 dose (RP2D) of Sirolimus 
combined with docetaxel and carboplatin in the treatment of metastatic 
castration resistant prostate cancer (CRPC). 
 
Secondary Objectives: Phase 1 
• To assess maximal PSA response to Sirolimus combined with 
docetaxel and carboplatin 
• To assess PSA response duration to Sirolimus combined with 
docetaxel and carboplatin 
• To assess response of measurable disease 
• To assess time to progression of bone lesions or measurable disease 
(RECIST 1.1) 
Phase 2: 
Primary Objective: Phase 2 
• To assess the ability of Sirolimus to suppress induction of DNA 
damage surrogates by docetaxel and carboplatin in metastatic cancer 
associated stroma. 
 
Secondary Objectives: Phase 2 
• To assess maximal PSA response to docetaxel and carboplatin with 
or without Sirolimus 
• To assess PSA response duration to Sirolimus combined with 
docetaxel and carboplatin 
• To assess response of measurable disease 
• To assess time to progression of bone lesions or measurable disease 
(RECIST 1.1) 
• To assess toxicity of the RP2D dose of Sirolimus with docetaxel and 
carboplatin. 
• To determine the effect of docetaxel and carboplatin therapy on the 
DNA damage secretory program (DDSP) in serum. 
• To determine response to sirolimus, docetaxel and carboplatin in 
tumors with mutation of DNA repair pathway genes (BRCA2, ATM and 
other FANC pathway genes involved in DNA repair) 
• To correlate the presence of DNA repair pathway mutations in 
circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) with 
tumor biopsy assessments and correlate changes in CTC number and 
ctDNA mutation status with PSA and clinical responses. 

 
 
 
A Phase 1-2 Study of Sirolimus, Docetaxel and Carboplatin for Treatment of Patients with Metastatic, Castration Resistant Prostate Cancer: 
(Rapamycin inhibition of DDSP [RID]) 
 
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STUDY SCHEMATIC: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
METHODS: 
Phase 1 
This is a dose finding scheme, where dose groups will be enrolled with a target of up to six (no 
less than three) patients per dose. Groups will be treated with de-escalating doses of Sirolimus 
combined with a fixed dose of docetaxel and carboplatin (60 mg/m2 and AUC 5 every 21 days). 
Sirolimus will be started at 35 mg given on Day -2 every 21 days, with dose de-escalations 
occurring within cohorts. Patients may continue in their cohort for repeated cycles of dosing; 
however, dose de-escalation within a patient will not occur. A safety review will be performed by 
the Principal Investigators for each individual patient at the end of Cycle 1 before the patient is 
allowed to continue to Cycle 2 in his dose level. 
Biopsy of suitable bone or soft tissue 
metastasis will be performed on day 21 to evaluate the DNA damage secretory program 
response to docetaxel, carboplatin and Sirolimus. 
 
Safety evaluations will be performed by the Principal Investigator for all patients at the end of 
Cycle 1 in each cohort. The Principal Investigator will decide whether proceeding to phase 2 or if 
dose de-escalation into the next cohort will be necessary. After the maximally tolerated dose 
(MTD) is defined (one dose level below observed dose limiting toxicity (DLT) rate of > 35%) the 
recommended phase 2 dose RP2D) will be determined. A DLT will be defined as febrile 
neutropenia, grade 3 or 4 thrombocytopenia or any Grade 3 or higher non-hematologic adverse 
event (AE), considered to be possibly, probably, or definitely related to therapy. Throughout 
Phase 1 of the study, safety and tolerability will be assessed by frequent recording of adverse 
events, vital signs, and safety laboratory assessments. 

 
 
 
A Phase 1-2 Study of Sirolimus, Docetaxel and Carboplatin for Treatment of Patients with Metastatic, Castration Resistant Prostate Cancer: 
(Rapamycin inhibition of DDSP [RID]) 
 
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Phase 2 
One dose will be chosen for study in Phase 2 to be tested in sequential vs. concurrent fashion. 
Forty (20 per cohort) new patients will be enrolled depending on response rate within each cohort. 
Patients in Cohort 1 will initiate docetaxel and carboplatin (60 mg/m2 and AUC 5 respectively) 
without sirolimus on Cycle 1 Day 1, followed by CT or ultrasound guided biopsy of suitable bone or 
soft tissue metastasis on day 21; to evaluate the DNA damage secretory program response 
(DDSP) to docetaxel and carboplatin. Sirolimus at the RP2D will be then be initiated on day 22, 
with docetaxel and carboplatin administered 2 days later. 
Patients in Cohort 2 will initiate docetaxel and carboplatin 60 mg/m2 and AUC 5 on Cycle 1 Day 1 
with Sirolimus administered on Cycle 1 Day -2 and with CT or ultrasound guided biopsy of suitable 
bone or soft tissue metastasis on day 21 to evaluate the DDSP response to docetaxel and 
carboplatin with Sirolimus. 
In both cohorts docetaxel and carboplatin will be administered at 60 mg/m2 and AUC 5 every 21 
days with Sirolimus administered on day -2 until progression by Prostate Cancer Working Group 2 
(PCWG2) criteria or undue toxicity. Throughout Phase 2 of the study, safety and tolerability will be 
assessed by frequent recording of adverse events, vital signs and safety laboratory assessments. 
Progression will be evaluated with bone scan, CT of the abdomen/pelvis and PSA as per PCWG2 
criteria. 
Number of Patients: Phase 1: 6-18 patients Phase 2: 40 patients 
Inclusion Criteria: 
 
Patients who meet 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 adenocarcinoma of the prostate (excluding 
neuroendocrine differentiation or 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 Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1) 
• Progression of metastatic bone disease on bone scan with > 2 new lesions 
6.   Prior therapy with abiraterone, enzalutamide and/or docetaxel. 
7.   The presence of metastatic disease amenable to CT or ultrasound guided biopsy. This may 
include thoracolumbar vertebral bodies, pelvis, femur or humerus, or soft tissue or nodal 
metastasis amenable to biopsy (excluding lung or pleural lesions). 

 
 
 
A Phase 1-2 Study of Sirolimus, Docetaxel and Carboplatin for Treatment of Patients with Metastatic, Castration Resistant Prostate 
Cancer: (Rapamycin inhibition of DDSP [RID]) 
 
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8.    Agree to participate in biopsy of metastatic lesion during the study at Day 21. 
9.    Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1 
10.  Life expectancy >12 weeks. 
11. 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 is currently disease free for at 
least one year 
12. Patients with any prior chemotherapy regimens are eligible. 
13. Patients with disease only in the bone may not have received Xofigo/Radium 223 to avoid 
ongoing DNA damage in bone marrow. 
14. Patients who are or are not receiving bisphosphonates or denosumab are eligible. 
Bisphosphonates or denosumab should not be initiated after registration and during active 
treatment. 
15. 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 bilirubin levels < 
1.5 x ULN 
• 
Total bilirubin < 1.5 x ULN 
• 
Serum creatinine < 1.5 X institutional ULN mg/DL OR eGFR > 50 mL/min 
 
Exclusion Criteria 
 
Patients must NOT meet any of the following exclusion criteria: 
 
1. Patients currently receiving active therapy for other neoplastic disorders. 
2. Patients with histologic evidence of small cell carcinoma of the prostate will not be eligible. 
3. Patients with disease only in the bone previously treated with radium-223 will not be eligible 
4. Known parenchymal brain metastasis. 
5. Active or symptomatic viral hepatitis or chronic liver disease. 
6. Estimated creatinine clearance less than 50 ml/minute. 
7. 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. 
8. Atrial fibrillation, or other cardiac arrhythmia requiring medical therapy. 
9. Administration of an investigational therapeutic within 30 days of Cycle 1, Day -2. 
10. Patients with dementia/psychiatric illness/social situations that would limit compliance with 
study requirements or would prohibit the understanding and/or giving of informed consent. 
11. Patients with medical conditions, which, in the opinion of the investigators, would jeopardize 
either the patient or the integrity of the data obtained will not be eligible. 
12. Any condition which, in the opinion of the investigator, would preclude participation in this trial. 
13. Patients on anticoagulation therapy which cannot be held for metastatic biopsies. 

 
 
 
A Phase 1-2 Study of Sirolimus, Docetaxel and Carboplatin for Treatment of Patients with Metastatic, Castration Resistant Prostate 
Cancer: (Rapamycin inhibition of DDSP [RID]) 
 
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A Phase 1-2 Study of Sirolimus, Docetaxel and Carboplatin for Treatment of Patients with Metastatic, Castration Resistant Prostate 
Cancer: (Rapamycin inhibition of DDSP [RID]) 
 
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CRITERIA FOR EVALUATION 
 
Safety:  Phases 1 and 2 
• The number and percentage of patients who experience a Serious Adverse Event; 
• The number and percentage of patients who experience an Adverse Event; and 
• The number and percentage of patients who discontinue study drug treatment early 
due to an adverse event. 
Anti-Tumor Effects: Phase 2 
• The percentage of patients achieving at least a 50% reduction in PSA according to 
PCWG2 criteria; 
• The percentage of patients achieving at least a 90% reduction in PSA according 
to the PCWG2 criteria. 
• The percentage of patients achieving a 30% reduction in measurable disease by 
RECIST 1.1. 
• Median time to tumor progression by PCWG2 criteria 
• Average tissue transcript level of DDSP components WNT16B, IL-6 or SFRP2 at 
day 21 biopsy 
 
STATISTICAL METHODS: 
Safety:  Phases 1 and 2 
Safety will be assessed through summaries of adverse events, vital signs, physical 
examinations, ECGs, and clinical laboratory test data (including change from baseline). 
Safety analyses will include all enrolled patients who receive any amount of study drug 
(safety population).  All adverse events will be captured using National Cancer Institute 
Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v. 4.0). 
Laboratory values will be classified by the NCI CTCAE V. 4.0 severity grade. Laboratory 
shift tables of the baseline results to each of the subsequent visits will be produced. 
Efficacy: Phase 2 
The primary endpoint is suppression of DDSP induction following genotoxic chemotherapy. 
Based on preliminary data, we anticipate that 50% of patients will increase the expression 
of at least one of WNT16, IL6, or SFRP2 (key members of the DNA damage response) >3-
fold over the background level in tissue stroma (microenvironment) following treatment with 
DNA damaging chemotherapy (carboplatin/docetaxel). We hypothesize that the 
administration of Sirolimus will suppress this induction in 90% of patients. 20 patients 
randomized to treatment with Sirolimus and 20 patients randomized to treatment without 
Sirolimus (for a total of N=40 patients) will provide 81% power to detect a difference in the 
proportions of patients with < 3-foldinduction of DDSP over background in at least one of 
the 3 markers at an alpha of 5% based on a 2-sided, 2-sample test of proportions. We will 
accrue up to 4 additional patients as necessary if patients drop out before the endpoint can 
be evaluated; final analysis will investigate sensitivity of inference to possible informative 
missing for any dropouts. 
 

 
 
 
A Phase 1-2 Study of Sirolimus, Docetaxel and Carboplatin for Treatment of Patients with Metastatic, Castration Resistant Prostate 
Cancer: (Rapamycin inhibition of DDSP [RID]) 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................. 7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 10 
1 
INTRODUCTION .............................................................................................. 13 
1.1 
Therapy for metastatic, castration resistant prostate cancer (CRPC) ........ 13 
1.2 
Sensitivity and resistance of CRPC to DNA damaging agents .................. 14 
1.3 
Inhibition of mTOR in combination with DNA damaging agents can improve 
response in prostate cancer ........................................................................ 15 
1.4 
The addition of the mTOR inhibitor Sirolimus to chemotherapy does not 
increase toxicity ........................................................................................... 16 
1.5 
Sirolimus .................................................................................................. 17 
1.5.1 
Chemistry ........................................................................................ 17 
1.5.2 
Clinical pharmacology ........................................................................ 17 
1.5.3 
Human Toxicity ................................................................................ 17 
1.5.4 
Pharmaceutical data ........................................................................ 18 
1.5.5 
Supplier ........................................................................................... 18 
1.5.6 
Dosing rationale for Sirolimus ............................................................ 18 
1.6 
Docetaxel and carboplatin ........................................................................... 22 
1.6.1 
Human toxicity ................................................................................. 22 
1.6.2 
Supplier ........................................................................................... 24 
1.6.3 
Rationale for study design .................................................................. 24 
2 
STUDY OBJECTIVES .......................................................................................... 26 
2.1 
Primary Objective (Phase 1) ..................................................................... 26 
2.2 
Exploratory Objectives (Phase 1) .............................................................. 26 
2.3 
Primary Objective (Phase 2) ..................................................................... 26 
2.4 
Exploratory Objectives (Phase 2) .............................................................. 26 
3 
INVESTIGATIONAL PLAN ................................................................................ 27 
3.1 
Overall study design and plan ..................................................................... 27 
4 
STUDY POPULATION SELECTION .................................................................... 30 
4.1 
Study Population ......................................................................................... 30 
4.2 
Inclusion Criteria .......................................................................................... 30 
4.3 
Exclusion Criteria ......................................................................................... 31 
5 
STUDY TREATMENT(S) ...................................................................................... 32 
5.1 
Treatments Administered ............................................................................ 32 
5.1.1 
Sirolimus ......................................................................................... 32 
5.1.2 
Docetaxel and carboplatin ................................................................. 34 
5.1.3 
Grapefruit Juice ............................................................................... 35 

 
 
 
A Phase 1-2 Study of Sirolimus, Docetaxel and Carboplatin for Treatment of Patients with Metastatic, Castration Resistant Prostate 
Cancer: (Rapamycin inhibition of DDSP [RID]) 
 
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5.1.4 
Antiemetics ...................................................................................... 35 
5.1.5 
Growth Factors ................................................................................ 35 
5.1.6 
Concomitant Therapy ...................................................................... 35 
5.1.7 
Restrictions ...................................................................................... 35 
5.1.8 
Potential for Drug-Drug Interactions .................................................. 36 
5.1.9 
Potential Drug Interactions with Grapefruit Juice ............................... 37 
5.1.10 Contraception…………………………………………………………….37 
5.2 
Supply, Packaging and Storage .................................................................. 36 
5.2.1 
Sirolimus Pharmacy Storage Requirements ...................................... 36 
5.2.2 
Docetaxel and Carboplatin Supply, Packaging, Storage .................. 37 
5.2.3 
Grapefruit Juice Supply, Packaging, Storage .................................... 37 
5.3 
Dose modifications for toxicity .................................................................. 37 
5.3.1 
Dose modifications for gastrointestinal toxicity .................................. 38 
5.3.2 
Dose modifications for Sirolimus ........................................................ 38 
6 
STUDY PROCEDURES ....................................................................................... 38 
6.1 
Informed Consent ........................................................................................ 38 
6.2 
Medical History ......................................................................................... 40 
6.3 
Physical Examination .................................................................................. 40 
6.4 
Laboratory Tests ....................................................................................... 40 
6.4.1 
Clinical Safety Laboratory Tests ...................................................... 40 
6.4.2 
Safety Labs Prior to Metastatic Biopsy ............................................ 42 
Coagulation tests or any additional laboratory tests will be collected per 
institutional policy prior to metastatic biopsy on Day 21 ................... 42 
6.4.3 
Tumor Markers ................................................................................... 42 
6.4.4 
Research Labs ................................................................................ 42 
6.4.5 
Sample Collection, Storage, and Shipping ........................................ 42 
6.4.6 
Biopsy acquisition and tissue handling ............................................ 42 
6.5 
Criteria for Evaluation .................................................................................. 43 
6.5.1 
Safety: Phases 1 and 2 .................................................................... 43 
6.5.2 
Anti-Tumor Effects: Phase 2 ........................................................... 43 
6.5.3 
Tissue Endpoints: Phase 2 .............................................................. 44 
6.6 
Safety Assessments .................................................................................... 44 
6.7 
Safety Data Collection, Recording and Reporting ...................................... 44 
6.7.1 
Definition of Adverse Event (AE) ..................................................... 45 
6.7.2 
Adverse Drug Reaction (ADR) ......................................................... 46 
6.7.3 
Definition of a Serious Adverse Event ............................................... 46 
6.7.4 
Dose Limiting Toxicity (DLT) ............................................................ 47 
6.7.5 
Dose De-escalation ............................................................................ 47 

 
 
 
A Phase 1-2 Study of Sirolimus, Docetaxel and Carboplatin for Treatment of Patients with Metastatic, Castration Resistant Prostate 
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6.7.6 
Reporting Procedures for Adverse Events ........................................ 48 
6.7.7 
Reporting Procedures for Serious Adverse Event (on-site SAEs)........48 
6.7.8 
Reporting to IRB .............................................................................. 48 
6.7.9 
Annual Safety Reports ..................................................................... 49 
6.8 
Criteria for Discontinuation of Study .......................................................... 50 
6.9 
Withdrawal from Study .............................................................................. 50 
7 
STUDY ACTIVITIES ............................................................................................. 50 
7.1 
Study Visit Overview ................................................................................... 50 
7.2 
Screening Period ......................................................................................... 51 
7.3 
Treatment Period ...................................................................................... 51 
7.3.1 
Day -2 .............................................................................................. 51 
7.3.2 
Day 1 ............................................................................................... 52 
7.3.3 
Days 8 & 15 (Phase 1 only) ............................................................. 53 
7.3.4 
Additional visits ................................................................................... 53 
7.3.5 
Termination Visit (28 days, ± 7 days, from withdrawal of protocol) . 53 
8 
PLANNED STATISTICAL METHODS .................................................................. 54 
8.1 
Determination of Sample Size ..................................................................... 54 
8.1.1 
Safety: Phases 1 and 2 .................................................................... 54 
8.1.2 
Suppression of DNA damage pathway: Phase 2 ............................. 53 
8.2 
Analysis Populations ................................................................................... 55 
8.3 
Demographics and Baseline Characteristics .............................................. 55 
8.4 
Safety Evaluations ....................................................................................... 55 
9 
REFERENCE LIST ............................................................................................ 56 
10 APPENDICES ................................................................................................................. 58 
APPENDIX 1 - SCHEDULE OF EVENTS ................................................................... 58 
APPENDIX 2 - TREATMENT SCHEMATIC .............................................................. 60 
APPENDIX 3 - ADVERSE EVENTS ........................................................................... 61 
APPENDIX 4 – PROGRESSION AND RESPONSE CRITERIA ............................... 62 
APPENDIX 5 – ECOG GRADING SCALE ................................................................ 68 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
AR 
Androgen receptor 
AST 
Aspartate aminotransferase (SGOT) 
BUN 
Blood urea nitrogen 
C 
Celsius 
CALGB 
Cancer and leukemia group B 
CBC 
Complete blood count 
CR 
Complete response 
CrCl 
Creatinine clearance 
CPK 
Creatinine phosphokinase 
CRF 
Case Report Form 
CRPC 
Castration resistant prostate cancer 
ctDNA 
Circulating tumor DNA 
CT 
Computed tomography 
CTC 
Circulating tumor cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
DDSP 
DNA damage secretory pathway 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Group 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
GCSF 
Granulocyte stimulating factor 
GFR 
Glomerular filtration rate 
GLP 
Good Laboratory Practice 
HEENT 
Head, Eyes, Ears, Nose, Throat 
Hct 
Hematocrit 

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Hgb 
Hemoglobin 
HIPAA 
Health Information Portability and Accountability Act 
HUS 
Hemolytic uremic syndrome 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemistry 
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 
MRI 
Magnetic resonance imaging 
MTD 
Maximally tolerated dose 
mTOR 
Mammalian target of Rapamycin 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
PBMC 
Peripheral blood mononuclear cell 
pCR 
pathologic complete response 
PCR 
Polymerase chain reaction 
PCWG2 
Prostate Cancer Working Group 2 
PD 
Progressive disease 
PFS 
Progression free survival 
PR 
Partial response 
PSA 
Prostate specific antigen 
PT 
Prothrombin time 
RECIST 
Response evaluation criteria in solid tumors 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SD 
Stable disease 
SOC 
System Organ Class 

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SRS 
Special reporting situations 
SU2C 
Stand Up to Cancer 
SUSAR 
Suspected unexpected adverse event reporting 
TMA 
Thrombotic microangiopathy 
TTP 
Thrombotic thrombocytopenic purpura 
ULN 
Upper limit of normal 
US 
Ultrasound 
WBC 
White blood cell (count) 
 
 

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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 disease 
is usually initially effective, almost all tumors become castration resistant after a median 
of 18-24 months. The currently FDA approved therapies for metastatic CRPC includes 
the androgen receptor (AR) targeting agents abiraterone or enzalutamide prior to or 
after docetaxel, radium 223 for patients declining docetaxel or after docetaxel, 
Provenge/sipuleucel-T prior to or after docetaxel, and cabazitaxel. In current clinical 
practice the vast majority of patients receive either abiraterone or enzalutamide, and 
often radium 223 prior to treatment with docetaxel. Patients who have then received 
docetaxel have very limited options except for cabazitaxel. The registration studies of 
cabazitaxel demonstrated a survival advantage compared to the use of mitoxantrone, 
with progression free survival of 2.8 months and a concerning toxic death rate of 5% [1] 
 
 
 
 
In 2004, two phase III randomized trials demonstrated the survival benefit of docetaxel- 
based chemotherapy in the treatment of metastatic castration resistant prostate cancer 
CRPC [2, 3] Although one of these studies utilized estramustine in combination with 
docetaxel, this drug is now considered toxic and does not add additional benefit to 
docetaxel. The principal anti-neoplastic mechanism of docetaxel and other taxanes is 
thought to be inhibition of microtubule depolymerization causing G2/M cell cycle arrest. 
Recent data has suggested that part of the mechanism by which docetaxel functions in 
prostate cancer may be by blocking nuclear translocation of the AR, suggesting the 
potential for cross resistance with other AR targeting agents [4] It is also important to 
note that the initial studies of docetaxel were carried out in an era when more effective 
AR targeting agents (enzalutamide or abiraterone) were not available. Although 
docetaxel-containing chemotherapy offers a survival advantage, the benefit is modest 
(median of approximately 2.5 months) and is not durable. 
 
The second generation AR targeting agents, abiraterone (Zytiga) and enzalutamide 
(Xtandi) are now FDA approved prior to docetaxel use in patients with metastatic 

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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. In the analysis by Mezynski, PSA decline by 50% (PSA50) was 26% with 
median PSA PFS of 4.6 months and overall survival of 12.5 months [5]. 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]. These studies 
support the concept that docetaxel efficacy in the current treatment environment is 
significantly less than reported in the registry studies, approximating 50% less likely to 
provide significant PSA declines and that approaches that improve docetaxel efficacy 
are needed. 
 
 
 
Regimen 
Indication 
PSA50 
PFS 
OS 
Reference 
 
Docetaxel 
mCRPC 
line 
1st 
45% 
NA 
18.9 
mos 
Tannock 
Docetaxel 
mCRPC 
line 
1st 
50% 
6 mos 
18 mos 
Petrylak 
Docetaxel after Abi 
mCRPC 
line 
1st 
26% 
4.6 mos 
12.5 
mos 
Mezynski 
Docetaxel after abi 
mCRPC 
line 
1st 
38  vs. 
63% 
4.4 mos 
NA 
Schweizer 
 
 
1.2 
Sensitivity and resistance of CRPC to DNA damaging agents 
 
The addition of other agents to docetaxel might improve response in untreated or 
abiraterone treated tumors. The first chemotherapeutic agent which was FDA approved 
for the treatment of CRPC was the anthracycline and DNA damaging agent 
mitoxantrone [6]. Subsequent studies of the use of Satraplatin, a platinum agent in 
phase III randomized studies as second line chemotherapy (including docetaxel) 
demonstrated a significant improvement in progression free survival (HR 0.67, PFS 11 
weeks, PSA50 25%) [7]. In that context investigators have considered that combining 
the DNA damaging agent carboplatin with docetaxel may 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 [8]. 
Estramustine is no longer considered to improve the clinical efficacy of chemotherapy 
because it did not enhance response or survival compared to docetaxel alone, while 
adding significant toxicity. In patients with tumors refractory to docetaxel, the addition of 
carboplatin induced a PSA50 rate of 18% and PFS of 3 months [9] 

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There are several potential explanations for the efficacy of platinum compounds in 
CRPC. First, unpublished results from the SU2C CRPC 500 collaborative study being 
carried out at UW/FHCRC shows that approximately 20% of metastatic CRPC contains 
biallelic inactivation of BRCA2 or inactivating mutations of ATM. These genes are 
critically important to repair of DNA damage and inactivation of these genes is predicted 
to provide sensitivity to agents such as carboplatin. Secondly, the transdifferentiation of 
adenocarcinoma of the prostate into a neuroendocrine/small cell phenotype is being 
recognized more commonly in patients with CRPC [10]. Platinum based chemotherapy 
is the most effective treatment for patients with small cell histologies from any primary 
site and carboplatin would be anticipated to be more effective in this subset of patients. 
 
 
 
Activity of carboplatin with docetaxel in prostate cancer 
Docetaxel/carboplatin 
mCRPC 
2nd 
18% 
3 mos 
12 mos 
Ross 
line 
 
Docetaxel/EMP 
carboplatin 
mCRPC 
1st 
68% 
8 mos 
19 mos 
Oh 
line 
 
1.3 
Inhibition of mTOR in combination with DNA damaging agents can 
improve response in prostate cancer. 
 
Mitoxantrone, carboplatin and radiation are DNA damaging agents used in the 
treatment of prostate cancer. Intrinsic and acquired resistance to DNA damage limits 
the magnitude and duration of response. One potential mechanism of tumor resistance 
to DNA damage is the tumor microenvironment. This microenvironment for all cancers 
is comprised of a variety of cell types including epithelial cells, fibroblasts, inflammatory 
cells, blood vessels and extracellular matrix which surround and infiltrate tumors and all 
may modulate tumor activity. For example, tumor associated fibroblasts enhance 
preneoplastic cell growth and tumor invasiveness, [11, 12] This dynamic environment 
may in part explain drug resistance by tumors against DNA damaging agents (e.g., 
radiation or carboplatin) commonly used to treat prostate cancer. [13 , 14] The 
microenvironment responds to DNA damage by secretion of cytokines and growth factors 
which augment the immune clearance of damaged cells while promoting tissue repair 
through angiogenesis and recruitment of epithelial and stromal cells. This DNA Damage 
Secretory Program (DDSP) elaborated by stroma can also promote tumor survival 
and metastasis [15]. The cytokines and growth factors that comprise the DDSP provide 
a survival advantage for the tumor itself through suppression of apoptosis and promotion 
of proliferation while also inducing epithelial-mesenchymal transition and metastasis 
[16]. Tumor clones which survive the initial chemotherapy cycle will grow to serve 
as a site of treatment failure and/or relapse. In this way, the DDSP in the tumor 
microenvironment can drive adverse cancer outcomes. Recent work from the Nelson 
laboratory at Fred Hutchinson Cancer Research Center (FHCRC) has demonstrated  
that  inhibition  of  different  components  of  the  DDSP  can  improve 

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responses to DNA damaging agents in preclinical models [17]. Unpublished results from 
the same group has demonstrated that the use of the mammalian Target Of Rapamycin 
(mTOR) 
 
inhibitor rapamycin (Sirolimus)  can 
block DDSP induction and augment 
activity to 
DNA 
damaging 
agents. 
Blocking mTOR activity may therefore 
improve prostate cancer responses to 
DNA 
damaging 
agents 
such 
as 
carboplatin based regimens. 
 
Based on these data we propose to 
attempt 
to 
improve 
response 
to 
docetaxel based chemotherapy through 
the combination of the DNA damaging 
agent 
carboplatin 
with 
an 
mTOR 
inhibitor, 
in 
order 
to 
prevent 
microenvironment induced resistance. 
 
 
 
 
 
 
1.4 
The addition of the mTOR inhibitor Sirolimus to chemotherapy does 
not increase toxicity. 
 
The combination of Sirolimus with gemcitabine and cisplatin is currently being used in a 
phase II neoadjuvant study of chemotherapy for patients with localized bladder cancer 
(CC-IRB 8027). The phase I portion of that study, utilizing the same mTOR inhibitor 
regimen proposed for the current study showed no evidence of increased toxicity, with 
one episode of grade 4 neutropenia seen in a patient who was heavily pretreated with 
myelotoxic agents. The safety seen in that study provides evidence that mTOR inhibition 
with chemotherapy is safe. In that study and in the current study we will administer 
Sirolimus at the time of chemotherapy improve the pharmacokinetics by administering 
the Sirolimus with grapefruit juice, which provides pharmacokinetics equivalent to once 
weekly administration of temsirolimus [18]. 
 
In summary, docetaxel is a standard therapy for prostate cancer with modest 
improvements in survival and there is evidence from recent studies that prior therapy 
with abiraterone or enzalutamide compromises responses to docetaxel. The rationale 
for the current study is that it is critical to identify approaches to improve taxane response 
in the current treatment environment which invariably involves treatment with 
AR 
targeting agents prior to a taxane. The study will also answer the question of 
whether inhibition of DDSP can be achieved and whether there is a suggestion of 
Figure 1 The addition of the mTOR inhibitor sirolimus 
improves activity of mitoxantrone PC3 prostate cancer 
xenografts ± benign PSC27 stromal cells were untreated, treated 
with mitoxantrone with and without rapamycin (sirolimus). 

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improved response with mTOR inhibition. The combination of  docetaxel  with carboplatin 
is active as an upfront regimen and combination with mTOR  inhibition carries the 
potential of improving responses by inhibiting intrinsic resistance mediated by the tumor 
microenvironment. In this study we will evaluate the ability to block the DDSP with the 
mTOR inhibitor Sirolimus while evaluating pilot data regarding objective tumor responses 
to this combination. 
 
 
1.5 
Sirolimus 
 
1.5.1 
Chemistry 
 
Sirolimus (Rapamycin, Rapamune) is a macrolide compound obtained from 
Streptomyces hygroscopicus that acts by selectively blocking the transcriptional 
activation of cytokines, thereby inhibiting cytokine production. It is bioactive only when 
bound to immunophilins. 
 
1.5.2 
Clinical pharmacology 
 
Mechanism of Action - Sirolimus inhibits T-lymphocyte activation and proliferation that 
occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) 
stimulation by a mechanism that is distinct from that of other immunosuppressants. 
Sirolimus also inhibits antibody production. In cells, Sirolimus binds to the immunophilin, 
FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The 
Sirolimus-FKBP-12 complex has no effect on calcineurin activity. This complex binds to 
and inhibits the activation of mTOR, a key regulatory kinase. This inhibition suppresses 
cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase 
of the cell cycle, as well as mTOR driven signaling in other tissues. 
 
The mTOR complex functions as a serine/threonine kinase and a key regulator of 
protein translation via its ability to phosphorylate S6K and 4EBP1. Sirolimus binds 
intracellularly to FKBP12, inhibiting mTOR and resulting in growth inhibition in 
preclinical tumor models primarily by inducing cell-cycle arrest or apoptosis. Intermittent 
dosing schedules in animal models have shown antitumor activity equivalent to 
continuous administration, but without prolonged immunosuppression. [19]. 
 
1.5.3 
Human Toxicity 
 
Human toxicity of Sirolimus alone given in a phase 1 study with grapefruit juice as 
planned in this study was as per section 1.5.6 [25] and consisted of hyperglycemia, 
hyperlipidemia, lymphopenia, anemia, and diarrhea. Other adverse effects include: 
bronchial anastomotic dehiscence in lung transplant patients, exfoliative dermatitis, 
angioedema, renal toxicity, anorexia, vomiting, fluid accumulation, impaired or delayed 
wound healing, hypertriglyceridemia, hypercholesterolemia, renal insufficiency with 
long-term combination with cyclosporine, interstitial lung disease, hemolytic uremic 
syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy. Increased 

 
 
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susceptibility to infection and the possible development of lymphoma and other 
malignancies may result from immunosuppression. 
 
Hypersensitivity reactions, including anaphylactic reactions, angioedema, exfoliative 
dermatitis and hypersensitivity vasculitis have been associated with the administration 
of Sirolimus. 
 
The most common (≥ 30%) adverse reactions observed with Sirolimus in clinical studies 
are: 
peripheral 
edema, 
hypertriglyceridemia, 
hypertension, 
hypercholesterolemia, 
creatinine increased, constipation, abdominal pain, diarrhea, headache, fever, urinary 
tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia. 
 
The following adverse reactions resulted in a rate of discontinuation of > 5% in clinical 
trials: increased creatinine, hypertriglyceridemia, and thrombotic thrombocytopenic 
purpura (TTP). 
 
 
1.5.4 
Pharmaceutical data 
 
Formulation: Each Sirolimus Oral Solution carton, NDC 0008-1030-06, contains one 2 
oz (60 mL fill) amber glass bottle of Sirolimus (concentration of 1 mg/mL). 
 
Storage: Oral Solution bottles should be stored protected from light and refrigerated at 
2°C to 8°C (36°F to 46°F). Once the bottle is opened, the contents should be used 
within one month. The product may be kept in the dosing syringe for a maximum of 24 
hours at room temperatures up to 25°C (77°F) or refrigerated at 2°C to 8°C (36°F to 
46°F). After dilution, the preparation should be used immediately. The syringe should be 
discarded after one use. 
 
1.5.5 
Supplier 
 
Commercial supplies of Sirolimus will be used. 
 
1.5.6 
Dosing rationale for Sirolimus 
 
The phase 1 component of the study is a dose de-escalation study. The rationale for a 
dose de-escalation study is that the side effect profile of all the drugs in the study has 
been defined over many years and through extensive experience in clinical practice. A 
short duration exposure of a non-cytotoxic compound in the form of Sirolimus during 
only the first week of therapy with docetaxel and carboplatin is not anticipated to adversely 
affect the pharmacokinetics of docetaxel and carboplatin and the toxicity profile has 
limited overlap. Given the expectation of limited toxicity, a dose de- escalation approach 
is favored in order to define the recommended phase 2 dose (RP2D) for testing in the 
phase 2 component of study. The planned dose de-escalation strategy is based on a 
series of phase 1 studies carried out with Sirolimus alone, Sirolimus with ketoconazole 
or Sirolimus with grapefruit juice.[18] and the safety seen in 
Sirolimus with 
gemcitabine/cisplatin in patients with bladder cancer. 
 

 
 
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Performing the phase 1 study with grapefruit juice was based on the defined ability of 
grapefruit juice to deactivate intestinal CYP3A4 and block metabolism of sirolimus. 
Inhibition of intestinal CYP3A4 lasts for at least 4 hours. Based on toxicity and 
pharmacokinetics, the recommended phase 2 dose of Sirolimus with grapefruit juice is 
35 mg weekly [18]. This study also demonstrated inhibition of phosphoS6 kinase levels 
in circulating PBMC at 48 hours after administration of Sirolimus; demonstrating effective 
mTOR signaling 2 days after Sirolimus. 
 
Toxicity of Sirolimus with grapefruit juice at all doses once weekly was limited. The most 
common toxicities attributed to Sirolimus observed in this phase 1 study of Sirolimus 
were hyperglycemia, hyperlipidemia, lymphopenia, anemia, and diarrhea. The toxicities 
of the treatment doses alone and in combination with drugs anticipated to improve 
pharmacokinetics are as shown in Table 1. 
 
 

 
 
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Table 1. Toxicities of Sirolimus alone, with ketoconazole, or with grapefruit juice. 
 
 

 
 
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In this study we are proposing to test the hypothesis that mTOR is a master regulator of 
the DDSP derived from the prostate cancer microenvironment. In this study we will 
assess whether administration of Sirolimus with grapefruit juice will inhibit mTOR for 7 
days, which would be substantially longer than the anticipated duration of DNA damage 
induced by a single administration of docetaxel and carboplatin and whether co- 
administration is safe and improves efficacy (as reflected by response in phase 2). 

 
 
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The planned dose de-escalation in phase 1 varies the dose of Sirolimus administered 
on Day -2 (with grapefruit juice (240 ml) administered on Days -3 through 4 and docetaxel 
and carboplatin (60 mg/m2 and AUC 5) administered on Day 1 every 21 days). 
 
The Sirolimus dose in dose level 0 is 35 mg once on Day -2. If zero or one dose limiting 
toxicity (DLT) occurs in the first three patients, an additional 3 patients will be treated in 
dose level 0. If the observed DLT rate is < 33% in six patients, dose level 0 will be the 
RP2D. Patients may continue in their cohort for repeated cycles of dosing; however, 
dose de-escalation within a patient will not occur. 
 
If the DLT rate is > 33% in 3 or 6 patients, the dose will be decreased to dose level -1, 
25 mg once per 21 day cycle on Day -2. The same cohort algorithm will occur at dose 
level -1 as above. If the DLT rate is > 33% at dose level -1 in 3 or 6 patients, the dose 
level will decrease to dose level -2 at 20 mg once per 21 day cycle on Day -2. 
 
If the DLT rate is > 33% at dose level -2, no phase 2 will be carried out. Dose 
de-escalation values: 
Dose Level 
Sirolimus 
100% (Dose Level 0) 
35mg 
First dose reduction (Dose Level - 
1) 
25mg 
Second dose reduction (Dose 
Level -2) 
20mg 
 
1.6 
Docetaxel and carboplatin 
 
Docetaxel (Taxotere) and carboplatin (Paraplatin) are synthetic antineoplastic agents 
which have been extensively used in the treatment of solid tumors. 
 
1.6.1 
Human toxicity 
 
Human 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 

 
 
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Cancer: (Rapamycin inhibition of DDSP [RID]) 
 
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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) 
 
 
Human 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%) 
 
The data regarding tolerance of docetaxel and carboplatin alone or myelotoxic 
chemotherapy with sirolimus/rapamycin comes from several sources. The tolerance of 
docetaxel/carboplatin alone comes from references #8 and #9 (Oh and Ross). In those 
studies there was no safety signal suggesting significantly increased toxicity to patients 
receiving the combination of docetaxel and carboplatin, with the primary difference 
between this regimen and docetaxel alone being an increased incidence of Grade 3 
neutropenia (56% vs. 32%), but febrile neutropenia was 1% with docetaxel/carboplatin vs. 
3% in the phase III study of docetaxel alone (Tannock, NEJM). 
 

 
 
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Cancer: (Rapamycin inhibition of DDSP [RID]) 
 
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We have an ongoing study combining sirolimus with gemcitabine and cisplatin in bladder 
cancer, with both a phase I and II component. In the phase I study 6 patients were 
treated with gemcitabine/cisplatin with rapamycin with no DLT’s and MTD was full dose 
gemcitabine and cisplatin with the same dose of sirolimus that is proposed for the current 
study (9388). Thus far 12 patients in total have been enrolled on the bladder cancer 
study with no safety signal for increased toxicity with sirolimus (incidence of toxicity 
70% grade 3 or 4 neutropenia, 10% febrile neutropenia, 5% other grade 3 or 4 
toxicities). This is consistent with toxicity seen in phase III studies of gemcitabine and 
cisplatin alone. For these reasons the combination proposed in this study appears 
reasonable given the inclusion of a phase I component to rule out an unforeseen 
interaction between sirolimus and docetaxel/carboplatin. 
 
1.6.2 Supplier 
 
Commercial supplies of docetaxel and carboplatin will be used. 
 
1.6.3 
Rationale for study design 
 
The combination of docetaxel and carboplatin has activity as first and second line 
therapy for patients with CRPC. The recognition that the tumor microenvironment may 
play a critical role in tumor resistance to DNA damaging agents provides a potential 
point of therapeutic leverage. The mTOR pathway is a master regulator of the DDSP 
cytokine and growth factor signaling pathway which supports tumor resistance to DNA 
damaging agents. This study proposes to use a short duration of mTOR inhibition only 
during the period of DNA damage to tumor and tumor microenvironment in an attempt 
to attenuate tumor resistance via suppression of the microenvironment secretory 
response. We are excluding prior therapy with the agent Radium-223 as it is anticipated 
that this agent may induce long lasting DNA damage responses in bone given the 
half-life of the agent and we would be unable to interrogate the effect of Sirolimus on 
DNA damage induced by carboplatin. 
 
After a RP2D dose of the mTOR inhibitor Sirolimus with docetaxel and carboplatin has 
been defined, the ability to suppress the relevant DDSP targets will be evaluated. In 
addition, if an improvement in response is demonstrated concurrent with suppression of 
DDSP, there would be strong rationale for additional studies with mTOR inhibition with 
docetaxel and carboplatin in patients with metastatic and localized prostate cancer. 
Successful implementation of mTOR inhibition with DNA damaging agents could then 
increase improvement in survival and palliative benefits for all patients with prostate cancer. 
 
2 STUDY OBJECTIVES 
2.1 
Primary Objective (Phase 1) 
 
The primary objective of the Phase 1 study is: 
 
• To define the RP2D of Sirolimus combined with docetaxel and carboplatin in the 
treatment of metastatic CRPC. 
 
2.2 
Exploratory Objectives (Phase 1) 

 
 
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The exploratory objectives of the Phase 1 study are: 
 
• To assess maximal PSA response to Sirolimus combined with docetaxel and 
carboplatin. 
• To assess PSA response duration to Sirolimus combined with docetaxel and 
carboplatin. 
• To assess response of measurable disease. 
• To assess time to progression of bone lesions or measurable disease (RECIST 1.1). 
• To assess effect of Sirolimus with docetaxel and carboplatin on DNA damage 
surrogates in cancer associated stroma compared to untreated and docetaxel and 
carboplatin treated stroma. 
 
2.3 
Primary Objective (Phase 2) 
 
The primary objective of the Phase 2 study is: 
 
• To assess the effectiveness of Sirolimus in suppressing the induction of the DNA 
damage secretory component WNT16B in tumor stroma following docetaxel and 
carboplatin. 
 
 
2.4 
Exploratory Objectives (Phase 2) 
 
The exploratory objectives of the Phase 2 study are: 
 
• To assess maximal PSA response to Sirolimus combined with docetaxel and 
carboplatin. 
• To assess PSA response duration to Sirolimus combined with docetaxel and 
carboplatin 
• To assess response of measurable disease (RECIST 1.1) 
• To assess time to progression of bone lesions or measurable disease (RECIST 
1.1) 
• To assess toxicity of the RP2D dose of Sirolimus with docetaxel and carboplatin. 
 
• To determine the effect of docetaxel and carboplatin therapy on the DDSP in 
serum. 
• To determine  response to Sirolimus, docetaxel and carboplatin in tumors with 
mutation of DNA repair pathway genes (BRCA2, ATM and other FANC pathway 
members) 
• To correlate the presence of DNA repair pathway mutations in circulating tumor 
cells (CTC) and circulating tumor DNA (ctDNA) with tumor biopsy and correlate 
changes in CTC number and ctDNA mutation levels with clinical responses. 
 
3 INVESTIGATIONAL PLAN 
3.1 
Overall study design and plan 
 

 
 
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This is an open-label study with separate phase 1 and phase 2 components. 
 
Phase 1: 
6-18 patients will be treated in a dose de-escalation study testing 3 dose levels of 
Sirolimus with fixed dose docetaxel (60 mg/m2 Day 1) and carboplatin (AUC 5 Day 1) 
every 21 days. 
 
Sirolimus will be administered on Day -2 every 21 days, at least two hours before or 
after grapefruit juice. 
 
The defined product of grapefruit juice will be ingested once daily for 7 consecutive 
days, on Days -3 through 4. The grapefruit juice dosage will be 8oz (240ml) daily. 
 
Docetaxel and carboplatin will be administered at 60 mg/m2 and AUC 5 on Day 1of a 
21 day cycle. Day -2 will occur two days prior to chemotherapy Day 1(there is no Day 
0). 
 
Dose Level 
Sirolimus 
100% (Dose Level 0) 
35mg 
First dose reduction (Dose Level - 
1) 
25mg 
Second dose reduction (Dose 
Level -2) 
20mg 
 
Patients will remain on treatment until any of the following occur: 
• intolerable toxicity 
• documented progression by imaging per RECIST 1.1 criteria 
• achieving complete response (CR) per RECIST 1.1 criteria 
• completion of 10 cycles of therapy – consideration for additional cycles at the 
investigator discretion if patients are responding and there is no evidence of 
cardiomyopathy. 
 
Adverse events for determination of maximally tolerated dose (MTD)/ RP2D and DLT 
will be evaluated within the first 21 days of treatment. 
 
Response in Phase 1 and 2 will be defined per Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1) and Prostate Cancer Working Group 2 Criteria (22) 
 
RECIST (1.1) – Appendix 5. For the purposes of this study, participants should be re- 
evaluated every 3 cycles or as clinically indicated with CT or MRI of the abdomen/pelvis 
and chest film or chest CT. 
 
Bone scan - Baseline bone scan will be performed during screening and repeated every 3 
cycles (9 weeks) or as clinically indicated. 
 
Biopsy at on Day 21 will be optional during phase I. Patients may opt for biopsy to 
determine status of DNA repair genes in tumor. 
 

 
 
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Phase 2: 
Patients will be randomized to either Cohort 1 or 2. The planned number of patients in 
each arm is 20, for a total of 40 patients enrolled in the Phase 2 portion of the study. 
 
Patients will be randomized by permuted blocks and randomization assigned by the 
Clinical Trials Service to either Cohort 1 or Cohort 2. 
 
Patients in Cohort 1 will receive only docetaxel and carboplatin during Cycle 1 (Cycle 1 
Day 1), followed by CT or US guided biopsy on Cycle 1 Day 21. The first dose of 
Sirolimus at RP2D, will be administered on Cycle 2 Day -2 with docetaxel and carboplatin 
administered on Cycle 2 Day 1; this dosing scheduled will continue for all subsequent 
cycles. 
 
Patients in Cohort 2 will receive Sirolimus at RP2D on Day -2 with docetaxel and 
carboplatin on Day 1 for all cycles. A CT or US guided biopsy will occur on Cycle 1 Day 
21. 
 
RP2D of Sirolimus will be administered on Day -2 every 21 days, at least two hours 
before or after grapefruit juice. 
 
The defined product of grapefruit juice will be ingested once daily for 7 consecutive 
days, on days -3 through 4. The grapefruit juice dosage will be 8oz (240ml) daily. 
 
Docetaxel and carboplatin will be administered at 60 mg/m2 and AUC 5 on Day 1of a 
21 day cycle. Day -2 will occur two days prior to chemotherapy Day 1(there is no Day 
0). 
 
Patients will remain on treatment until any of the following occur: 
• intolerable toxicity 
• documented progression by imaging per RECIST 1.1 criteria 
• achieving CR per RECIST 1.1 criteria 
• Completion of 10 cycles of therapy. If patients are continuing to respond, additional 
cycles can be administered at the investigator’s discretion. 
 
Response will be defined per Response Evaluation Criteria in Solid Tumors (RECIST 
1.1). 
 
RECIST (1.1) – Appendix 5. For the purposes of this study, participants should be re- 
evaluated every 3 cycles or as clinically indicated with CT or MRI of the abdomen/pelvis 
and chest film or chest CT. 
 
Bone Scan- Baseline bone scan will be performed during screening and repeated every 3 
cycles or as clinically indicated. 
 
4 STUDY POPULATION SELECTION 
4.1 
Study Population 
 

 
 
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Patients for the study will be recruited from within the Seattle Cancer Care Alliance 
(SCCA) and the University of Washington, which are separate practice sites within the 
same practice and share a single Institutional Review Board (IRB). 
 
Patients will be identified by their oncologist as eligible for the study and the study will 
be discussed with the patient by the provider. If patients are interested in participating, 
they will be counseled, and informed consent will be obtained by one of the 
investigators. A total of 6-18 subjects will be enrolled into the study in Phase 1, and up 
to 20 patients per cohort will be enrolled in Phase 2. 
 
4.2 
Inclusion Criteria 
 
Patients who meet 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 serum testosterone <50ng/ml 
and at least 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. 
• Progression of metastatic bone disease on bone scan with > 2 new lesions. 
6. Prior therapy with abiraterone, enzalutamide and/or docetaxel. If a patient has not 
received docetaxel or cabazitaxel chemotherapy, the patient must be informed of 
this treatment choice as an alternative. If the patient has received docetaxel or 
cabazitaxel chemotherapy or refuses one of both of these therapies, this rationale 
must be documented, and the patient is then eligible. Patient must be offered and 
made aware of all FDA‐approved treatment options. Patients with bone only disease may not 
have received radium-223. 
7. The presence of metastatic disease amenable to CT or ultrasound guided biopsy. 
This may include thoracolumbar vertebral bodies, pelvis, femur or humerus or soft 
tissue or nodal metastasis amenable to biopsy (excluding lung or pleural lesions). 
8. Agree to participate in biopsy of metastatic lesion during the study at Day 21. 
9. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1. 
10. Life expectancy >12 weeks. 
11. 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 is currently disease 

 
 
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free for at least one year 
12. Patients with any prior chemotherapy regimens are eligible. 
13. Patients with disease only in the bone may not have received Xofigo/Radium 223 to 
avoid ongoing DNA damage in bone marrow. 
14. Patients who are or are not receiving bisphosphonates or denosumab are eligible. 
Bisphosphonates or denosumab should not be initiated after registration and during 
active treatment. 
15. 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 bilirubin 
levels < 1.5 x ULN 
• Total bilirubin < 1.5 x ULN 
• Serum creatinine < 1.5 X institutional ULN mg/DL OR eGFR > 50 mL/min 
 
All pre-study labs required for determination of eligibility are to be completed within 14 
days prior to Day -2 (or the next business day if falls on a weekend or holiday). 
 
X-rays and/or scans to assess all disease sites are to be completed within 30 days 
prior to Day -2 (or the next business day if falls on a weekend or holiday). 
 
 
 

 
 
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4.3 
Exclusion Criteria 
 
Patients who meet any of the following criteria will be excluded from the study: 
1. Patients currently receiving active therapy for other neoplastic disorders. 
2. Patients with histologic evidence of small cell carcinoma of the prostate will not be 
eligible. 
3. Patients with disease only in the bone previously treated with radium-223 will not be eligible 
4. Known parenchymal brain metastasis. 
5. Active or symptomatic viral hepatitis or chronic liver disease. 
6. Estimated creatinine clearance less than 50 ml/minute. 
7. 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. 
8. Atrial fibrillation, or other cardiac arrhythmia requiring medical therapy. 
9. Administration of an investigational therapeutic within 30 days of Cycle 1, Day -2. 
10. Patients with dementia/psychiatric illness/social situations that would limit compliance 
with study requirements or would prohibit the understanding and/or giving of informed 
consent. 
11. Patients with medical conditions, which, in the opinion of the investigators, would 
jeopardize either the patient or the integrity of the data obtained will not be eligible. 
12. Any condition which, in the opinion of the investigator, would preclude participation 
in this trial. 
13. Patients on anticoagulation therapy which cannot be held for metastatic biopsies. 
 
5 STUDY TREATMENT(S) 
5.1 
Treatments Administered 
 
5.1.1 Sirolimus 
 
Patients will be instructed to take Sirolimus Oral Solution on study Day -2, two days 
prior to chemotherapy Day 1 (there is no Day 0), of each 21 day cycle. Sirolimus is to 
be administered orally in combination with water or orange juice, and can be taken with 
or without food. 
 
On Day -2 of every cycle a single dose of Sirolimus Oral Solution will be provided by the 
Institutional Investigational Pharmacy in a dosing syringe. The dosing syringe may be 
dispensed by the Institutional Investigational Pharmacy up to 24 hours prior to scheduled 
dosing of Sirolimus. At the time of administration, the Sirolimus Oral Solution will be 
emptied into only a glass or plastic container and mixed with up to 120ml (4oz) of water or 
orange juice. This will be stirred vigorously and the patient will drink at once. This will 
be repeated until the entire contents or Sirolimus Oral Solution has been consumed. 
 
5.1.1.1 Sirolimus risks and precautions 
 
Please refer to the Package Insert for all risks and precautions. 
 
 
 

 
 
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Increased susceptibility to infection and the possible development of lymphoma 
and other malignancies, particularly of the skin, may result from myelosuppression. 
Over suppression of the immune system can also increase susceptibility to infection, 
including opportunistic infections such as tuberculosis, fatal infections, and sepsis. 
 
Hypersensitivity 
reactions, 
including 
anaphylactic/anaphalactoid 
reactions, 
angioedema, exfoliative dermatitis, and hypersensitivity vasculitis have been associated 
with Sirolimus. 
 
Angioedema has been associated with Sirolimus. The concomitant use of Sirolimus 
with other drugs known to cause angioedema, such as ACE inhibitors, may increase the 
risk of developing angioedema. 
 
Fluid accumulation and wound healing: There have been reports of impaired or 
delayed wound healing in patients receiving Sirolimus, including lymphocele and wound 
dehiscence. Patients with a body mass index greater than 30kg/m2 may be at increased 
risk of abnormal wound healing based on data from medical literature. There have also 
been reports of fluid accumulation, including peripheral edema, lymphedema, pleural 
effusion, ascites, and pericardial effusions in patients receiving Sirolimus. 
 
Hyperlipidemia: There were increased incidences of hypercholesterolemia (43-46%) 
and/or hypertriglyceridemia (45-57%) in patients receiving Sirolimus compared with 
placebo (each 23%). 
 
Renal Function: Renal function should be closely monitored with administration of 
Sirolimus because long term administration with Sirolimus with cyclosporine has been 
associated with deterioration of renal function. 
 
Interstitial Lung Disease: Cases of interstitial lung disease, some fatal, with no identified 
infectious etiology have occurred in patients receiving immunosuppressive regimens 
including Sirolimus. 
 
Increased risk of Calcineurin Inhibitor-Induced Hemolytic Uremic Syndrome/ 
Thrombotic Thrombocytopenic Purpura/ Thrombotic Microangiopathy (HUS/TTP/TMA): 
The concomitant use of Sirolimus with a calcineurin inhibitor may increase the risk of 
HUS, TTP or TMA. 
 
Skin Cancer Events: Patients on immunosuppressive therapy are at increased risk for 
skin cancer, including squamous cell carcinoma, basal cell carcinoma, and malignant 
melanoma of the skin. Exposure to sunlight and ultraviolet light should be limited by 
wearing protective clothing and using sunscreen with a high protection factor. 
 
 
 

 
 
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The most common (≥ 20%) adverse reactions observed with Sirolimus in clinical 
studies are: 
• peripheral edema (54-58%) 
• 
edema (18-20%) 
• hypertriglyceridemia (45-57%) 
• hypertension (45-49%) 
• hypercholesterolemia (43-46%) 
• creatinine increased (39-40%) 
• constipation (36-38%) 
• abdominal pain (29-36%) 
• diarrhea (25-36%) 
• headache (34%) 
• 
fever (23-34%) 
• urinary tract infection (26-33%) 
• 
anemia (23-33%) 
• 
nausea (25-31%) 
• arthralgia (25-31%) 
• pain (29-33%) 
• thrombocytopenia (14-30%) 
• acne (22%) 
• rash (10-11%) 
 
 
The following adverse reactions resulted in a rate of discontinuation of > 5% in 
clinical trials: 
• creatinine increased 
• hypertriglyceridemia 
• thrombotic thrombocytopenic purpura (TTP) 
 
 
5.1.2 Docetaxel and carboplatin 
 
Docetaxel and carboplatin will be administered per Standard Practice Guidelines.  
 
• 
Docetaxel 60 mg/m2 will be administered on Day 1 of a 21 day cycle.  
• 
Carboplatin AUC 5 will be administered on Day 1 of a 21 day cycle. 
 
 

 
 
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5.1.2.1 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 
 
5.1.3 Grapefruit Juice 
 
The grapefruit juice will be provided to the patient by the study. Eight ounces (240ml) 
of grapefruit juice will be ingested once daily for 7 consecutive days, on Days -3 through 
4 of every 21 day cycle. 
 
5.1.4 Antiemetics 
 
Dose modifications for nausea and vomiting should not be made until patients are on 
adequate doses of antiemetics. Chemotherapy regimens which include docetaxel and 
carboplatin are categorize as moderately emetogenic, with a frequency of emesis 30- 
60%. Institutional guidelines for moderately emetogenic chemotherapy should be 
followed. 
 
5.1.5 Growth Factors 
 
Filgrastim (GCSF), 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. The National Comprehensive Cancer Network (NCCN) 
guidelines for use of growth factors and prophylactic antibiotics will be followed based 
on patient risks of neutropenia and infection [20]. 
 
5.1.6 Concomitant Therapy 
 
The use of any concurrent drug from screening and while on study, prescription or over- 
the-counter, is to be included in the clinic note from study visits.  
 
Concurrent enrollment in another clinical investigational drug or device study is 
prohibited. Supportive care medications are permitted with their use following institutional 
guidelines. 
 
The following supportive care medications are considered permissible during the study: 

 
 
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• Conventional multivitamins 
• Selenium 
• Soy supplements 
 
If the permissibility of a specific drug/treatment is in question, please contact the study 
investigator-sponsor. 
 
5.1.7 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. 
 
5.1.8 
Potential for Drug-Drug Interactions 
 
Sirolimus is known to be a substrate for both cytochrome P-450 3A4 (CYP3A4) and p- 
glycoprotein (P-gp). Inducers of CYP3A4 and P-gp may decrease Sirolimus 
concentrations whereas inhibitors of CYP3A4 and P-gp may increase Sirolimus 
concentrations. 
 
Co-administration of Sirolimus with strong inhibitors of CYP3A4 (such as ketoconazole, 
voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong 
inducers of CYP3A4 (such as rifampin or rifabutin) should be avoided. 
 
Additional inducers and inhibitors of CYP3A4 and P-gp: 
 
• Drugs that could increase Sirolimus blood concentrations: Bromocriptione, cimetidine, 
cisapride, clomitrazole, danazol, diltiazem, fluconazole, protease inhibitors, nicardipine, 
troleandomycin, verapamil 
 
• Drugs that could decrease Sirolimus blood concentrations: Carbamazepine, 
phenobarbital, phenytoin, rifapetine, St. John’s Wort 
 
• Drugs with concentrations that could increase when given with Sirolimus: Verapamil 
 
Immunosuppressants may affect response to vaccination. Therefore, during treatment 
with Sirolimus vaccination may be less effective. The use of live vaccines should be 
avoided. 
 
5.1.9 Potential Drug Interactions with Grapefruit Juice 
 
Grapefruit interacts with medications via several mechanisms, most notably by inhibition 
of CYP3A enzymes in the small bowel wall.  Co-administration of grapefruit juice with 
medications known to be metabolized by the CYP3A pathway will be reviewed by the 
study PI. Medications deemed by the study PI to not be safely administered with 
grapefruit juice will be discontinued prior to starting therapy on study. 
 

 
 
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5.1.10  Contraception 
 
Participants must agree to the use of an effective method of contraception. This should be 
started from the signing of the informed consent and continue throughout period of study 
treatment until at least 30 days after the last dose of sirolimus, docetaxel and carboplatin. 
 
 
5.2 
Supply, Packaging and Storage 
 
5.2.1 Sirolimus Pharmacy Storage Requirements 
 
Sirolimus Oral Solution will be provided to the Institutional Investigational Pharmacy, 
packaged for dispensing on a per patient basis. Patients will be provided with a single 
dose of Sirolimus in a dosing syringe, which may be dispensed up to 24 hours prior to 
scheduled dosing of Sirolimus on Day -2. 
 
Storage: Oral Solution bottles should be stored protected from light and refrigerated at 
2°C to 8°C (36°F to 46°F). If necessary, bottles may be stored at room temperatures upto 
25°C (77°F) for up to 15 days. Once the bottle is opened, the contents should be used 
within one month. 
 
The product may be kept in the dosing syringe for a maximum of 24 hours at room 
temperatures up to 25°C (77°F) or refrigerated at 2°C to 8°C (36°F to 46°F). 
 
5.2.2 Docetaxel and Carboplatin Supply, Packaging, Storage 
 
Docetaxel and carboplatin are stored and administered per institutional protocol. 
 
5.2.3 Grapefruit Juice Supply, Packaging, Storage 
 
Grapefruit juice will be supplied in the form of frozen juice concentrate. Individual cans of 
frozen grapefruit juice concentrate will be stored in an onsite freezer at or below 0º C. 
Patients will be instructed to maintain concentrate in a frozen state until instructed to drink 
the grapefruit juice. 
 
 

 
 
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5.3 Dose modifications for 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 present 
dose.  
If treatment is delayed by more than 4 weeks, 
the patient should be removed from 
chemotherapy treatment. 
Alkaline phosphatase 2.5-5X ULN (and no 
bone metastases) or AST/ALT 1.5-5X ULN 
Decrease docetaxel dose to 75% 
Alkaline phosphatase >-5X ULN (and no 
bone metastases) or AST/ALT > 5X ULN or 
total bilirubin > ULN 
Hold therapy until less than grade 1 and 
restart at previously administered 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) 
Documented infection with Grade 3 
neutropenia (defined as an ANC <1.0 x 109 
cells/L) 
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 docetaxel and carboplatin to 75% 
starting dose for all subsequent cycles. 
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, the 
patient should be removed from chemotherapy 

 
 
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Treatment may be delayed for other hematological and non-hematological reasons at the discretion 
of the treating physician and/or PI. Treatment may also be delayed for situations other than 
treatment-related adverse events such as medical/surgical events not related to therapy. 
 
5.3.1 
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 present 
dose. If Grade 4 nausea and vomiting recur despite maximal antiemetic therapy, the 
patient should be removed from chemotherapy. 
 
5.3.2 
Dose modifications for Sirolimus 
 
There will be no dose modification of Sirolimus in phase 2. In chronic dosing of 
Sirolimus dose adjustment is performed to maintain blood levels within defined 
parameters. This is not necessary with single dose administration. 
 
Any non-hematological toxicity, grade 4 lasting > 5 days and considered related to 
Sirolimus, will result in dose reduction of Sirolimus by one level at next dosing cycle and 
all subsequent cycles. If toxicity does not resolve to grade >2 or subsequent non- 
hematological toxicity grade 4 lasting > 5 days considered related to Sirolimus occurs a 
second dose reduction of Sirolimus will occur. 
 
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. 
 
Explanation of Genomic Results: 
 
Recent work from the Stand Up to Cancer (SU2C) Prostate Cancer Metastasis 
sequencing project and currently in press show that 20% of CRPC tumors contain 
biallelic inactivation of DNA damage repair genes, including BRCA1, BRCA2, ATM, 
ATR, FANC and RAD51. Of these tumors, half have an associated deleterious germline 
mutation as the cause of inactivation of one allele, with copy loss of the other allele as 
the cause of homozygous inactivation. Therefore 10% of men with CRPC may have a 
deleterious germline mutation in BRCA1, BRCA2 or other DNA repair gene which would 

 
 
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put them or other family members at risk for malignancy. A prospective objective of the 
current study is to determine status of these genes as a predictor of response to 
docetaxel/carboplatin and Sirolimus. 
 
We consider that patients and family members, who are dealing with the  difficult situation 
of advanced cancer, might prefer to focus on care of their disease rather than receive 
extraneous information that could be perceived as  overwhelming  and distracting. We do 
not have a proven, evidence-based way to implement the informed consent regarding 
patients’ disclosure option preferences yet, we must adopt a reasonable practice in 
order to conduct this study. 
 
The proposed solution has been to adopt a “provisional” model, pioneered at the 
University of Michigan and which is currently a component of the SU2C protocol in 
place at UWMC/FHCRC that is based on the following considerations (Table 4). First, 
from the patient’s perspective, it makes sense to distinguish between results that inform 
management of the patient’s specific cancer (“Cancer of interest”) and those incidental 
results which may affect the patient’s and/or their family member’s risks of other 
conditions (“Conditions other than cancer of interest”). Patients should be offered results 
based on best clinical judgment (i.e., offered a default option), but their preferences 
regarding incidental findings ought to be respected when possible (i.e., the default can 
be changed). This is called the Flexible-Default Model of Informed Consent. 
 
Table 4: Provisional Informed Consent: Flexible Default Model 
 
 
 
Disease 
Domain 
Impact/Significance 
Default 
Decline 
Results? 
Description 
Cancer of 
Interest 
Direct impact on care 
of current cancer 
Disclose 
Not 
flexible 
Marketed treatment available 
Targeted clinical trial 
available 
Significance for 
biological family 
Disclose 
Flexible 
Increased risk of cancer for 
biological family 
Significance is 
unknown 
Not 
disclose 
Not 
flexible 
Mutation function or role 
unknown 
Conditions 
other than 
cancer of 
interest 
Potential medical 
impact 
Disclose 
Flexible 
Clinically significant relative 
risk of disease or outcomes 
Significance for 
biological family 
Disclose 
Flexible 
Significant implications for 
biological family decisions 
Significance is 
unknown 
Not 
disclose 
Not 
flexible 
Mutation function or role 
unknown 
 
Flexible-Default Model of Informed Consent: 
 
Patients will be given the option to decline certain results. Ultimately, patients should be 
offered results about their cancer based on best clinical judgment (i.e., default), but their 
preferences regarding incidental findings ought to be respected when possible (i.e., 

 
 
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flexible). Therefore, the default consent is to disclose results to patients and clinicians 
for results related to “Cancer of interest”, which we designate as “not flexible,” since it is 
anticipated that patients who consent will expect these results. The default consent for 
“Conditions other than cancer of interest” is to disclose results. For the remaining 
categories of results that considered “flexible”, patients will be given an option to share 
their preferences and say “Yes” or “No” to these other results before they begin the 
study. The default for these categories is disclosure. However, if patients prefer, they 
may decline such results at the time of consent. They will be asked for their preference 
for two simplified categories: A) “Results that may have significance for biological family 
members” and B) “Results that are not related to your cancer, but may have potential 
medical impact for you”. 
 
A study investigator will assist the patient in completing this section of the informed 
consent. Categorization of findings is performed by the current Precision Tumor Board 
at UWMC/SCCA which meets monthly to review Oncoplex results and SU2C 
sequencing results. 
 
6.2 
Medical History 
 
Medical history, such as previous treatments, procedures, and conditions will be 
collected during the screening period. 
 
6.3 
Physical Examination 
 
Evaluations should be performed as below whenever possible. 
 
Physical examination to include HEENT (head, eyes, ears, nose, and throat), chest, 
cardiac, abdominal, extremities, neurologic, and lymph node examinations. 
 
Vital signs include blood pressure, heart rate and temperature on Day 1 of each cycle. 
Weight will be determined on Day 1 of each cycle. Height will be assessed at screening 
visit only. 
 
6.4 
Laboratory Tests 
 
6.4.1 Clinical Safety Laboratory Tests 
 
Phase 1: During the Phase 1 portion of the study clinical safety labs will be collected at 
the following time points: 
 
• Screening 
• Day -2 (± 2 days) prior to Sirolimus dosing 
• Days 8 & 15 (± 4 days) 
• Termination Visit 
 
 

 
 
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Phase 2: During the Phase 2 portion of the study clinical safety labs will be collected at 
the following time points: 
 
• Screening 
• Day -2 (± 2 days) prior to Sirolimus dosing 
• Termination Visit 
 
If clinical safety labs are drawn within 2 days prior to Day 1 (i.e., Day -2), and patient 
labs qualify patient to safely receive chemotherapy at standard dosing, clinical safety 
labs do not have to be repeated on Day 1. However, clinical safety labs may be repeated 
on Day 1 at the PI or provider’s discretion or if treatment dose reduction is necessary. 
 
Clinical safety labs will include the following: 
 
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 
 
Serum Chemistry: 
Albumin (ALB) 
Blood urea nitrogen (BUN)  
Calcium (Ca) 
Carbon dioxide (CO2) 
Chloride (Cl)  
Creatinine 
Glucose  
Potassium (K)  
Sodium (Na) 
 
 
 
 
 
Liver Functions: 
Alanine aminotransferase (ALT; SGPT) 
Aspartate aminotransferase (AST; 
SGOT) 
Alkaline phosphatase (ALK-P)  
Total bilirubin 
 
 
 
6.4.2 Safety Labs Prior to Metastatic Biopsy 
 
Coagulation tests or any additional laboratory tests will be collected per institutional 
policy prior to metastatic biopsy on Day 21. 
 
6.4.3 Tumor Markers 
 
PSA level will be assessed during the screening period, on Day -2 of every cycle and 
at the Termination Visit. 
 
6.4.4 Research Labs 
 
Please refer to the laboratory manual for details. 
 
6.4.5 Sample Collection, Storage, and Shipping 

 
 
 
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The institutional laboratories at the SCCA and University of Washington (UW) 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. 
 
6.4.6 
Biopsy acquisition and tissue handling 
 
Patients will undergo a CT guided or US guided biopsy of a metastatic lesion on Day 
21(±4 days, but prior to start of next cycle). An optional repeat biopsy may be 
performed if the patient consents in order to assess whether suppression of DDSP 
is lost after initial mTOR inhibition or to identify additional potential mechanisms of 
resistance to mTOR targeting. If the patient undergoes second optional biopsy (any 
time after initial biopsy), the biopsy site does not have to be the same location at each 
time point. Issues that would cause biopsy delay must be discussed with study 
PI. Biopsy tissue acquisition procedure should be followed per the laboratory manual. 
 
A formalin section of biopsy is evaluated under H and E for tumor content. Less than 
20% of tumor content makes the sample inevaluable. This is the standard used 
to assess the suitability of a tumor biopsy in the ongoing SU2C/AACR from which 
we recently published the results of the first 150 patients (Robinson, Cell, 2015; 161 
(5): 1215). The UWMC site contributed more biopsies than any other site. Based 
on our experience, we anticipate that 80-90% of biopsies will be informative. The 
statistics include the potential that 10% of biopsies will not be informative (4 additional 
patients). 
 
Please refer to the laboratory manual for detailed instructions regarding acquisition and 
handling of tissue specimens. 
 
 
 

 
 
 
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6.5 Criteria for Evaluation 
 
6.5.1 Safety: Phases 1 and 2 
• The number and percentage of patients who experience a Serious Adverse Event; 
• The number and percentage of patients who experience an Adverse Event; and 
• The number and percentage of patients who discontinue study drug treatment 
early due to an adverse event. 
Safety will be assessed through summaries of adverse events, vital signs, 
physical examinations, and clinical laboratory test data (including change from 
baseline). 
 
Safety analyses will include all enrolled patients who receive any amount of study 
drug (safety population). 
 
Grade 4 hematological laboratory values and grade 3-4 non-hematological AEs will 
be collected and classified by the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE v. 4.0). 
 
6.5.2 Anti-Tumor Effects: Phase 2 
 
• The percentage of patients achieving at least a 50% reduction in PSA according 
to PCWG2 criteria; 
• The percentage of patients achieving at least a 90% reduction in PSA according 
to the PCWG2 criteria. 
• The percentage of patients achieving a 30% reduction in measurable disease 
by RECIST 1.1. 
 
6.5.3 
Tissue Endpoints: Phase 2 
 
Immunohistochemistry (IHC) and quantitative polymerase chain reaction (PCR) will 
be used to evaluate microenvironment damage response gene products and 
proteins in the resected tumor/tissue. IHC will be performed and evaluated using 
antibodies to IL6, WNT16B and SFRP2 and will assess mTOR blockade using 
antibodies to S6. Immunohistochemical assays of tumor and microenvironment 
damage will quantitate 53BP1 and gammaH2AX expression. 
 
Quantitative reverse transcription PCR will quantitate microenvironment damage- 
responsive transcripts, and attendant responses within tumor cells. Panels of 
microenvironment transcripts will be quantitated including WNT16B, SPINK1, IL6, 
MMPs, and Amphiregulin. Tumor cell transcripts will include Ki67, p16, p27, Myc 
and EMT markers including vimentin and Snail. 
 
Immune cell infiltration in the tumor microenvironment will be assessed by IHC or flow 

 
 
 
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cytometry of white blood cell types: CD45 as a general marker of leukocytes; CD68 
for monocyte/macrophages; CD3, CD4, CD8 for T cells. 
 
6.6 
Safety Assessments 
 
All participants receiving investigational agents will be evaluated for safety. The safety 
parameters include laboratory tests and hematological abnormalities, physical 
examination findings, and spontaneous reports of adverse events reported to the 
investigator by participants. Grade 4 hematological laboratory values and grade 3-4 
non-hematological AEs encountered during the study will be evaluated according to 
the NCI criteria specified in the protocol and recorded prior to each course of therapy 
and reported in accordance with local reporting requirements. 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 
 
Please see section 8.4 concerning safety evaluation information.  
 
6.7 
Safety Data Collection, Recording and Reporting 
 
The PI of the study will have primary responsibility for ensuring that the protocol 
is conducted as approved by the FHCRC/UW Cancer Consortium Scientific Review 
Committee and Institutional Review Board. The PI will ensure that the monitoring plan 
is followed, that all data required for oversight of monitoring are accurately reported to 
the FHCRC/UW Cancer Consortium Data and Safety Monitoring Committee (DSMC), 
that all adverse events are reported according to the protocol guidelines, and that 
any adverse reactions reflecting patient safety concerns are appropriately reported. 
 
Under the provisions of the FHCRC/UW Cancer Consortium Data and Safety 
Monitoring Plan (DSMP), Cancer Consortium Clinical Research Support (CRS) 
provides monitoring for quality process and compliance by qualified monitors 
unaffiliated with the conduct of the study. Monitoring visits occur at specified intervals 
determined by the assessed risk level of the study and the findings of the previous 
visit as described in the Cancer Consortium DSMP.” 
 
All observed or volunteered Grade 3 and 4 adverse events regardless of causal 
relationship to study drug will be recorded on the adverse event page(s) of the case 
report form (CRF). 

 
 
 
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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 v 4.0), Causality (relationship 
to docetaxel and carboplatin and/or Sirolimus) 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 

 
 
 
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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 immediately notify the UW/FHCRC Cancer Consortium IRB, and 
FDA. See Section 6.7.3 for definition of SAEs and SUSARs, and 6.7.7 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 

 
 
 
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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). 
 
6.7.4 Dose Limiting Toxicity (DLT) 
 
DLT is defined as drug-related febrile neutropenia, grade > 3 non-hematological toxicity 
or grade 4 hematologic toxicity lasting > 5 days, occurring during the phase 1 
component of the study. Only those events which occur in cycle 1 will be considered 
a DLT. 
 
6.7.5 Dose De-escalation 
 
The planned dose de-escalation in phase 1 varies the dose of Sirolimus administered 
on day -2 with docetaxel and carboplatin 60 mg/m2 and AUC 5 on day 1every 21 days. 
 
The Sirolimus dose in dose level 0 is 35 mg once on Day -2. If zero or one DLT’s occur 
in the first three patients, an additional 3 patients will be treated in dose level 0. If 
the observed DLT rate is < 33% in six patients, dose level 0 will be the RP2D. Patients 
may continue in their cohort for repeated cycles of dosing; however, dose de-
escalation within a patient will not occur. If the DLT rate is > 33% in 3 or 6 patients, the 
dose will be decreased to dose level -1, 25 mg once per 21 day cycle on Day -2. The 
same cohort algorithm will occur at dose level -1 as above. If DLT rate is > 33% is seen 
at dose level 
-1 at 3 or 6 patients, the dose level will decrease to dose level -2 at 20 mg once per 
21 day cycle on Day -2. If DLT rate is > 33% at dose level -2, no phase 2 will be 
carried out. 
 
Dose de-escalation values: 
 
Dose Level 
Sirolimus 
100% (Dose Level 0) 
35mg 
First dose reduction (Dose Level - 1) 
25mg 
Second dose reduction (Dose Level -2) 
20mg 
 
6.7.6 Reporting Procedures for Adverse Events 
 
The investigator is responsible for ensuring that all 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, 

 
 
 
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acceptable medical terms. 
 
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 the course of a subject’s 
participation in a trial must be reported as an SAE, as previously stated. 
 
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. 
 
6.7.7 
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 Seattle Cancer Care 
Alliance must be reported to the Cancer Consortium IRB. 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. 
 
 
SUSARs will be reported on the Expedited Reporting Form for Unanticipated 
Problems or Noncompliance. 
 

 
 
 
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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 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, PI shall submit, once a year throughout 
the clinical trial or on request a safety report to the competent authority and 
InstitutionalReview Board, taking into account all new available safety information 
received during the reporting period. 
 

 
 
 
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6.8 
Criteria for Discontinuation of Study 
 
 The patient develops an unacceptable toxicity, refer to Sections 6.7.3 & 6.7.4. 
 Disease progression per RECIST 1.1 criteria, refer to Appendix 5. 
 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. 
 
6.9 
Withdrawal from Study 
 
The investigator may withdraw a patient from any phase of the study for any of 
the following reasons. 
 
• Discontinuation of treatment criteria as defined in Section 6.8 
 
• Sustained Side Effects: Patients who have sustained toxicities, such as 
hyperglycemia or hypertension that do not return to NCI CTCAE (version 4.0) Grade 
1 or less with appropriate medical management, should be discontinued from 
the study treatment. 
 
• Administration of prohibited medications: The patient will be discontinued from 
the protocol treatment when prohibited drug is administered. Supportive care 
medications are permitted with their use following institutional guidelines. The 
concurrent administration of other anticancer therapy, or immunotherapy is 
prohibited during study treatment Phase. Use of other investigational drug therapy 
for any reason is prohibited. 
 
• 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. A patient’s decision to take part in the study is 
voluntary and he may choose not to take part in the study or to stop taking part at 
any time. If he chooses not to take part or to stop at any time, it will not affect his 
future medical care or medical benefits. 
 
If a subject terminates the study early, an Early Termination visit will be performed. 
 
7 STUDY ACTIVITIES 
7.1 
Study Visit Overview 
 
Expected toxicities and potential risks as well as dose modifications for Sirolimus, 
docetaxel and carboplatin 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. 

 
 
 
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7.2 
Screening Period 
 
Patients for the study will be recruited from sites from within the SCCA and UW. 
Patients will be identified as eligible for the study and the study will be discussed with 
the patient by their provider. If patients are interested in participating, they will be 
counseled and informed consent will be obtained by one of the investigators. 
 
Screening  procedures  to  be  completed  within  30  days  prior  to  the  start  of  
study treatment, Day -2: 
 
 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 
 Clinical laboratory tests: 
 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, glucose, calcium) 
 PSA 
 Testosterone 
 Bone scan 
 CT or MRI of the abdomen/pelvis 
 Chest film or chest CT 
 Concomitant medications listing: 
Obtain a complete and thorough listing of all prescription and nonprescription (over 
the counter) medications currently taken including pain medications. This also 
includes any nutritional supplements and/or herbal preparations. 
 
7.3 
Treatment Period 
 
7.3.1 Day -2 
 
Patients will complete all Day -2 tests and assessments prior to Sirolimus Oral Solution 
dosing. Day -2 occurs two days prior to Day 1 chemotherapy infusion (there is no 
Day 0). 
Grapefruit juice will be consumed on Days -3 through 4, as described in Section 
5.1.3. for each cycle administered with Sirolimus. 
 
The following procedures should be completed on Day -2 (± 2 days): 
 Physical exam 
 Vital signs (blood pressure, heart rate, temperature, and weight) 
 ECOG performance status 

 
 
 
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 PSA 
 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) 
 Research blood draw (Refer to lab manual for details) 
 Concomitant Medications 
 Adverse Events 
 Administer Sirolimus Oral Solution* 
 
*Patients enrolled in Phase 2 portion of the study will be randomized to either Cohort 
1 or Cohort 2. Sirolimus dosing on Day -2 for each cohort is described below: 
 
Cohort 1: Patients randomized to Cohort 1 will receive first dose of Sirolimus Oral 
Solution on Cycle 2 Day -2 after the metastatic biopsy is complete, and will receive 
Sirolimus on Day -2 for all subsequent cycles. Patients will not receive Sirolimus during 
Cycle 1. 
 
Cohort 2: Patients randomized to Cohort 2 will receive first dose of Sirolimus Oral 
Solution on Cycle 1 Day -2 prior to metastatic biopsy, and will receive Sirolimus on Day 
-2 for all subsequent cycles.  Patients will receive Sirolimus for all cycles. 
Dosing and administration of Sirolimus is discussed in Section 5.1.1. 
7.3.2 Day 1 
 
The following procedures should be completed on Day 1 (± 2 days): 
 
 Patients will be evaluated for compliance 
 Vital signs (blood pressure, heart rate, temperature) 
 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)** 
 Concomitant Medications 
 Adverse Events 
 Administer docetaxel and carboplatin 
 
** If clinical safety labs are drawn within 2 days prior to Day 1 (i.e., Day -2), and patient 
labs qualify patient to safely receive chemotherapy at standard dosing, clinical safety 
labs do not have to be repeated on Day 1. However, clinical safety labs may be 
repeated on Day 1 at the PI or provider’s discretion or if treatment dose reduction 
is necessary. 
 
Dosing and administration of docetaxel and carboplatin is discussed in Section 5.1.2. 
7.3.3 Days 8 & 15 (Phase 1 only) 

 
 
 
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During Cycle 1 of the Phase 1 portion of the study, patients will get weekly safety 
labs while receiving treatment. Additional safety labs will be drawn on Days 8 and 15 
(± 4 days). Additionally weekly safety labs during subsequent cycles may be drawn per 
the discretion of the PI and/or sub-investigators. 
The following procedures should be completed on Days 8 & 15 (± 4 days): 
 
 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) 
 Concomitant Medications 
 Adverse Events 
 
7.3.4 Additional visits 
 
A CT or US guided metastatic biopsy will occur on Day 21. In the Phase 1 portion 
of the study the biopsy on Day 21 is optional. In the Phase 2 portion of the study 
the biopsy on Day 21 is mandatory. There is an opportunity for an additional biopsy 
during the Phase 2 study if the patient opts for this (in addition to the required biopsy on 
Day 21). 
 
Research labs are optional for the Phase 1. Research labs will be drawn during 
the Phase 2 portion of the study. Please refer to lab manual and for details. 
 
CT or MRI of the abdomen/pelvis and Chest film or chest CT will be performed 
as outlined below, or as clinically indicated. 
• Phase 1: CT or MRI imaging will be repeated every 3 cycles 
• Phase 2: CT or MRI imaging will be repeated every 3 cycles 
 
A bone scan will be performed as outlined below or as clinically indicated. 
• Phase 1: Bone scan will be repeated every 3 cycles 
• Phase 2: Bone scan will be repeated every 3 cycles 
 
7.3.5 
Termination Visit (28 days, ± 7 days, from withdrawal of protocol) 
 
All patients who receive study drug must have a termination visit within 28 days of 
the last dose of study medication unless unable to return to the institution due to 
illness or ongoing disease treatment. All serious adverse events and grade 3 or 
higher adverse events must be followed until the event resolves or is assessed as 
chronic. 
 
The following study procedures will be performed at the Termination Visit: 
 
 Physical exam 
 Vital signs (blood pressure, heart rate, temperature and weight) 

 
 
 
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 ECOG performance status 
 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) 
 Concomitant Medications 
 Adverse Events 
 
8 PLANNED STATISTICAL METHODS 
8.1 
Determination of Sample Size 
 
8.1.1 
Safety: Phases 1 and 2 
 
Safety will be assessed through summaries of adverse events, vital signs, physical 
examinations, and clinical laboratory test data. Safety analyses will include all enrolled 
patients who receive any amount of study drug. 
 
Grade 4 hematological laboratory values and grade 3-4 non-hematological AEs will 
be collected and classified by the NCI CTCAE v. 4.0. 
 
The study design is a dose de-escalation with a minimum of 6 patients at the 
anticipated RP2D dose. If the first six patients do not suffer an unacceptable DLT rate 
(> 33%), the study would then proceed to phase 2. Sample size 6-18 patients. 
 
8.1.2 
Efficacy: Suppression of DNA damage pathway, Phase 2 
 
The primary endpoint is suppression of DDSP induction following genotoxic 
chemotherapy. Based on preliminary data, we anticipate that 50% of patients will 
increase the expression of at least one of WNT16, IL6, or SFRP2 (key members of 
the DNA damage response) >3-fold over the background level in tissue stroma 
(microenvironment) 
following 
treatment 
with 
DNA 
damaging 
chemotherapy 
(carboplatin/docetaxel). We hypothesize that the administration of Sirolimus will 
suppress this induction in 90% of patients. 
 
We will measure the expression of transcripts and encoded proteins that are 
upregulated following DNA damage and constitute a component of the DDSP. We 
will focus on 3 genes that are the most robustly induced: WNT16B, IL6, and SFRP2. 
We will measure each individually at the transcript level by qRT-PCR and also by 
immunohistochemistry. As qRT-PCR is quantitative, this will be the primary metric 
of induction, but in the event of RNA degradation in sample processing, the IHC 
measure will be the alternative which is semi-quantitative (0-2 scale of expression). 
We will also include a more expansive assessment of a signature of the DDSP derived 
from microarray profiling of gene expression. We will measure the levels of these 
transcripts: WNT16B, IL6, SFRP2 (and protein where necessary) after chemotherapy 

 
 
 
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and 
compare 
the 
levels 
against 
chemotherapy 
plus 
rapamycin. 
The 
background/baseline measurement for the comparison comprises a cohort of samples 
from untreated patients (n=10) where the expression of these genes is very low (qRT-
PCR cycle numbers >30). We expect that WNT16B, IL6 or SFRP2 will be elevated 
>3-fold following chemotherapy compared to these baseline measurements (untreated 
patients) and that rapamycin treatment will attenuate this response so that levels will 
remain <3- fold over the baseline/reference cohort. For this study, feasibility 
prevented obtaining pretreatment tissue biopsies for study subjects followed by the 
additional post-treatment biopsy. 
 
20 patients randomized to treatment with Sirolimus and 20 patients randomized to 
treatment without Sirolimus (for a total of N=40 patients) will provide 81% power 
to detect a difference in the proportions of patients with < 3-foldinduction of DDSP 
over background in at least one of the 3 markers at an alpha of 5% based on a 2-
sided, 2- sample test of proportions. We will accrue up to 4 additional patients as 
necessary if patients drop out before the endpoint can be evaluated; final analysis 
will investigate sensitivity of inference to possible informative missing for any dropouts. 
 
8.2 
Analysis Populations 
 
All patients who receive at least one dose of study drug will be included in the analysis 
of safety (Safety Population). 
 
8.3 
Demographics and Baseline Characteristics 
 
Demographic variables will include age, race, ethnicity, height, and weight. Baseline 
disease characteristics will include clinical TNM stage, date of diagnosis, histology. 
 
8.4 
Safety Evaluations 
 
Treatment emergent AEs directly related to Sirolimus are those events that occur 
or worsen on or after first dose of study drug up through 28 days post last dose. 
Grade 4 hematological laboratory values and grade 3-4 non-hematological AEs will 
be collected and classified by the NCI CTCAE v 4.0. 
 
All adverse events resulting in discontinuation, dose modification, dosing interruption, 
and/or treatment delay of study drug will also be listed and tabulated by preferred term. 
 
Clinical laboratory test results will be collected pretreatment and through 28 days post 
last dose of study treatment. All laboratory test results will be classified according to 
the NCI CTCAE v. 4.0 criteria. Standard reference ranges will be used for missing 
or discrepant normal ranges. Baseline laboratory test values are the results from the 
last blood samples drawn on or prior to the first day of study treatment. On-study 
laboratory test values are those results from blood samples drawn a day after the 
first study treatment up until 28 days after the last dose of study drug administration. 
 
 

 
 
 
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9 REFERENCE LIST 
 
1. 
de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis 
G, Bodrogi I, Mackenzie MJ, Shen L et al: Prednisone plus cabazitaxel or 
mitoxantrone for metastatic castration-resistant prostate cancer 
progressing after docetaxel treatment: a randomised open-label trial. 
Lancet 2010, 376(9747):1147-1154. 
2. 
Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jr., Jones JA, Taplin ME, 
Burch PA, Berry D, Moinpour C, Kohli M et al: Docetaxel and estramustine 
compared with mitoxantrone and prednisone for advanced refractory 
prostate cancer. N Engl J Med 2004, 351(15):1513-1520. 
3. 
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, 
Theodore C, James ND, Turesson I et al: Docetaxel plus prednisone or 
mitoxantrone plus prednisone for advanced prostate cancer. N Engl J 
Med 2004, 351(15):1502-1512. 
4. 
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Gjyrezi A, Chanel-Vos C, Shen R, Tagawa ST et al: Taxane-induced 
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Mezynski J, Pezaro C, Bianchini D, Zivi A, Sandhu S, Thompson E, Hunt 
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Armitage GR, Wilson JJ, Venner PM, Coppin CM et al: Chemotherapy 
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patients with castrate-refractory prostate cancer progressing after prior 
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L, Gleave ME, Soule H et al: Aggressive variants of castration-resistant 
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Cohen EE, Wu K, Hartford C, Kocherginsky M, Eaton KN, Zha Y, Nallari A, 
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Schweizer MT, Zhou XC, Wang H, Bassi S, Carducci MA, Eisenberger 
MA, Antonarakis ES The influence of prior abiraterone treatment on the 
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Scher HI et al. Design and end points of clinical trials for patients with 
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Clin Oncol. 2008 Mar 1;26(7):1148-59. 

 
 
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10 APPENDICES 
APPENDIX 1 - SCHEDULE OF EVENTS 
 

 
 
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Chest film or chest CT10 
X 
Grapefruit Juice7 
X21 
X21 
Sirolimus Oral Solution 
X21 
Docetaxel and carboplatin 
X 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant  Medications 
X 
X 
X 
X 
X 
X 
Tumor Biopsy4 
X 
 
 
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 registration. All screening should be complete prior to registration. 
2 All study assessments and medications should be administered ±4 days of the protocol-specified date, unless otherwise noted. 
3 For patients taking anti-coagulation medication at baseline, a PT/INR test should be done at screening. Repeat PT/INR prior to biopsy per 
institutional guidelines. 
4 Tumor biopsy to be completed prior to starting Cycle 2. 
5 Vital Signs will include blood pressure, heart rate, temperature and weight. Vital signs should also be documented with any adverse signs or 
symptoms during or immediately after an infusion. Height will be measured at screening visit only. 
6 Day -2 and Day 1 visit to occur ± 2 days. 
7 Study coordinator will provide patient with grapefruit juice. Patient will drink grapefruit juice at home on the specified days (Days -3 through 4). 
8 Hepatic function includes AST, ALT, alkaline phosphatase and total bilirubin. 
9 Days 8 & 15 Safety Labs will only be drawn during the Phase 1 portion of the study. 
10 CT or MRI of abdomen/pelvis and chest film of chest CT will be repeated as detailed in Section 7.3.4 or as clinically indicated. 
11 A bone scan will be repeated as detailed in Section 7.3.4 or as clinically indicated. 
12 Include plasma for DDSP components. Blood specimens should be optimally drawn before 10:00am, Monday – Friday. Saturday and Sunday 
research blood draws are not permissible. Please refer to laboratory manual for specific instructions regarding obtaining research labs. 
13 If safety labs drawn within 2 day prior to Day 1 (i.e. Day -2), and patient labs qualify patient to safely receive chemotherapy at standard dosing, 
labs do not have to be re-drawn on Day 1. 
14 Day -2 dosing of Sirolimus will occur two days prior to chemotherapy Day 1. There is no Day 0. 
15 CBC includes: hematocrit, hemoglobin, platelet, RBC, WBC with differential. 
16 Chemistry & electrolyte labs include: albumin, BUN, calcium, carbon dioxide, chloride, creatinine, glucose, potassium, sodium 
17 Termination visit to occur within 28 days (± 7 days) of last dose of study medication. 
18 Day -2 visit to occur ± 2 days. 
19 Research labs will be drawn in the Phase 2 study during Cycle 1. Research labs are not required for subsequent cycles. 
20 Research labs will be drawn for the Phase 1 study at baseline and day 21. The research blood collection is optional for Phase 1 of the study. 
21 Patient in Phase 2 Cohort 1 will not start grapefruit juice and sirolimus until Cycle 2. Patient in Phase 2 Cohort 2 will start grapefruit juice and sirolimus at 
Cycle 1.  
 

 
 
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APPENDIX 2 - TREATMENT SCHEMATIC 
 
 
 

 
 
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APPENDIX 3 - 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 
 
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 4 – 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. 
 
 

 
 
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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. 
 
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. 
 
 
 

 
 
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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: 
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 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. 
 
 

 
 
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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 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. 
 
 

 
 
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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 make a determination 
of overall response based on the evaluation of target, non-target, and new 
lesions, as shown in Table 10 and Table 11. 
 
Table 10. Time Point Response: Patients with Target (± Non-target) Disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
 
 
 
 
 
 
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 
 
 
 
 
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 
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 

 
 
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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. 
 
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. 
 
 
 

 
 
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APPENDIX 5 – 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.