Changes in 18F-fluciclovine Positron Emission Tomography (PET) in Patients With Metastatic Castration Resistant Prostate Cancer Treated With With Life Prolonging Therapies: A Pilot Study
Phase: PHASE2
Conditions: Metastatic Castration-resistant Prostate Cancer
Sponsor: Tulane University

 
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BED-IIT-382:  Changes in 18F-fluciclovine Positron Emission 
Tomography (PET) in Patients with Metastatic Castration 
Resistant Prostate Cancer Treated with Life-Prolonging Therapies:  
(A Pilot Study)  
 
 
 
 
 
NCT Number: NCT04158245 
 
January 5, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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BED-IIT-382:  Changes in 18F-fluciclovine Positron Emission 
Tomography (PET) in Patients with Metastatic Castration 
Resistant Prostate Cancer Treated with Life-Prolonging Therapies:  
(A Pilot Study)  
 
 
IRB Protocol # 2019-591 
Protocol Version 4.0 
Date: January 5, 2021  
ClinicalTrials.gov Identifier: NCT04158245 
 
 
 
Principal Investigator: 
 
Pedro C. Barata, MD MSc 
 
Co-Investigators: 
 
 
Alton O. Sartor, MD 
 
 
 
 
 
Brian Lewis, MD 
 
 
 
 
 
Jodi Layton, MD 
 
 
 
 
 
 
 
 
 
Funding and 18F-fluciclovine provided by Blue Earth Diagnostics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Glossary:  
ADT androgen deprivation therapy 
AR androgen receptor 
BAT bipolar androgen therapy 
CI confidence interval 
CT computerized tomography 
ctDNA circulating tumor deoxyribonucleic acid 
DNA deoxyribonucleic acid 
ECOG PS performance status 
HR hazard ratio 
LHRH luteinizing hormone-releasing hormone  
mCRPC metastatic castration-resistant prostate cancer 
NGS next-generation sequencing 
PARP poly ADP ribose polymerase 
PCWG3 prostate cancer working group 3 
PET positron emission tomography 
PSA prostate-specific antigen 
RECIST response evaluation criteria in solid tumors 
SBRT stereotactic body radiation therapy 
 
 
 

 
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Synopsis:  
PROJECT TITLE:   
Changes in 18F-fluciclovine Positron Emission Tomography (PET) in Patients with 
Metastatic Castration Resistant Prostate Cancer Treated with Life-Prolonging Therapies: A Pilot 
Study 
 
RATIONALE:  
Prostate cancer is the most common non-cutaneous cancer in men and the second leading 
cause of cancer-related death in the United Sates, with 164,690 estimated cases leading to 29,430 
deaths, in 2018.1 While the incidence of localized prostate cancer has begun to decline in the last 
few years as a result, at least in part, due to the change in the recommendations for prostate-specific 
antigen (PSA) screening by the U.S. Preventive Task Force2, the number of patients diagnosed with 
metastatic prostate cancer has increased over 2.7% per year after 2012.3  
Similar to breast cancer, prostate cancer is a hormonally driven disease and androgens are 
key in the growth of both normal prostate and prostate cancer cells. While androgen deprivation 
therapy (ADT) has become the cornerstone of medical treatment for metastatic disease after the 
studies from Charles Huggins and Clarence Hodges in 1941, ultimately all patients eventually 
progress in the setting of castrate levels of serum testosterone (< 50 ng/dL) and thus develop 
metastatic castration-resistant prostate cancer (mCRPC).4,5 Once mCRPC is evident, most patients 
receive a second-generation hormonal therapy to further suppress the synthesis of androgens 
(abiraterone) and to block androgen receptor (AR) activation, nuclear translocation and DNA 
binding (enzalutamide).6,7 Abiraterone acetate (abiraterone) and enzalutamide were approved in this 
setting based on the results of two large phase III trial in patients with mCRPC who had not 
received previous chemotherapy.8,9 Our internal data and other published data show that most 
responses are detectable by 12 weeks, and this is in line with published data on PSA changes at 12 
weeks and overall survival, hence we emphasize this early time point as a way to assess these 
patients relatively early in their treatment course.8,10 
In addition to novel hormonal therapies, life-prolonging therapies also include 
chemotherapy with docetaxel 11,12 and cabazitaxel13, the alpha-emitter radium-22314 and the 
autologous active cellular immunotherapy sipuleucel-T15 based on the pivotal phase 3 trials that 
demonstrated an overall survival advantage in CRPC setting. More recently, the poly ADP-ribose 
polymerase (PARP) inhibitor olaparib has also demonstrated a survival advantage over the 
physician’s choice of enzalutamide or abiraterone among men with mCRPC who had qualifying 

 
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alterations in homologous recombination repair genes and whose disease has progressed during 
previous treatment with a next generation hormonal agent.16 
The management of patients with metastatic prostate cancer continues to rapidly change 
with more and more patients being offered treatment intensification with the addition of 
chemotherapy or novel hormonal therapy to castration in the castration-sensitive setting.17 
Consequently, and since the findings of the phase III CARD trial have shown cabazitaxel to be 
superior to next generation hormonal agent for mCRPC patients previously treated with docetaxel 
and next generation hormonal agent, the sequence of two novel hormonal therapies is being used 
less frequently.18 
While data with functional imaging in the metastatic setting is lacking, conventional imaging 
of prostate cancer has known limitations in staging, restaging after biochemical relapse, and response 
assessment. Functional imaging with positron emission tomography (PET) can target various aspects 
of tumor biology and is clearly superior in the detection of extra-prostatic disease. A number of PET 
tracers are available and/or in development, including FDG, 18F-NaF, 11C-choline, 18F-choline, 68Ga-
PSMA, 18F-PSMA, and 18F-fluciclovine (Axumin).  
                   18F-fluciclovine is a synthetic amino acid transported across mammalian cell membranes by 
amino acid transporters that are upregulated in prostate cancer cells.19,20 18F-fluciclovine was 
approved by the US FDA for PET imaging to identify sites of prostate cancer recurrence in men with  
elevated prostate specific antigen (PSA) following prior definitive treatment.21 This approval was 
based on two prospective studies comparing 18F-fluciclovine with histopathology results22,23 and with 
11C-choline PET in patients with biochemical recurrent prostate cancer.24 These compared the 
efficacy and safety of 18F-fluciclovine with 11C-choline PET and biopsy results, revealing a very good 
performance in terms of lesion detection rate for low, intermediate and high PSA levels, with higher 
sensitivity than 11C-choline PET.  
 Based on the observations above and the lack of data in the advanced setting especially in 
the CRPC setting for disease monitoring, we propose to conduct a pilot phase II study describing the 
changes in 18F-fluciclovine PET scan in mCRPC patients treated with life-prolonging therapies and 
compare these results with PSA, conventional CT and bone scans. Initially, this study was designed 
to include mCRPC patients treated with abiraterone-prednisone, yet the changes in the management 
of metastatic disease support the changes in the eligibility criteria to include other life-prolonging 
therapy in the CRPC setting. This study will exclude treatment with radium-223 due to the very 
different mechanism of action of this agent and the heterogeneous response between skeletal 
metastases that may exist. 

 
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The results of this study can potentially leverage further data supporting the use of 18F-
fluciclovine for response assessment in the metastatic setting. Furthermore, we are extremely 
interested in understanding disease heterogeneity and how PET scans depict both early responses and 
possible heterogeneous progression.  
We hypothesize that using 18F-fluciclovine PET scanning will allow a more sensitive 
assessment of mCRPC patients at the initiation of systemic therapy and changes observed in 18F-
fluciclovine PET will correlate better with the serologic changes in PSA, allowing superior disease 
monitoring, as compared to conventional imaging modalities. In addition, we hypothesize that 18F-
fluciclovine PET will detect heterogeneity in disease response and thus identify potential lesions 
amenable to targeted therapy. We hypothesize that the PET scan will detect more disease than 
conventional scanning and thus provide more sensitive, and earlier information about tumor 
response to life prolonging-therapies than conventional scanning. Exploratory objectives are to 
understand disease heterogeneity and possible heterogeneous progression and change in patient 
management as well as to compare the 18F-fluciclovine PET findings with genomic alterations 
found in ctDNA especially in the AR gene, using an NGS assay of patients with mCRPC treated 
with life prolonging-therapies.  
 
STUDY DESIGN: This is a pilot phase 2 single-arm study of men with mCRPC. Patients will have 
a baseline 18F-fluciclovine PET scan, then treated with a life-prolonging therapy (ie, abiraterone 
acetate, enzalutamide, docetaxel) for mCRPC. After 12 weeks they will have a second 18F-
fluciclovine PET scan and then move to the follow-up phase of the study for 2 years.  
 
TREATMENT PLAN:  
We will include adult patients with mCRPC, with a detectable baseline PSA of at least 2 
ng/mL. Evidence of metastatic disease is required but measurable disease (RECIST version 1.1) is 
not a prerequisite on conventional staging scans (CT and bone scans) done within 42 days of 
starting a life-prolonging therapy. The use of docetaxel in the hormone-sensitive setting is allowed.  
After informed consent, patients will get a screening 18F-fluciclovine PET scan before 
starting a life-prolonging therapy for CRPC and only patients with a positive PET scan (study 
procedure) will be included in the study. Patients will repeat both 18F-fluciclovine PET scan and 
conventional CT and bone scans 12 weeks after starting abiraterone therapy or earlier if disease 
progression (by serologic or clinical criteria) is noted, per physician’s discretion. All 18F-

 
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fluciclovine PET/CT scans will be interpreted by a single trained reader and with the same camera 
at Tulane University.  
When feasible, a next generation sequencing (NGS) testing of ctDNA (Guardant360 assay) 
and a germline testing (Invitae assay) will be conducted at baseline; a repeated NGS testing of 
ctDNA will also be repeated at 12 weeks following initiation of the therapy of choice.   
Patients will be treated with any of the approved life-prolonging therapies: abiraterone 1000 
mg daily plus prednisone 5 mg (or dexamethasone 0.5 mg) daily, enzalutamide 160 mg daily, or 
docetaxel 50 mg/m2 every two weeks or 75 mg/m2 every three weeks. All patients will remain on 
luteinizing hormone-releasing hormone (LHRH) agonist therapy, except those who have been 
surgically castrated. At week 1 and 12, we will assess patients for PET-CT scan related toxicity, 
clinical evaluation and with standard laboratory measures including but not limited to complete 
blood count, complete metabolic panel, prostate specific antigen (PSA) and testosterone. The 
clinical evaluation will be at the discretion of the treating physician with clinical visits, imaging and 
laboratory tests based on routine clinical practice. Objective response for patients with measurable 
disease will be defined using RECIST version 1.1. PSA progression will be defined as a repeated 
increase in PSA of at least 2 ng/dL and 25% from nadir values, at least 1 week apart, according to 
PCWG3 criteria and clinical or radiographic progression by RECIST version 1.1.25 PSA response 
will be defined as a ≥50% decline from baseline. 
 
Patients may remain on their assigned therapy in the setting of PSA progression, if the treating 
physician believes the patient is still gaining clinical benefit. Patients with a treatment delay of 
longer than 4 weeks due to toxicity will be discontinued from treatment. The duration of therapy 
and dose adjustments is allowed at the discretion of the treating physician to ensure patient´s safety.  
 
OBJECTIVES: The primary objective of the study is to describe the 18F-fluciclovine PET findings 
for patients with mCRPC prior to starting treatment with first line life-prolonging therapy (i.e., 
abiraterone acetate, enzalutamide, docetaxel-based regimen), and at 12 weeks after therapy 
initiation.  
Secondary objectives include a comparison of 18F-fluciclovine PET with conventional CT 
and bone scans for patients with mCRPC prior to starting first-line mCRPC treatment, and at 12 
weeks later; and to correlate these changes with PSA response and progression. 
Exploratory objectives are to understand disease heterogeneity and possible heterogeneous 
progression and change in patient management as well as to compare the 18F-fluciclovine PET 

 
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findings with genomic alterations found in ctDNA especially in the AR gene, using an NGS assay 
of patients with mCRPC treated with life prolonging therapies.  
 
STUDY POPULATION: Adult patients (18 years or older) with mCRPC according to serologic, 
radiographic or clinical criteria, despite a castrate concentration of testosterone of ≤ 50 ng/dL.  
 
NUMBER OF PATIENTS: 12  
 
PATIENT SELECTION CRITERIA 
INCLUSION CRITERIA 
1. ECOG Performance status 0-2; 
2. Age  18 years; 
3. Histologically confirmed adenocarcinoma of the prostate; 
4. Ongoing use of LHRH required in the absence of surgical castration and castrate 
concentration of testosterone (≤50 ng/dL); 
5. Detectable PSA of at least 2 ng/dL; 
6. Metastatic disease documented by CT or bone scan within 42 days of cycle 1 day 1 
7. Life expectancy of ≥ 6 months; 
8. Must have disease progression despite a castrate concentration of testosterone of ≤ 50 ng/dL 
based on: 
A. PSA progression defined as increase in PSA of at least 2 ng/dL and 25% from nadir 
values of prior therapy, determined by 2 separate measurements taken at least 1 week 
apart; 
And/or 
B. Radiographic disease progression based on RECIST 1.1 for soft tissue disease and/or 
≥2 new bone lesions for bone-only disease; 
9. No prior life-prolonging therapies for mCRPC are allowed; 
10. The use of docetaxel in the mHSPC setting is allowed; 
11. Low dose prednisone (10 mg or less) or equivalent is allowed; 
12. Acceptable liver function (within 28 days from enrollment) defined as: 
A. Bilirubin < 2.5 times upper limit of normal (ULN), except for patients with known 
Gilbert disease (in such cases bilirubin < 5 times ULN) 
B. AST (SGOT) and ALT (SGPT) < 3 times ULN 

 
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13. Acceptable renal function (within 28 days from enrollment): 
A. Serum creatinine ≤ 2.0 x ULN or creatinine clearance ≥30 mL/min 
14. Acceptable hematologic status (within 28 days from enrollment): 
A. Absolute neutrophil count (ANC)  1000 cell/mm3 (1 x 109/L) 
B. Platelet count  100,000 platelet/mm3 (100 x 109/L) 
C. Hemoglobin  9 g/dL 
15. At least 2 weeks since prior radiation before starting life-prolonging therapy of choice;  
16. Able to understand and willing to sign a written informed consent document; 
17. Patients who have partners of childbearing potential must be willing to use a method of birth 
control with adequate barrier protection as determined to be acceptable by the principal 
investigator and sponsor during the study and for 1 week after last dose of abiraterone 
acetate; 
 
EXCLUSION CRITERIA 
1. Pathological findings consistent with small cell carcinoma of the prostate; 
2. Treatment with radium-223; 
3. Patients with normal 18F-fluciclovine PET/CT scans at baseline; 
4. Known allergies, hypersensitivity, or intolerance to 18F-fluciclovine or their excipients; 
5. Major surgery (e.g., required general anesthesia) within 2 weeks before screening;  
6. Uncontrolled active infection (including hepatitis B or C or AIDS). Patients with hepatitis 
B/C who have disease under control and no significant liver function impairment, and 
undetectable viral load will be allowed to participate; Similarly, patients with known HIV 
and ≥ 400 CD4+ T cells are allowed to participate; 
7. Evidence of other metastatic malignancies within the last year; 
8. Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition 
(including laboratory abnormalities) that could interfere with patient safety or provision of 
informed consent to participate in this study; 
 
STUDY ENDPOINTS: 
PRIMARY: 
18F-fluciclovine PET findings within 42 days prior to start of treatment with first line 
mCRPC life-prolonging therapy and at 12 weeks after therapy initiation; 

 
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SECONDARY: 
Comparison of 18F-fluciclovine PET with conventional CT and bone 
scans, as well as PSA changes, for patients with mCRPC prior to 
starting treatment for mCRPC, and at 12 weeks later; 
 
Comparison of PET scan (study procedure) findings to PSA response 
and progression;  
 EXPLORATORY: 
Understand disease heterogeneity and possible heterogeneous 
progression and change in patient management  
Compare the 18F-fluciclovine PET findings with genomic alterations 
found in ctDNA especially in the AR gene, using an NGS assay of 
patients with mCRPC treated with a life-prolonging therapy.  
 
STUDY SCHEMA: 
 
 
 
 

 
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Table of contents: 
1 
Background and Study Rationale 
13 
1.1 
Background 
13 
1.2 
Patient Selection Criteria 
15 
2 
Trial Design 
17 
3 
Objectives of the Trial 
17 
3.1 
Primary objective 
17 
3.2 
Secondary Objectives 
17 
3.3 
Exploratory Objectives 
18 
4 
Study Treatments, Procedures and Treatment Scheme 
18 
4.1 
Study Treatment 
18 
4.1.1 
Treatment Scheme 
19 
4.1.1.1 
Dose Adjustments 
19 
4.1.2 
Criteria for Removal of Patients from Study 
19 
4.1.3 
Concomitant therapy 
20 
5 
Study Activities 
21 
5.1 
Screening Period 
21 
5.1.1 
Initial Registration Process 
21 
5.1.2 
Screening Studies  
21 
5.2 
Treatment Period 
22 
5.3 
Week 12 Visit or at time of treatment discontinuation, whichever occurs earlier 
23 
5.4 
30-day Safety Follow-up 
24 
5.5 
Follow-up Visits 
25 
6 
Study Assessments 
25 
6.1 
PSA Response assessment 
25 
6.2 
Radiographic Response assessment 
25 
6.3 
Correlative Studies 
26 
6.3.1 
AR-genomic alterations studies 
26 
7 
Statistical considerations 
26 
8 
Standard of Care Therapies 
27 
8.1 
Abiraterone acetate 
27 
8.2 
Enzalutamide 
29 
8.3 
Docetaxel 
30 
9 
18F-Fluciclovine PET/CT Scan 
31 

 
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9.1 
Administration 
31 
9.2 
Pharmacology 
31 
9.3 
Safety 
33 
10 
Study calendar 
34 
11 
Data Monitoring and reporting requirements 
35 
11.1 
Case Report Form Submission 
35 
11.2 
Adverse Event Monitoring and Reporting 
35 
11.2.1 
Evaluating Adverse Events 
36 
11.2.2 
Documenting Adverse Events 
37 
11.2.3 
Expedited Reporting of Serious Adverse Events 
38 
11.3 
Protocol Amendments 
38 
11.4 
Informed Consent 
39 
12 
Ethical considerations 
39 
12.1 
Patient protection 
39 
12.2 
Subject identification 
39 
13 
Publication Policy 
40 
14 
References 
40 
15 
Appendix 
43 
15.1 
ECOG Performance Status / Karnofsky Performance Scale 
43 
 
 
 
 
 

 
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1 Background and Study Rationale 
1.1 
Background  
Metastatic Castrate Resistant Prostate Cancer 
 
Prostate cancer, though the most common cancer among men, has proven to be an 
extraordinarily diverse and challenging conundrum for clinicians, researchers and patients.1 African 
American men have about 60% greater incidence of being diagnosed with prostate cancer and 
nearly two-fold greater chance of dying from the disease than Caucasian men, yet the underlying 
cause for this increased mortality remains controversial.26,2728 
Since the work of Dr. Huggins and Dr. Hodges almost 80 years ago, androgen suppression 
has been the mainstay of treatment for advanced prostate cancer.29 Despite suppressed levels of 
testosterone, the disease invariably progresses to CRPC, usually with metastases.  
Persistent activation of the androgen-AR axis underlies resistance to ADT and progression 
to mCRPC.30 Once mCRPC is evident, most patients receive a second-generation hormonal therapy 
to further suppress the synthesis of androgens (abiraterone) and to block AR activation, nuclear 
translocation and DNA binding (enzalutamide), based on pivotal phase III trials showing that 
further inhibition of the AR pathway translates into further disease control and prolongation of 
overall survival.6,7 Clinically, most patients respond to abiraterone or enzalutamide initially, but  
subsequent tumor progression occurs in nearly all of them, typically after 9 to 16 months with either 
agent.6,7 
In addition to novel hormonal therapies, life-prolonging therapies include chemotherapy 
with docetaxel 11,12 and cabazitaxel13, the alpha-emitter radium-22314 and the autologous active 
cellular immunotherapy sipuleucel-T15 based on the pivotal phase 3 trials that demonstrated an 
overall survival advantage in CRPC setting. More recently, the poly (ADP-ribose) polymerase 
(PARP) inhibitor olaparib has also demonstrated a survival advantage over the physician’s choice 
of enzalutamide or abiraterone among men with mCRPC who had qualifying alterations in 
homologous recombination repair genes and whose disease has progressed during previous 
treatment with a next generation hormonal agent.16 
The management of patients with metastatic prostate cancer continues to rapidly change 
with more and more patients being offered treatment intensification with the addition of 
chemotherapy or novel hormonal therapy to castration in the castration-sensitive setting.17 
Consequently, and since the findings of the phase III CARD trial have shown cabazitaxel to be 
superior to next generation hormonal agent for mCRPC patients previously treated with docetaxel 

 
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and next generation hormonal agent, the sequence of two novel hormonal therapies is being used 
less frequently.18 
 
Novel Imaging Techniques 
For the first time in 1995, Hellman and Weichselbaum introduced the concept of oligo- 
(Greek “oligo”: few) metastatic state as an intermediate state in the malignancy spectrum between 
localized disease and prior to disseminated disease.31 The definition of oligometastatic prostate 
cancer is not consensual but usually includes patients with up to five extra-pelvic lesions on 
conventional imaging.32,33 
 
The rise in the diagnosis of oligometastatic prostate cancer is likely due to multiple factors, 
that may include closer monitoring of patients, improved survival secondary to emergent agents and 
most of all advances in imaging techniques.34  
Conventional imaging of prostate cancer has known limitations in staging, restaging after 
biochemical relapse, and response assessment. Functional imaging with PET scans (study 
procedure) can target various aspects of tumor biology and is clearly superior in the detection of 
extra-prostatic disease. A radionuclide produced from either a cyclotron or a generator is attached to 
a biologically active molecule to form a PET radiotracer. A number of PET tracers have been 
developed specifically for prostate cancer in the last few years and are now available or under 
investigation (18F-NaF, 11C-choline, 18F-choline, 68Ga-PSMA, 18F-PSMA and 18F-fluciclovine). 
PSMA agents labeled with 68Ga, 18F and 18F-fluciclovine are being increasingly used in this 
field. 18F-fluciclovine is a synthetic amino acid transported across mammalian cell membranes by 
amino acid transporters that are upregulated in prostate cancer cells.19,20 18F-Fluciclovine was recently 
approved by the US FDA for PET imaging to identify sites of prostate cancer recurrence in men with 
elevated prostate specific antigen (PSA) following prior definitive treatment.21 This approval was 
based on two prospective studies comparing 18F-fluciclovine (Axumin) with histopathology 
results22,23 and with 11C-choline PET in patients with biochemical recurrent prostate cancer.24 These 
studies compared the efficacy and safety of 18F-fluciclovine with 11C-choline PET/CT and biopsy 
results, revealing a very good performance in terms of lesion detection rate for low, intermediate and 
high PSA levels, with higher sensitivity than 11C-choline PET.  
While the benefit of 18F-fluciclovine PET is established, the role of this imaging to monitor 
response to mCRPC therapies is largely unknown. We hypothesize that using 18F-fluciclovine PET 
scanning will allow a more sensitive staging of mCRPC patients at time of starting systemic therapy 
and changes observed in 18F-fluciclovine PET will correlate better with the serologic changes in 
PSA, allowing better disease monitoring. In addition, we hypothesize that 18F-fluciclovine PET will 

 
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detect heterogeneity in disease response and thus identify potential lesions for SBRT. We 
hypothesize that the PET scan (study procedure) will detect more disease than conventional 
scanning and thus give more sensitive, and earlier, information about tumor response than 
conventional scanning. Lastly, we hypothesize that the functional changes observed in 18F-
fluciclovine PET scans will correlate with genomic alterations found in ctDNA, especially in the 
AR gene, using a commercially available NGS assay (Guardant) of mCRPC patients. 
 
1.2 
Patient Selection Criteria 
INCLUSION CRITERIA: 
1. ECOG Performance status 0-2; 
2. Age  18 years; 
3. Histologically confirmed adenocarcinoma of the prostate; 
4. Ongoing use of LHRH required in the absence of surgical castration and castrate 
concentration of testosterone (≤ 50 ng/dL); 
5. Detectable PSA of at least 2 ng/dL; 
6. Metastatic disease documented by CT or bone scan within 42 days of cycle 1 day 1 
7. Life expectancy of ≥ 6 months; 
8. Must have disease progression despite a castrate concentration of testosterone of ≤ 50 ng/dL 
based on: 
A. PSA progression defined as increase in PSA of at least 2 ng/dL and 25% from nadir 
values of prior therapy, determined by 2 separate measurements taken at least 1 week 
apart; 
And/or 
B. Radiographic disease progression based on RECIST 1.1 for soft tissue disease and/or 
≥2 new bone lesions for bone only disease; 
9. No prior life-prolonging therapies for mCRPC are allowed; 
10. The prior use of docetaxel in the mHSPC setting is allowed; 
11. Low dose prednisone (10 mg or less) or equivalent is allowed; 
12. Acceptable liver function (within 28 days from enrollment) defined as: 
A. Bilirubin < 2.5 times upper limit of normal (ULN), except for patients with known 
Gilbert disease (in such cases bilirubin < 5 times ULN) 
B. AST (SGOT) and ALT (SGPT) < 3 times ULN 

 
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13. Acceptable renal function (within 28 days from enrollment): 
A. Serum creatinine ≤ 2.0 x ULN or creatinine clearance ≥30 mL/min 
14. Acceptable hematologic status (within 28 days from enrollment): 
A. Absolute neutrophil count (ANC)  1000 cell/mm3 (1 x 109/L) 
B. Platelet count  100,000 platelet/mm3 (100 x 109/L) 
C. Hemoglobin  9 g/dL 
15. At least 2 weeks since prior radiation before starting life-prolonging therapy of choice;  
16. Able to understand and willing to sign a written informed consent document; 
17. Patients who have partners of childbearing potential must be willing to use a method of birth 
control with adequate barrier protection as determined to be acceptable by the principal 
investigator and sponsor during the study and for 1 week after last dose of abiraterone 
acetate. 
 
EXCLUSION CRITERIA 
1. Pathological findings consistent with small cell carcinoma of the prostate; 
2. Treatment with radium-223 for metastatic CRPC; 
3. Patients with normal 18F-fluciclovine PET/CT scans at baseline; 
4. Known allergies, hypersensitivity, or intolerance to abiraterone, prednisone, 18F-fluciclovine 
or their excipients; 
5. Any chronic medical condition requiring ≥ 10 mg daily of systemic prednisone (or 
equivalent) 
6. Major surgery (e.g., required general anesthesia) within 2 weeks before screening;  
7. Uncontrolled active infection (including hepatitis B or C or AIDS). Patients with hepatitis 
B/C who have disease under control and no significant liver function impairment, and 
undetectable viral load will be allowed to participate; Similarly, patients with known HIV 
and ≥ 400 CD4+ T cells are allowed to participate; 
8. Evidence of other metastatic malignancies within the last year; 
9. Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition 
(including laboratory abnormalities) that could interfere with patient safety or provision of 
informed consent to participate in this study. 
 

 
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2 Trial Design 
 
This is a pilot phase 2 single-arm study at Tulane University, New Orleans, of 12 men with 
mCRPC beginning treatment with standard of care life prolonging therapy (ie, abiraterone 1000 mg 
daily plus prednisone 5 mg or dexamethasone 0.5 mg daily, enzalutamide 160 mg daily, docetaxel 
50 mg/m2 every two weeks or 75 mg/m2 every three weeks). This study will: 1) describe the 18F-
fluciclovine PET findings for patients with mCRPC prior to starting treatment with first line 
mCRPC life prolonging therapy, and at 12 weeks after therapy initiation with an emphasis on 
understanding the heterogeneity of lesions. This study will begin after approval by the Institutional 
Review Board at Tulane University and all accrued patients will provide informed consent. All 18F-
fluciclovine PET/CT scans will be interpreted by a single trained reader and with the same camera 
at Tulane University. 
 
Study Design Schematic 
 
 
 
 
 
3 Objectives of the Trial 
3.1 
Primary objective  
• To describe the 18F-fluciclovine PET findings for patients with mCRPC prior to starting 
treatment with first line mCRPC  life-prolonging therapy and at 12 weeks later, with an 
emphasis on understanding the heterogeneity of lesions. 
 
3.2 
Secondary Objectives 
• To compare 18F-fluciclovine PET with conventional CT and bone scans, as well as PSA 
changes for patients with mCRPC prior to starting treatment for mCRPC, and at 12 weeks 
later; 

 
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• Comparison of PET results with PSA changes. 
 
3.3 
Exploratory Objectives 
• Understand disease heterogeneity and possible heterogeneous progression and change in 
patient management  
• To compare the 18F-fluciclovine PET findings with genomic alterations found in ctDNA 
especially in the AR gene, using a commercially available NGS assay (Guardant360) in 
patients with mCRPC treated with first-line therapy. 
 
4 Study Treatments, Procedures and Treatment 
Scheme  
 
4.1 
Study Treatment  
After eligibility and informed consent procedures, patients will get a baseline 18F-
fluciclovine PET scan as well as the required conventional CT and bone scans (standard of care). 
Patients will be treated with any of the approved life-prolonging therapies: abiraterone 1000 mg 
daily plus prednisone 5 mg (or dexamethasone 0.5 mg) daily, enzalutamide 160 mg daily, docetaxel 
50 mg/m2 every two weeks or 75 mg/m2 every three weeks. All patients will remain on luteinizing 
hormone-releasing hormone (LHRH) agonist therapy, except those who have been surgically 
castrated. We will assess patients on day one of each cycle for toxicity both clinically, and with 
standard laboratory measures including complete blood count, complete metabolic panel and 
prostate specific antigen (PSA). Patients will repeat both 18F-fluciclovine PET/CT scan and 
conventional CT and bone scans 12 weeks after starting a life prolonging therapy or earlier if 
disease progression (by serologic or clinical criteria) is noted, per physician’s discretion. Objective 
response for patients with measurable disease will be defined using RECIST version 1.1. PSA 
progression will be defined as a repeated increase in PSA of at least 2 ng/dL and 25% from nadir 
values, at least 1 week apart, according to PCWG3 criteria and clinical or radiographic progression 
by RECIST version 1.1.35 
 
Patients may remain on therapy in the setting of PSA progression, if the treating physician 
believes the patient is still gaining clinical benefit. Patients with a treatment delay of longer than 4 

 
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weeks due to toxicity will be discontinued from treatment. The duration of therapy and dose 
adjustments is allowed at the discretion of the treating physician.  
 
4.1.1 
Treatment Scheme 
Patients can remain on therapy indefinitely if clinically benefiting, at the discretion of the 
treating physician. Patients will have PSA level checked on day 1 of every cycle. Staging scans (CT 
and bone scans) as well as 18F-fluciclovine PET scan will be done at baseline and then 12 weeks 
after starting a life prolonging therapy. Patients will remain on treatment until evidence of clinical 
or radiographic progression as determined by the Principal Investigator (PI), RECIST version 1.135 
(for measurable disease) or PCWG3 criteria25 (if no measurable disease) respectively. PSA 
progression will be defined as repeated increase in PSA of at least 2 ng/dL and 25% from nadir 
values, according to PCWG3 criteria25. Patients may remain on therapy in the setting of PSA 
progression without clinical and/or radiographic progression, per treating physician´s choice. 
Patients with a treatment delay of longer than 4 weeks due to toxicity will discontinue treatment and 
proceed to the 30-day safety follow-up visit. 
4.1.1.1 
Dose Adjustments 
 
Therapy of choice will be started on day 1 of week 1 and will be taken as prescribed by the 
treating physician as standard of care. Patients will be evaluated for safety and tolerability of the 18F-
fluciclovine PET. Patients will be evaluated for safety and tolerability of their therapy per routine 
clinical practice.  
 
Dose modifications are allowed according to the approved guidelines for each therapy (see 
package inserts).   
Patients may temporarily suspend study treatment if they experience toxicity that is considered 
related to study drugs and requires a dose to be held. Dose may be held for up to 4 weeks.  
Dose interruptions for reason(s) other than toxicity, such as surgical procedures, patient 
travel, etc. may be allowed with Principal Investigator´s approval. The acceptable length of 
interruption will depend on agreement between the Investigator and the Principal Investigator. 
 
4.1.2 
Criteria for Removal of Patients from Study 
A patient may be removed from the study for a number of reasons, including: 

 
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1. Evidence of disease progression based on radiographic or clinical criteria (worsening 
symptoms) as defined by the protocol; 
2. Unacceptable adverse event(s), including: new or worsening pain deemed by the 
investigator to be due to prostate cancer progression; development of urinary outlet 
obstruction secondary to disease progression and requiring urinary catheterization; patients 
who develop seizures, pulmonary embolus or any other thromboembolic event will be 
removed from study; patients who develop treatment-related  grade 3 toxicities, including 
laboratory abnormalities; patients who develop hypersensitivity or anaphylactoid reactions 
to abiraterone or steroids; 
3. Incurrent illness that prevents further participation; 
4. Experiencing a treatment delay longer than 4 weeks due to toxicity; 
5. Patient refuses further treatment through the study or withdraws consent to participate; 
6. Patient is noncompliant with respect to taking drugs, keeping appointments, or having tests 
required for evaluation of drug safety and efficacy; 
7. In case a patient withdraws consent from the study, care will not be affected under any 
circumstance; 
8. Deterioration in ECOG performance status to  3 
9. If treating physician thinks that staying on study may cause increased harm to the patient or 
if another systemic treatment for prostate cancer is required. 
4.1.3 
Concomitant therapy 
The use of any concurrent medication from date of informed consent and while on study, 
whether prescription or over-the-counter, will be recorded on the patient's CRF along with the 
reason the medication was taken, on week one and week 12.  
Concurrent use of another investigational drug or device while on study is prohibited. Supportive 
care medications are allowed with their use following institutional guidelines. The following 
supportive care medications are considered permissible during the study:  
• Conventional vitamins, selenium and soy supplements  
• Additional systemic glucocorticoid administration such as “stress dose” glucocorticoid is 
permitted if clinically indicated for a life-threatening medical condition, and in such cases, 
the use of steroids will be documented as concomitant drug 
• Bone modifying agents (denosumab or bisphosphonates)  
• Transfusions and hematopoietic growth factors per institutional practice guidelines 

 
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• External beam radiation therapy (including radiosurgery) per the investigator’s discretion  
• LHRH agonist or antagonist  
 
5 Study Activities 
5.1 
Screening Period 
All patients must sign a written informed consent form before study specific screening 
procedures are performed. Screening procedures to evaluate patient eligibility will be performed 
within 28 days prior to Cycle 1 Week 1 (day of start life prolonging therapy), with the exception of 
radiological assessments (CT and bone scans) which can be performed within 42 days of Cycle 1 
Week 1. If the patient meets all eligibility and screening requirements, he will have blood drawn for 
an NGS testing of ctDNA (Guardant360 assay) and a germline testing (Invitae assay), whenever 
feasible (at baseline, Cycle 1 Week 1, or within 28 days after starting life prolonging therapy). Prior 
NGS testing results available through routine care and within the screening window will also be 
accepted. Patient will return to the site for the Cycle 1 Week 1 visit and start therapy. All subsequent 
visits, study procedures and assessments must be done within  7 days of the specified study visit 
date following the first dose of therapy.  
5.1.1 
Initial Registration Process  
Eligible patients will be registered on study at Tulane Cancer Center by the Research Team. 
The Research Team will review the documents to confirm eligibility, including eligibility checklist 
and related source documents, and assign a patient identifier (number). Patients found to be ineligible 
for participation after being consented will be considered screen failures and documented as such. 
Screen-failures will be replaced by other eligible patients to ensure that each cohort will consist of 12 
patients.  Each patient identifier is unique and will not be repeated in the case of screen failure.  
 
5.1.2 
Screening Studies (performed within 28 days before Cycle 1 
Day 1, except staging imaging) 
• Vitals including height (screening only), weight, body mass index, blood pressure, pulse, 
respiratory rate, and temperature 
• Comprehensive medical history 

 
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• Prior and concomitant medications (including up to 30 days prior to signing the ICF)Physical 
examination 
• ECOG performance status  
• Comprehensive metabolic panel (sodium, potassium, chloride, BUN, creatinine, glucose, 
calcium, total protein, total albumin, AST, ALT, alkaline phosphatase, LDH) 
• CBC with differential (white blood cell count, red blood cell count, platelets, hemoglobin, 
hematocrit) 
• Serum PSA 
• Total testosterone 
• Research blood including NGS ctDNA and germline assay, when feasible (at baseline or 
within 28 days after starting therapy)  
•  18F-fluciclovine PET scan 
• Staging imaging with CT of the chest, abdomen, and pelvis with contrast (unless 
contraindicated), bone scan, within 42 days before starting life-prolonging therapy. 
 
5.2 
Treatment Period 
All required treatment and post-treatment study procedures and assessments must be done 
within  7 days of the specified study visit date following initiation of life-prolonging therapy. 
During the initial 12 weeks following initiation of life-prolonging therapy, subjects will have a clinic 
visit on week 1 of study and at week 12 or at time of treatment discontinuation. During the study 
visits patients will undergo the following study assessments: 
• Physical examination 
• Update concomitant medications  
• Adverse event assessment related with 18F-fluciclovine PET/CT scan 
• Vital signs 
• ECOG performance status 

 
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• Comprehensive metabolic panel (sodium, potassium, chloride, BUN, creatinine, glucose, 
calcium, total protein, total albumin, AST, ALT, alkaline phosphatase, LDH) 
• CBC with differential (white blood cell count, red blood cell count, platelets, hemoglobin, 
hematocrit) 
• Serum PSA 
• Research blood including NGS ctDNA and germline assay, when feasible (at baseline, or 
within 28 days after starting life-prolonging therapy) 
 
In addition to study visits, patients will be regularly seen by the treating physician as 
standard of care visits that include clinical visits, laboratory tests and scans.  
 
 
5.3 
Week 12 Visit or at time of treatment discontinuation, 
whichever occurs earlier 
After 12 weeks of treatment with life prolonging therapy or at time of treatment 
discontinuation due to progressive disease (clinical or radiographic) or adverse events, whichever 
occurs earlier, the following assessments will be performed: 
• Physical examination 
• Update concomitant medications  
• Adverse event assessment related with 18F-fluciclovine PET/CT scan 
• Vital signs 
• ECOG performance status 
• Comprehensive metabolic panel (sodium, potassium, chloride, BUN, creatinine, glucose, 
calcium, total protein, total albumin, AST, ALT, alkaline phosphatase, LDH) 
• CBC with differential (white blood cell count, red blood cell count, platelets, hemoglobin, 
hematocrit) 
• Serum PSA 
• Total testosterone 

 
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• Patients must also have CT, bone scan, and 18F-fluciclovine PET/CT scan  
• Blood drawn for cfDNA NGS testing, when feasible 
 
Patients with serologic progression on life-prolonging therapy are allowed to continue on 
treatment and/or switch prednisone for dexamethasone or discontinue treatment, at the discretion of 
the treating physician to ensure that safety of the patient is prioritized. Patients with radiographic 
progression within 12 weeks after initiating therapy may also continue on study and will have 
confirmatory CT and bone scans at least 6 weeks later per PCWG3. Patients may remain on therapy 
if radiographic progression is confirmed if the treating physician thinks that patient still benefits from 
treatment.  
 
5.4 
30-day Safety Follow-up 
Subjects on study will come back to the clinic for a 30-day safety follow-up 30 days (+ 7 day 
window) following the time of the second PET/CT scan. The following assessments will be 
performed:  
• Vital signs 
• Adverse event assessment related with 18F-fluciclovine PET/CT scan 
• ECOG performance status 
• Comprehensive metabolic panel (sodium, potassium, chloride, BUN, creatinine, glucose, 
calcium, total protein, total albumin, AST, ALT, alkaline phosphatase, LDH) 
• CBC with differential (white blood cell count, red blood cell count, platelets, hemoglobin, 
hematocrit) 
• Serum PSA 
• Record life-prolonging therapy status and/or additional systemic anti-cancer therapies 
received 
 

 
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5.5 
Follow-up Visits  
Subjects will be followed for survival as well as treatment duration with life-prolonging 
therapy and information about the next subsequent systemic therapy following 
discontinuation of therapy on study. Follow-up visits will occur every 12 weeks (+/- 30 
days. Visits can be done in clinic (preferred) or via phone and will continue for a maximum 
of 2 years from the week 12 visit (or discontinuation visit prior to 12 weeks), until 
progression or discontinuation of therapy, whichever occurs earlier.   
Visit assessments will include: 
• Survival Status  
• Record life-prolonging therapy status and/or additional systemic anti-cancer therapy 
received 
• PSA  
• Radiographic imaging, only if performed as part of routine care (at the time of 
progression, discontinuation of therapy, or end of 2 years, whichever comes first) 
 
 
6 Study Assessments 
6.1 
PSA Response assessment 
PSA response will be defined according to PCWG3 with some modifications: 
• Patients with PSA progression will have a sequence of rising values of at least 2 
ng/dL and 25% above baseline, at least 1 week apart;  
• Patients with PSA decreases >50% below pretreatment baseline while on abiraterone 
will be considered a PSA responder; 
• Patients with an increasing PSA that then declines from peak levels but does not 
drop >50% below baseline will not be considered a PSA responder; 
• Patients with an increasing PSA that subsequently declines from peak levels to > 
50% below baseline will be considered a PSA responder; 
6.2 
Radiographic Response assessment 
 
Patients tumor response will be evaluated using CT, bone scans and 18F-fluciclovine PET at 
12 weeks following week 1 day 1. Progression for soft tissue lesions will be based on RECIST v. 1.1 

 
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(>20% increase in the sum of target lesions) and for bone lesions based on PCWG3 criteria ( 2 new 
metastatic bone lesions). At 12 weeks, if radiographic progression is noted, patients will have a 
confirmatory CT and bone scan performed at least six weeks later as standard of care. Regardless, 
subjects will still complete study and come back to clinic for 30 Day safety follow-up visit.  
 
6.3 
Correlative Studies 
6.3.1 
AR-genomic alterations studies  
As described in the background section, we aim to serially evaluate the genomic aberrations 
in AR that commonly occur with life-prolonging therapy and establish a strategy for assessing 
clonal evolution and correlate with radiographic and functional (PET) changes.  
To fulfil this objective, we will use a commercially available targeted ctDNA assay. cfDNA 
NGS will be performed by Guardant Health (Guardant360; Redwood City, California), a Clinical 
Laboratory Improvement Amendments (CLIA)-licensed, College of American Pathologists-
accredited, New York State Department of Health-approved clinical laboratory, using their standard 
collection protocol. This comprehensive genomic test performs complete exon sequencing of all 
critical exons (those with known hotspots) and reports all 4 major classes of GAs (single-nucleotide 
variants [SNVs] in 73 genes, indels in 23 genes, fusions in 6 genes, and copy number amplifications 
[CNAs] in 18 genes). As per Guardant360’s standard protocol, blood is collected in two 10-mL 
Streck tubes to obtain 5.0 ng to 30.0 ng of cfDNA from plasma and analyzed as described 
previously.36 
 
7 Statistical considerations 
This pilot study is designed to accrue 12 patients and gather preliminary data on the use of 
18F-fluciclovine PET scan findings to monitor response to FDA-approved life-prolonging therapies 
compared with conventional CT and bone scans. Therefore, no formal statistics are required, and 
this study is mainly descriptive.  
 

 
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8 Standard of Care Therapies  
8.1 
Abiraterone acetate  
Abiraterone is a CYP17 inhibitor indicated in combination with prednisone for the treatment of 
patients with mCRPC. The patients included in the study may be scheduled for standard treatment 
with commercially available abiraterone acetate according to institutional practice and the approved 
product information (see the most up to date version of the abiraterone prescribing information for 
detailed information on this agent www.zytigahcp.com).  
 
Supplier  
Commercial supplies of abiraterone will be used and charged to the patient and/or his insurance 
company.  
 
Summary of Adverse Events Associated with Abiraterone  
The most common adverse reactions (≥10%) reported in the two randomized clinical trials that 
occurred more commonly (>2%) in the abiraterone arm were fatigue, joint swelling or discomfort, 
edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and 
contusion. The most common laboratory abnormalities (>20%) reported in the two randomized 
clinical trials that occurred more commonly (≥2%) in the abiraterone arm were anemia, elevated 
alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, 
elevated AST, hypophosphatemia, elevated ALT and hypokalemia.  
 
The following warnings are associated with the use of abiraterone (from the April 2017 prescribing 
information):  
• Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Abiraterone 
may cause hypertension, hypokalemia, and fluid retention as a consequence of increased 
mineralocorticoid levels resulting from CYP17. In the two randomized clinical trials, grade 3 to 4 
hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 
4 edema in 1% of patients treated with abiraterone. Use caution when treating patients whose 
underlying medical conditions might be compromised by increases in blood pressure, hypokalemia 
or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular 
arrhythmia. Use abiraterone with caution in patients with a history of cardiovascular disease. The 

 
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safety of abiraterone in patients with LVEF < 50% or NYHA Class III to IV heart failure is not 
established.  
 
• Adrenocortical insufficiency: Adrenal insufficiency occurred in the two randomized clinical 
studies in 0.5% of patients taking abiraterone and in 0.2% of patients taking placebo. 
Adrenocortical insufficiency was reported in patients receiving abiraterone in combination with 
prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use 
caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients 
are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. 
Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated 
with mineralocorticoid excess seen in patients treated with abiraterone.  
 
• Hepatotoxicity: In post-marketing experience, there has been abiraterone-associated severe hepatic 
toxicity, including fulminant hepatitis, acute liver failure and deaths. In the two randomized clinical 
trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who 
received abiraterone, typically during the first 3 months after starting treatment. Patients whose 
baseline ALT or AST were elevated were more likely to experience liver test elevation than those 
beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 
1% of patients taking abiraterone. No deaths clearly related to abiraterone were reported due to 
hepatotoxicity events. The safety of abiraterone re-treatment of patients who develop AST or ALT 
greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. 
 
Prednisone and dexamethasone 
Prednisone and dexamethasone are synthetic adrenoglucocorticoids. They are commercially 
available as generics in tablet form for oral administration. They are indicated for a variety of 
medical conditions, including cancer.  
 
Summary of Adverse Events Associated with Prednisone/dexamethasone  
See reference for a more complete summary of AEs associated with glucocorticoids.37 The side 
effects from systemic glucocorticoids are usually dose and duration dependent and can impact 
virtually all body systems. Common side effects include thinning of the skin, purpura, Cushingoid 
appearance, weight gain, sleep disturbance and mood changes. Hyperglycemia is common if these 
agents are used in patients with pre-existing diabetes or those at risk of diabetes for other reasons. 

 
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Cataracts are also common with prolonged (>1 year) of glucocorticoids. Other risks of concern with 
glucocorticoids include an increased risk of cardiovascular disease and hypertension (particularly 
when glucocorticoids are prescribed in patients with pre-existing cardiac or renal disease), increased 
risk of peptic ulcer disease and gastritis (especially when patients are also taking nonsteroidal anti-
inflammatory agents), osteoporosis, increased fracture risk, osteonecrosis, myopathy, edema, and 
immunosuppression with an increased risk of infection. With the exception of cataracts and some of 
the cardiac and bone toxicities, adverse effects from glucocorticoids are at least partially reversible 
upon discontinuation.38  
 
8.2 
Enzalutamide   
Enzalutamide is an AR inhibitor indicated for the treatment of patients with mCRPC.  
The patients included in the study may be scheduled for standard treatment with commercially 
available enzalutamide according to institutional practice and the approved product information (see 
the most up to date version of the enzalutamide prescribing information for detailed information on 
this agent (www.xtandi.com). 
 
Supplier  
Commercial supplies of enzalutamide will be used and charged to the patient and/or his insurance 
company.  
 
 
Summary of Adverse Events Associated with Enzalutamide  
The most common adverse reactions (≥10%) reported in the two randomized placebo-controlled 
clinical trials that occurred more commonly (>2% over placebo) in the enzalutamide arm were 
asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper 
respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weigh decreased, 
headache, hypertension, and dizziness/vertigo. The following warnings are associated with the use 
of enzalutamide (from the October 2016 prescribing information):  
• Seizure: Seizure occurred in 0.5% of patients receiving enzalutamide in clinical studies. Seizure 
occurred from 31 to 603 days after initiation of enzalutamide. Patients experiencing seizure were 
permanently discontinued from therapy and all seizure events resolved. There is no clinical trial 
experience re-administering enzalutamide to patients who experienced seizure. Limited safety data 

 
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are available in patients with predisposing factors for seizure because these patients were generally 
excluded from the trials. Because of the risk of seizure associated with enzalutamide use, patients 
should be advised of the risk of engaging in any activity where sudden loss of consciousness could 
cause serious harm to themselves or others. 
• Posterior Reversible Encephalopathy Syndrome (PRES): There have been reports of PRES in 
patients receiving enzalutamide. PRES is a neurological disorder which can present with rapidly 
evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual 
and neurological disturbances, with or without associated hypertension. A diagnosis of PRES 
requires confirmation by brain imaging, preferably MRI. 
 
8.3 
Docetaxel 
Docetaxel is an anti-neoplastic chemotherapeutic agent which acts by disrupting the microtubular 
network that is essential for mitotic and interphase cellular functions.  
The patients included in the study may be scheduled for standard treatment with commercially 
available docetaxel according to institutional practice and the approved product information 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/201525s002lbl.pdf) 
 
Solution preparation  
Docetaxel comes at a 10 mg/mL solution that must be diluted prior to administration in at least 250 
mL of normal saline or D5W  
 
Route of administration:  
• _Administer intravenous infusion over 1 hour through non-sorbing polyethylene lined (non-
DEHP) tubing  
• _Some formulations contain alcohol; use caution in patients who should avoid/minimize alcohol 
intake  
• _Irritant with vesicant-like properties; assure proper needle or catheter position prior to 
administration to avoid extravasation  
− _If extravasation occurs, stop infusion immediately and disconnect, gently aspirate extravasated 
solution, remove needle/cannula, and elevate extremity  
 
Agent ordering/Availability: May use commercial supply 

 
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Adverse Events  
Common Adverse Events: edema, hair loss, rash, pruritus, vomiting, nausea, diarrhea, constipation, 
infection, fever, myelosuppression, fatigue, peripheral neuropathy, pain. 
Hypersensitivity reactions include anaphylactic-like reactions. Tachycardia, bronchoconstriction, 
hypotension, facial edema and erythema may occur and should be treated with antihistamine, 
corticosteroids, and epinephrine as per institutional hypersensitivity management protocol. These 
reactions typically occur in patients with prior exposure to the drug. If appropriate based on the 
discretion of the treating Physician to continue with treatment then desensitization required for 
future doses, pretreat with the same medications for at least 24-hour and at time of infusion.  
Please refer to the package insert for additional AEs. 
 
 
9 
18F-Fluciclovine PET/CT Scan  
9.1 
Administration 
The recommended dose is 370 MBq (10 mCi) administered as an intravenous bolus 
injection. The (radiation absorbed) effective dose resulting from this dose of 18F-fluciclovine is 8 
mSv. The clinical trial database for 18F-fluciclovine includes data from 877 subjects including 797 
males diagnosed with prostate cancer. Most patients received a single administration of 18F-
fluciclovine, a small number of subjects (n = 50) received up to five administrations of the drug. 
The mean administered activity was 370 MBq (range, 163 to 485 MBq).  
 
9.2 
Pharmacology 
Three studies have evaluated biodistribution and radiation dosimetry in healthy volunteers39-
41. In general, the results of these studies are consistent. The primary evidence on the biodistribution 
and radiation dosimetry from the phase I study conducted by GE Healthcare41,42 is reviewed in more 
detail below. This trial (GE-148-001) in 6 healthy volunteers and 6 subjects with biopsy-proven 
prostate cancer started in June 2009 and the clinical phase was completed in November 2009. The 
first part of the trial investigated the safety, biodistribution, and internal radiation dosimetry of 18F-

 
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fluciclovine injection in 6 healthy volunteers (3 males and 3 females). Overall, there was no 
evidence indicating that 18F-fluciclovine is metabolized in vivo.  
Qualitative assessment of the distribution of 18F-fluciclovine activity in all 6 subjects 
showed that the distribution was largely uniform throughout the body with the exception of the 
liver, pancreas, lung, red bone marrow, and heart wall. The initial uptake of 18F-fluciclovine in each 
subject was assessed at the first imaging time point, on average 7.9 mins (6.5 to 10.2 mins) post 
injection. Initial uptake of 18F-fluciclovine activity in the liver, pancreas, and the red bone marrow 
of the thoracic and lumbar vertebrae and skull was immediately evident in all subjects. There was 
very little brain uptake, 1.6% (0.7% to 2.2%). With increasing time post injection, distributed 
uptake was apparent and, on the basis of the anatomical distribution, was mostly associated with 
skeletal muscle. This uptake could not be isolated for quantification as it was not possible to 
segment the muscle in the whole-body image. Hence, muscle was included in the “remaining 
tissues” category. Uptake in the spleen was apparent in some subjects. Uptake in the uterus was 
apparent in some female subjects and initial activity uptake in the uterus was limited, 1.2% (0.3% 
to1.7%). It was assumed, based on the general skeletal muscle uptake, to be associated with the 
muscle of the uterine wall. The four organs with the highest initial uptake of 18F-fluciclovine were 
the liver at 13.8% (8.3% to 17.1%), red bone marrow at 11.1% (4.8% to 20.4%), lung at 7.1% 
(5.2% to 8.6%), and pancreas at 4.2% (3.4% to 5.2%). Based on comparison with washout of 
activity from the whole-blood samples, washout of activity from the lung was consistent with 
washout of activity from the pulmonary blood content. Excretion of 18F-fluciclovine activity was 
limited and was only found for the renal pathway, reaching 3.2% (1.1% to 7.4%) at the last imaging 
time point an average of 4.2 hours post injection (3.8 to 4.7 hours). The small amount of activity 
entering the gastrointestinal (GI) tract could not be clearly identified due to the surrounding activity 
in muscle and mesentery. On the basis of activity washout from the liver and the pancreas, and 
assuming that all of this activity was to enter the duodenum through hepatobiliary and pancreatic 
transport, the activity excreted via the GI tract was estimated to be of the order of 10 % or less.  
Although this could not be accurately quantified, any activity present in the contents of the 
GI tract was grouped within the “remaining tissues” category for evaluation of internal radiation 
dosimetry. No differences considered to be of likely clinical significance were noted between the 3 
males and the 3 females. 
 

 
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9.3 
Safety 
According to clinical review of 18F-fluciclovine by the US FDA (Reference ID: 3897370) that 
supported the approval of 18F-fluciclovine for patient with recurrent prostate cancer, no deaths were 
reported in any of the studies evaluated in this review. Two serious adverse events were reported for 
the BED001 study; one subject was from the Norway site and one was from the Bologna site. Table 
1 summarizes the treatment emergent adverse events and adverse reactions in healthy volunteers 
(N=12). Moreover, adverse reactions were reported in ≤1% of subjects during clinical studies with 
18F-fluciclovine. The most common adverse reactions were injection site pain, injection site 
erythema and dysgeusia. 
 
 
 
 
 
 
 
 
 
 
Table 1 - Treatment Emergent Adverse Events and Adverse Reactions of healthy volunteers 
(n=12) (adapted from CDER Clinical Review version date: June 25, 2015) 
 
 

 
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10 Study calendar  
 
 
Screening1 
Week 1 Day 1 
visit 
Week 12 visit or 
at time of 
treatment 
discontinuation 
30-day 
Safety 
Follow-up 
Follow-up4 
Informed consent 
X 
 
 
 
 
History and physical exam  
X 
X 
X 
 
 
Eligibility review  
X 
X 
 
 
 
Adverse event assessment9 
X 
X 
X 
X 
 
Concomitant medications 
 
X 
X 
 
 
Vital Signs7 
X 
X 
X 
X 
 
ECOG performance status 
X 
X 
X 
X 
 
CBC w/ differential2 
X 
X 
X 
X 
 
CMP2 
X 
X 
X 
X 
 
Serum PSA 
X 
X 
X 
X 
X 
Total testosterone 
X 
 
X 
 
 
Bone Scan3 
X 
 
X5 
 
X6 
CT of C/A/P w/ contrast3 
X 
 
X5 
 
X6 
18F-Fluciclovine PET/CT 
X 
 
X5 
 
 
ctNGS blood collection8 
X 
X 
 
 
Survival status 
X 
X 
X 
X 
X 
Cancer therapy assessment  
 
 
 
X 
X 
 
1 Within 28 days prior to Week 1 Day 1 
2 CBC to include white blood cell count, red blood cell count, platelets, hemoglobin, hematocrit, and differential. 
Chemistry to include sodium, potassium, chloride, BUN, creatinine, glucose, calcium, total protein, total albumin, AST, 
ALT, alkaline phosphatase, and LDH. 
3Within 42 days prior to Week 1 Day 1, within 7 days of all other cycles at which they are required. IV contrast may be 
omitted if contraindicated.  
4Follow-up visits should take place as standard of care, usually every 12 weeks +/- 30 days and should be measured 
from the date of the Week 12 or time of treatment discontinuation visit, whichever occurred earlier. Subject follow-up 
will occur until disease progression, discontinuation of study therapy, initiation of subsequent systemic anti-cancer 
therapy, or a maximum of 2 years, whichever comes first.)  
5Week 12 assessments (CT, bone, and 18F-fluciclovine PET/CT scans) should be performed irrespective of treatment 
delays. 
6Standard of care CT scan and bone scan should be completed at the time of progression (serologic, radiographic or 
clinical), at the time of discontinuation of life-prolonging therapy or at the end of 2 years, whichever comes first. 
Imaging is optional at these timepoints, and will only be collected if completed as part of standard of care 
7 Vitals to include height (screening only), weight, body mass index, blood pressure, pulse, respiratory rate, and 
temperature 
8Collected only as feasible. Baseline assessment may occur at Screening, week 1 Day 1, or within 28 days after starting 
life-prolonging therapy. 
9Adverse events occurring within 2 days from imaging test and related with 18F-fluciclovine PET/CT scans will be 
collected 
 
 
 

 
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11 Data Monitoring and reporting requirements  
Data Monitoring of this protocol will occur at every six months. The protocol will be 
monitored internally at Tulane University by the Principal Investigator and Research Team 
accordant with Institutional guidelines. Trial monitoring and reporting will be done through the 
Principal Investigator and Research Team. 
Additionally, scheduled meetings will take place every three months and will include the 
principal investigator, co-investigators, research coordinators and when appropriate, the 
collaborators and sub-investigators involved with the conduct of the protocol. During these 
meetings the investigators will discuss the safety of protocol participants, validity and integrity of 
the data, enrollment rate relative to expectation, characteristics of participants, retention of 
participants, adherence to protocol (potential or real protocol violations), data completeness, and 
progress of data for secondary objectives. Criteria for stopping or ending the clinical trial will 
include determination of unexpected, significant, or unacceptable risk to patients; or insufficient 
compliance to protocol requirements. 
Monitoring plan has been established in a separate document, which will be filed in the 
electronic study file.  
 
11.1 Case Report Form Submission 
Electronic Case Report Forms (eCRFs) will be provided by Principal Investigator (PI) and 
should be handled in accordance with instructions from PI. The investigator is responsible for 
maintaining adequate and accurate eCRFs which have been designed to record all observations and 
other data pertinent to the clinical investigation. Each eCRF should be filled out completely by the 
investigator or delegate as stated in the Site Delegation List. All data captured for the study is 
planned to be electronic.  
11.2 Adverse Event Monitoring and Reporting 
 
An Adverse Event (AE) is defined as any untoward medical occurrence or experience in a 
patient or clinical investigation subject which occurs following the administration of the trial 
medication regardless of the dose or causal relationship. As patients will be treated with standard of 
care while the intervention is the 18F-fluciclovine PET/CT at two time points, AEs occurring until 
two days after the imaging test and related with 18F-fluciclovine PET/CT will be reported. This can 
include any unfavorable and unintended signs (such as rash or enlarged liver), or symptoms (such as 

 
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nausea or chest pain), an abnormal laboratory finding (including blood tests, x-rays or scans) or a 
disease temporarily associated with the use of the protocol treatment. Laboratory abnormalities will 
only be reported as AEs when deemed clinically significant by the site’s investigator. 
 
An Adverse Drug Reaction (ADR) is defined as any response to a medical product, that is 
noxious and/or unexpected, related to any dose. Response to a medicinal product (used in the above 
definition) means that a causal relationship between the medicinal product and the adverse event is 
at least a reasonable possibility, i.e. the relationship cannot be ruled out. 
 
An Unexpected Adverse Drug Reaction is any adverse reaction for which the nature or 
severity is not consistent with the applicable product information (e.g., Investigators’ Brochure).  
 
A Serious Adverse Event (SAE) is defined as any undesirable experience occurring to a 
patient, whether or not considered related to the protocol treatment. A Serious Adverse Event (SAE) 
which is considered related to the protocol treatment is defined as a Serious Adverse Drug Reaction 
(SADR). 
 
Adverse events and adverse drug reactions which are considered as serious are those which 
result in: death; a life-threatening event (i.e. the patient was at immediate risk of death at the time 
the reaction was observed); hospitalization or prolongation of hospitalization; persistent or 
significant disability/incapacity; a congenital anomaly/birth defect; any other medically important 
condition (i.e. important adverse reactions that are not immediately life threatening or do not result 
in death or hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the other outcomes listed above). 
11.2.1 
Evaluating Adverse Events 
Adverse events will be reported in the context of 18F-fluciclovine PET scan that is being 
used off label. The event term, grade and severity of the event will be determined using the 
DCT/NCI Common Terminology Criteria, CTCAE version 5.0. All appropriate treatment areas 
should have access to a copy of the CTCAE version 5.0. Study staff must use one of the CTCAE 
criteria to define the event. Adverse events not included in the CTCAE v.5.0 should be reported and 
graded under the “Other” adverse event within the appropriate category and grade 1 to 5 according 
to the general grade definitions, mild, moderate, severe, life-threatening, fatal or disabling, as 
provided in the CTCAE.  
The event will be determined to be expected or unexpected. The determination of whether an AE is 
expected is based on agent-specific adverse event information provided in Section 8 Pharmaceutical 

 
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Information. Unexpected AEs are those not listed in the agent-specific adverse event information 
provided in Section 9 Pharmaceutical Information.  
The event will be evaluated for relationship to the medical treatment or procedure. The  
Investigator should document his/her opinion of the relationship of the event to the imaging agent 
(18F-fluciclovine) as follows:  
• Unrelated- The adverse event is clearly not related to the investigational agent(s).  
• Possible-The adverse event may be related to the investigational agent(s).  
• Probable-The adverse event is most likely related to the investigational agent(s).  
• Definite- The adverse event is clearly related to the investigational agent(s).  
 
 
Based on this information, a decision will be made whether an adverse event should be 
reported as an expedited report in addition to the routinely reported clinical data. All expedited 
adverse event reports should be submitted to the Institutional Review Board (IRB) and to the FDA. 
11.2.2 
Documenting Adverse Events 
The investigator is responsible for ensuring that all adverse events (as defined in Section 10.2 
and as further specified below) observed by the investigator or reported by subjects are collected and 
recorded in the subjects’ medical records and in the CRF. These adverse events will include the 
following:  
• 
All serious and non-serious adverse events (as defined in Section 10.2) that occur after the 
subject has signed the informed consent form and for 2 days after each 18F-fluciclovine 
PET/CT scan will be documented.   
The following serious adverse event attributes must be assigned by the investigator: adverse 
event diagnosis or syndrome(s) (if known, signs or symptoms if not known); event description (with 
detail appropriate to the event); dates of onset and resolution; severity; assessment of relatedness to 
18F-fluciclovine PET scan; and action taken. The investigator may be asked to provide follow-up 
information, discharge summaries, and extracts from medical records.  
For all adverse events, sufficient information should be obtained by the investigator to 
determine the causality of the adverse event (e.g. 18F-fluciclovine PET scan or other cause). The 
relationship of the adverse event to the imaging study will be assessed as described at 10.2.1.    

 
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In addition, all SAEs should be reported to Blue Earth Diagnostics via any of the contact 
routes below. Email:  drugsafetyUS@blueearthdx.com 
Phone:  +1 855 Axumin1 (1-855-298-6461); option 1 
Fax:  +1 609 514 2522 
11.2.3 
Expedited Reporting of Serious Adverse Events 
Serious adverse events and protocol problems will be reported in compliance with Tulane 
University Human Research Protections Office Standard Operating Procedures (revised 6/25/20). A 
copy of this document is available at https://research.tulane.edu/hrpo/policies 
All study investigators will be notified by the Principal Investigator of all SAEs that are 
unexpected (i.e., not previously described in the characterization of 18F-fluciclovine PET scan in 
section 9 of this protocol), and definitely or possibly related to the 18F-fluciclovine PET scan.  
The Sponsor-Investigator is responsible for safety reporting and to identify and follow-up on 
Serious Adverse Events (SAEs) experienced by participants in the study and to forward the 
information to the local regulatory authorities and Blue Earth Diagnostics, as required by local 
regulations (for regulatory reporting) and as required by the ISS agreement (for reporting to Blue 
Earth Diagnostics).  
The following reportable events must be submitted to Blue Earth Diagnostics within 2 
business days or 3 calendar days (whichever comes first) using the applicable safety report form 
provided. The Principal Investigator will assume responsibility for submitting the reportable 
event(s) to Blue Earth Diagnostics as well as ensuring that any local reporting requirements are 
completed in parallel. 
Serious adverse events defined by at least one of the following: 
o Results in death; 
o Is life threatening; 
o Results in persistent or significant disability/incapacity; 
o Results in or prolongs an existing inpatient hospitalization;  
o Is a congenital anomaly/birth defect; 
o Is another medically important event  
 
11.3 Protocol Amendments 
Any changes to the protocol will be made in the form of an amendment and must be 
approved by the site IRB before implementation. 

 
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11.4 Informed Consent 
Written informed consent will be obtained by a study investigator or study research 
coordinator working on this study. An explanation of the nature of study, its purpose, procedures 
involved, expected duration, potential risks and benefits will be provided to each participant by the 
investigator or the research nurse. Each participant will be informed that participation in the study is 
voluntary and that he may withdraw from the study at any time, and that withdrawal of consent will 
not affect his subsequent medical treatment. Participants will be informed that de-identified images 
and medical data may be shared with our study collaborator (Blue Earth Diagnostics). Participants 
will be allowed time needed to make an informed decision. Participants will be encouraged to ask 
questions about the study and the consent form before signing the consent form. Consent forms will 
be filed with the Clinical Research Office and copies stored securely with the study coordinator. No 
patient will enter the study before his informed consent has been obtained.  
 
12 Ethical considerations 
12.1 Patient protection 
 
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations Title 
21), and with the ethical principles laid down in the Declaration of Helsinki. National Ethics 
Committee will approve the protocol. 
 
12.2 Subject identification 
Data collected during this study may be used for research purposes. All data collection 
during the study will abide by all relevant data protection laws. The patient’s name, however, will 
not be disclosed outside the hospital. They will be known by a unique patient number. Patients will 
be assigned a number by the study team, when their eligibility is confirmed.  Assigned number will 
go in sequence, every number is unique, and screen failed patients will get a number, which will not 
be re-used for the next patient.  

 
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The results of this study may be used by Investigators that have ensured an adequate level of 
protection for personal data. 
13 Publication Policy 
The primary investigator will be involved in all steps of the trial, including enrollment, 
safety meetings, data analysis and presentation of trial results. Dr. Pedro Barata will be first-author 
and present study results at major oncology national meetings, including the Annual Meeting of 
American Society Clinical Oncology (ASCO), ASCO Genitourinary Symposium, European Society 
of Clinical Oncology and American Association of Clinical Research. At least four abstracts at 
national meetings and two original publications in a peer-review indexed journal are expected, 
within 6 years from enrollment start date. 
Co-authors of all research abstracts and publications will involve co-investigators and 
members of the research team included in this protocol. Additional co-authors may be added 
according to their contribution to the completion of the study.  
14 References 
References 
 
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Kelly SP, Anderson WF, Rosenberg PS, Cook MB. Past, Current, and Future Incidence 
Rates and Burden of Metastatic Prostate Cancer in the United States. European urology focus 
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Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without 
previous chemotherapy. The New England journal of medicine 2013;368:138-48. 
7. 
Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in Metastatic Prostate Cancer 
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Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo 
plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate 
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9. 
Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer 
before chemotherapy. N Engl J Med 2014;371:424-33. 

 
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10. 
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Change in Patients with Metastatic Hormone Sensitive Prostate Cancer Treated with 
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Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus Prednisone or Mitoxantrone plus 
Prednisone for Advanced Prostate Cancer. New England Journal of Medicine 2004;351:1502-
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Petrylak DP, Tangen CM, Hussain MHA, et al. Docetaxel and Estramustine Compared 
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de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone 
for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a 
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Parker C, Nilsson S, Heinrich D, et al. Alpha Emitter Radium-223 and Survival in 
Metastatic Prostate Cancer. New England Journal of Medicine 2013;369:213-23. 
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16. 
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Barata PC, Sartor AO. Metastatic castration-sensitive prostate cancer: Abiraterone, 
docetaxel, or…. Cancer 2019;125:1777-88. 
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Tombal BF, Castellano D, Kramer G, et al. CARD: Overall survival (OS) analysis of 
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<sup>14</sup>C]cyclobutanecarboxylic acid in prostate cancer cells. Nuclear Medicine and 
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Okudaira H, Shikano N, Nishii R, et al. Putative Transport Mechanism and Intracellular 
Fate of Trans-1-Amino-3-18F-Fluorocyclobutanecarboxylic Acid in Human Prostate Cancer. 
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21. 
Nanni C, Schiavina R, Brunocilla E, et al. 18F-Fluciclovine PET/CT for the Detection of 
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91. 
22. 
Schuster DM, Nieh PT, Jani AB, et al. Anti-3-[(18)F]FACBC positron emission 
tomography-computerized tomography and (111)In-capromab pendetide single photon 
emission computerized tomography-computerized tomography for recurrent prostate 
carcinoma: results of a prospective clinical trial. The Journal of urology 2014;191:1446-53. 
23. 
Odewole OA, Tade FI, Nieh PT, et al. Recurrent prostate cancer detection with anti-3-
[(18)F]FACBC PET/CT: comparison with CT. Eur J Nucl Med Mol Imaging 2016;43:1773-83. 
24. 
Nanni C, Zanoni L, Pultrone C, et al. (18)F-FACBC (anti1-amino-3-(18)F-
fluorocyclobutane-1-carboxylic acid) versus (11)C-choline PET/CT in prostate cancer relapse: 
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Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-
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subtype using data from the Surveillance Epidemiology and End Results Program, 1992-2013. 
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Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2013, 
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28. 
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www.ourworldindata.org/cancer.) 
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Huggins C, Hodges CV. Studies on Prostatic Cancer. I. The Effect of Castration, of 
Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the 
Prostate. Cancer research 1941;1:293-7. 
30. 
Sridhar SS, Freedland SJ, Gleave ME, et al. Castration-resistant prostate cancer: from 
new pathophysiology to new treatment. European urology 2014;65:289-99. 
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journal of the American Society of Clinical Oncology 1995;13:8-10. 
32. 
Tosoian JJ, Gorin MA, Ross AE, Pienta KJ, Tran PT, Schaeffer EM. Oligometastatic 
prostate cancer: definitions, clinical outcomes, and treatment considerations. Nature reviews 
Urology 2017;14:15-25. 
33. 
Tran PT, Antonarakis ES. Altering the Natural History of Oligometastatic Prostate 
Cancer With Local Therapies: Reality Versus Illusion. Journal of oncology practice 2017;13:21-
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34. 
Ahmad AE, Leao R, Hamilton RJ. Radical Prostatectomy for Patients With 
Oligometastatic Prostate Cancer. Oncology (Williston Park, NY) 2017;31:794-802. 
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Schwartz LH, Litiere S, de Vries E, et al. RECIST 1.1-Update and clarification: From the 
RECIST committee. European journal of cancer (Oxford, England : 1990) 2016;62:132-7. 
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Lanman RB, Mortimer SA, Zill OA, et al. Analytical and Clinical Validation of a Digital 
Sequencing Panel for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor 
DNA. PloS one 2015;10:e0140712. 
37. 
Saag KG, Furst DE. Major side effects of systemic glucocorticoids. UptoDate 2012. 
38. 
Fizazi K, Chi KN, de Bono JS, et al. Low Incidence of Corticosteroid-associated Adverse 
Events on Long-term Exposure to Low-dose Prednisone Given with Abiraterone Acetate to 
Patients with Metastatic Castration-resistant Prostate Cancer. Eur Urol 2016;70:438-44. 
39. 
Nye JA, Schuster DM, Yu W, Camp VM, Goodman MM, Votaw JR. Biodistribution and 
radiation dosimetry of the synthetic nonmetabolized amino acid analogue anti-18F-FACBC in 
humans. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 
2007;48:1017-20. 
40. 
Asano Y, Inoue Y, Ikeda Y, et al. Phase I clinical study of NMK36: a new PET tracer with 
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McParland BJ, Wall A, Johansson S, Sorensen J. The clinical safety, biodistribution and 
internal radiation dosimetry of [(1)(8)F]fluciclovine in healthy adult volunteers. European 
journal of nuclear medicine and molecular imaging 2013;40:1256-64. 
42. 
Sorensen J, Owenius R, Lax M, Johansson S. Regional distribution and kinetics of 
[18F]fluciclovine (anti-[18F]FACBC), a tracer of amino acid transport, in subjects with 
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43. 
West H, Jin JO. Performance status in patients with cancer. JAMA oncology 2015;1:998-. 
 
 
 
 
 
 

 
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15 Appendix  
15.1 ECOG Performance Status / Karnofsky Performance 
Scale 
 
Performance Status Criteria43 
WHO Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to carry 
on all pre-disease performance without 
restriction. 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or 
symptoms of disease. 
1 
Symptoms, but ambulatory.  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) 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal activity 
or to do active work. 
2 
In bed <50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities.  Up and about 
more than 50% of waking hours. 
60 
 
Requires occasional assistance but is able to 
care for most of his/her needs. 
 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined in bed or chair 
more than 50% of waking hours. 
50 
Requires considerable assistance and frequent 
medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  
Death not imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair 
20 
Very sick, hospitalization indicated.  Death not 
imminent. 
10 
Moribund, fatal processes progressing rapidly. 
5 
Deceased. 
0 
Deceased.