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!  
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ion Date: 8/8/18
eviated Title: Docetaxel & PROSTVAC in mCSP
ombination of preclinical and clinical studies performed by our group here at the NCI provide a strong foundation for combinin
axel and PROSTVAC in metastatic castration sens cer.  (Tumor growth rates are based on tumor growth and regression kinetics and have been modeled using several relevant dise eductive therapies in other tumor types. Chemotherapy-based treatment temporarily altered or decreased the growth rate whil en off-study growth rate and a far better survival time than would have been predicted using this apparent disconnect.
The following the content nts were on the therapy, but once the therapy became less effective or was discontinued, the growth rate reverted to pretreatment nd death was predictable based on the mathematical equation and off-study growth kinetics. [ 17 ]  The vaccine trial involvin while patients were on-study, consistent with that the trial had a median disease progression by conventional measures at 3 ective data from several studies suggests that therapeutic cancer vaccines may slow the growth rate of tumors and this can ding using disease-specific metrics, such as M-spike in multiple myeloma, tumor size in renal cell cancer and PSA in prosta mportant implications.  Using a mathematical equation to calculate tumor growth, survival can be predicted in several canc nypothesis regarding this outcome with chemotherapy or hormonal therapy alone, give their ransient clinical impact ine PROSTVAC, evaluated the impact of the various treatments on tumor growth rates and survival which can be calculated y growth rates. Instead, these patients' survival times were more prolonged than would have been anticipated by their off-s l on these growth rates. [ 17 ] When the 4 NCI trials that used cytotoxic were evaluated, the results were consistent with oth
[ 10 ] However, unlike patients on chemotherapy, these patients' mortality could not be predicted by their post-treatment nters. [ 15 , 16 ] Using this equation, an analysis of 5 prostate cancer studies conducted at the NCI, including one using t ond the treatment period.  Other vaccine trials in prostate cancer have supported this hypothesis.  
nitiating Therapies with Vaccines Earlier May Enhance Clinical Outcomes rsion Date: 8/8/18
Previated Title: Docetaxel & PROSTVAC in mCSPO
addition, larger consisten without
there suction hase II fields of speed improved sorry a phase II trial of RECRT-base in median disease progression frees survial. (6, 1)
ng
` it is possible for therapeutic cancer vaccines to induce a dynamic and sustained immune response that indeed slows the growth rate mors, then it would appear rationale that initiating such an immune response earlier would have a greater impact than initiatin nt immune response later in the disease process nis is one aspect of the new CHAARTED data that is so appealing.  Six cycles of docetaxel with ADT improved survival by large
agnitudes (growth rate and having more impact o horter.  
² when see also can be in the immere sesson yi i is possible will be
alena a tool a position of a seson an effect to consider consider consider consider a relation formal of Antigen Spreading/Antigen Cascade as an Endpoin sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO
proves, it would seem that the breadth of immune response should be an important focus in the development of future immune nnt strategies have yet to be compared in prospective randomized trials and could inform future clinical trials with vaccines emains unclear whether vaccines combined with an immune stimulatory chemotherapy such as docetaxel enhances the immun ciated immunosuppressive effects of the tumor have been diminished may also be a sound treatment strategy. [ 25 ]  These two nse more than sequential use.  The use of vaccine after chemotherapy when the tumor has been cytoreduced and the volu her immunotherapies ell-specific response against PSA had favorable clinical outcomes. [ 10 ]  That same trial also suggested that changes in tioned and have the experience as the LTIB to conduct this rigorous immune testing from clinical samples of patients treated w latory T-cell function were also associated with improved clinical outcomes. [26]  While thethese findings are not surrogate hat factors are potentially important in mounting a sufficient anti-tumor immune response that could be associated with impr l outcomes.  These and other data have allowed us to optimize vaccines in subsequent clinical trials. Few groups are as we roup in the LTIB has previously evaluated immunologic parameters in clinical trials with PROSTVAC among several Evaluating Immune Response ROSTVAC
PSA-Specific Immune Response hile many clinical trials have been done in biochemically recurrent prostate cancer, there is little reported on the impact of tho dies will be done on all patients by the Laboratory of Tumor Immunology and Biology at the NCI Clinical Center under t pies on the immunologic response that is near the depth and scope that is proposed in this trial.  The proposed immuno rection of Dr. Jeffrey Schlom
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-  
sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO
perimental Imaging May Help improve our understanding of castration sensitive disease progressing to castration resistanc dy advancing the field fradiology. In collaboration will be evaluated with the disease and its ultimate progression to sistent with in vitro data that the wild-type SLCOIB3 is more functional at importing testosterone vs the mutant (G-allele) [ 28 ]
tional imaging in prostate cancer primarily consists of computed tomography (CT) scans and technetium-99m bone scans, rostate cancer dorectal contace or locally unreated prostate cance, the prostate (in the prostate (in the cause of prof
anced Drectal contate often with high reatly and more profoundly than eneer there centeen further consider in the bon seen feeting
mation there said uplake of the ration becan were centill im fill our immeed fort the feeting.  
rogressive disease.  Thus, sodium fluoride PET/CT is the most sensitive method to detect prostate cancer bone metastases.  One m fluoride images, which can then be monitored over time.  Increases in standardized uptake value (SUV) are associated sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO
eason, substantial changes in SUV are required before one can conclude that disease is progressing or regressing on NaF scan me bone metastases continue to show activity on sodium fluoride PET/CT due to the ongoing osteoblastic remodeling.  
primary goal of this clinical trial is to evaluate the optimal timing of immunotherapy with chemotherapy as this is largely Rationale for Arm C
inical/immunologic data on this from human sequence.  Certainly an activated immune response prior to cytotoxic therapy
inical/immunologic data on this from human studies.  T
cond). This was largely due to the fact that we did not anticipate having patients contact us who recently started ADT. In fact, initiate ADT and then subsequently start chemotherapy within 4 months, it provided an opportunity to initiate vaccine prior Given that Arm A and B have nearly completed accrual, we are unable to randomize patients among all 3 Arms.  Thus Arm C will l I to be taken into account with any analysis done.  Regardless, the nature of this study would require a future confirmatory stu patients who have started ADT within 1 month of enrollment.  The statistical design compensates for the lack of random nary endpoints are immunologic and will be assessed at the end of the study, they cannot be influenced by provider knowledg n A and B will provide valuable insight into optimal sequencing of immunotherapy with chemotherapy.  Furthermore, since t andomized arm.  It is possible that patient variations may exist between Arm A or B vs. Arm C, but that is something that  
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! "  
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sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO
noved from isolation after the vaccine is administered and bandage is secured over the injection site. Appendix C defin
lividuals at risk for vaccinia exposure.  
OSTVAC-F (fowlpox) will be administered subcutaneously at a dose of 1x10 9 infectious units starting in week 21. Administration
as a complete and the continue for 6 cycles.  
ROSTVAC-F (fowlpox) will be administered subcutaneously at a dose of 1x10 9 infectious units starting on day 1, week
dministration on day 1 of each cycle will continue for 6 OSTVAC-V (vaccinia) will be administered subcutaneously in week 19 at a dose of 2x10 8 infectious units.  
OSTVAC-V (vaccinia) will be administered subcutaneously in week -2 at a dose of 2x10 8 infectious units Arm B - concurrent docetaxel + PROSTVAC
Arm A - sequential docetaxel + PROSTVAC
Arm C - PROSTVAC prior to Docetaxe ROSTVAC-F (fowlpox) will be administered subcutaneously at a dose of 1x109 infectious units starting on week 3. Administration
the confirmed rise in PSA based on investigato OSTVAC-V (vaccinia) will be administered subcutaneously in week 1 at a dose of 2x10 8 infectious units.  
evious  studies.   The  investigator  may  use  clinical  discretion  to  forgo  dose  4  and  5  of  fowlpox-PROSTVAC  and  initiat motherapy.[ 10 ]
addition, for patients who may have a rise in PSA while on vaccine alone, vaccine can be discontinued early at the discretion of th
restigator and docetaxel can be initiated Dosing Delay atients must have recovered to ≤ grade 1 toxicity related to vaccine for the parameters used to assess levels of org
inction required for eligibility (see Section 2.1) after  
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sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO  
  
  
  
ocetaxel 75mg/m² will be administered intravenously as described in Appendix D every 21 days (i.e., a 3-week cycle) for up
ceive dexamethasone 12 mg intravenously prior to d o minimize patient exposure to phthalate plasticizers (e.g., DEHP), which may be leached from PVC containers and administration.
Its administer docetaxel only through polyet he event of a hypersensitivity reaction, infusion times may be longer.  Hypersensitivity reactions may be managed clinically.
Proding to PI discretion.  Please see Appendix Dose Reduction 2.3.1  
  
2.3.2  Docetaxel Dose Modifications ents should have an ANC ≥1500 cells/mm³, a platelet count ≥ 75,000 cells/mm³ (grade 1 hematologic toxicity) and resolution or febrile neutropenia developed within a prior cycle, docetaxel can be continued during future cycles at a dose reduction d and or baseline  
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-
sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO  
ombocytopenia should be treated conservatively. In the absence of bleeding or a planned invasive procedures platelet transfusion.
The first should be administered in accorda 0/mm3.  
y evidence of disseminated intravascular coagulation (DIC), hemolytic uremic syndrome (HUS), or thrombotic thrombocytopeni
luated and closely monitored and supported as clini rposes are acceptable while the subject is enrolled on study.  Pain medications administered as dictated by safet
ceptable while the patient is enrolled on the study.  
abject requires additional systemic anticancer treatment, study treatment must be discontinued.  Local intervention is discourage
nent at the investigator's discretion.  
phosphonates started prior to screening activities or initiated during the course of the study to control bone pain may be used wi owth factors may be used as medically indicated if patient develops fever and neutropenia.  Dose reduction or interruption
cetaxel is also recommended as described.  
bects must be instructed to inform the investigators of the current or planned use or all other medications during the study.
ponsibility of the investigator to ensure that d ONCURRENT MEDICATIONS/INTERVENTIONS
nficult investigational agents are permitted nticancer Therapy ther Medications Ieutropenia ution.  
\#$%&'$(&)$*+,'- .)', - .)'$.*)-*(/0.-'$.*)1234  
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!"  
-
rsion Date: 8/8/18
Previated Title: Docetaxel & PROSTVAC in mCSPO
he evaluation of CTCs may give valuable insight into how treatment affects changes in CTC
nenotype, such as AR splice variants, and how such changes are associated with clin
.2.2.3.2 Handling and Processing of Specimens for Epic Analysis Blood Processing Core will be paged at 102-11964 for tube pick up and shipping via FedEx Priority Overnight to Epic Sciences.  
Ryan Dittamore l Judicial Drive, S
Diego, CA  92121
-356-6610, ext. 12 Sciences munologic Parameters tibodies to PSA, vaccinia, fowlpox may be tested ukocyte CD3, CD4, CD8 subsets; CD4:CD8 ratio will be drawn at baseline and at each visit when on treatment and them
each follow-up visit while the patient remains on trial.  
ditional studies will include but are not limited to quantitative and qualitative assessments of regulatory T-cells, Natural essment of levels of cytokines.  
atment will be followed until they have resolved, or have been determined not to be treatment-related.  
pheral blood mononuclear cells (PBMC):
acellular cytokine staining assays for Brachyury-specific T lymphocytes using PSA, MUC-1 and Brachyury-spec
ides CD3, CD4, CD8, and CD
notypic and functional analysis of immune cell subsets by flow cytomer
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q-R6>.DC6,>820+,k60951A,>@87?01,sk5?tB@6/, .1A09,FB@2+9. ,8 19.8 >201,9@82+,-Rk1.90s.h-./MDC6,>t=2@6S,9/32+,k5?!*+@> .,A=1C07.DFB@2+.A,>20-Rk1.906@D@2,90 ,4@89I@7 6./C,1>08,6FB+0.1,@>=,9@8 G =.6>,1.A0=82>!E82.6 @084-Rk1.90@>6D@2,90ADC=2,1>C,A@49/3H1!I@7!*+,>A0DC=2,1>.6+G,C.>B019,>2@A,9607@8>A1,8!R6I@7 6./C,1>08,6B@2+.A,>20C.@,8401D.2@08. =63A0DC6,2+ iEj086@,5102,A@084j=D.8M=/u,A2>0=1>,!-Rk1.90A,.2>=8@v,/.1A09,EH401,G 3>.DC6,.89>DC6,/0lFB+@A.802/,1.A,9/.Ah20C.@,8>B@+0=-Rk1.90.A,>!*+,9.21,A09 401,.A+>DC6,@8A6=9,>2+ C.2@,8EHF8.D,F21@.68D,wC102A68=D/,1F2@D,91.B8FA36,2@D,C0@82F90>,FD.21@.623C,F.>B,6.>/0l.8941,S 60A.2@8!5.2@,89D071.C+@A>. 0A@.2,9B@2+ ,A6@8 .6,821C.2@,8=D/,1.  
!  
-  
sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO
ided in the system. For each sample, there are notes associated with the processing method (delay in sample processing, storag
itions on the ward, etc.).  
cess to stored clinical samples is restricted. Samples will be stored until requested by a researcher named on the samples are manned.
the BPC. It is the responsibility of th lowing completion of this study, samples will remain in storage as detailed above. Access to these samples will only be granted
lowing IRB approval of an additional protocol, an time, a patient withdraws from the study and does not wish for their existing samples to be utilized, the individual must
eported as such to the IRB. Any samples lost (in coded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C according to stability requirements.
ratory are required to be accompanied by laboratory ple barcodes are linked to patient demographics and limited clinical information. This information will only be provided
strmation such as race, age, dates of diagnosis and d Iandling and Storage for Research Samples Managed by Jane Trepel's Laboratory e a secimen containers will be specimen with to with identifiers de-lifers.
Mention will be applied to all subbecimen containers will be information with processing aticimen he inventory process contains other security provisions sufficient to safeguard patient privacy and confidentiality. Access to 46 propriate. All laboratory personnel are trained to appropriate personnel only. SOPs ensure that any changes in the informed
propriate. All laboratory personnel are trained t sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO
ata associated with patient samples are protected by a secure database. All samples drawn at the NIH Clinical Center will be
ported to the NCI Frederick Central Repository b Samples Sent to Clinical Services Program (CSP)
uples will be tracked and managed by the Central Repository database. All samples will be stored in liquid nitrogen. These freezers
located at NCI Frederick Central Reposito CC role is limited to clinical research databases and repositories containing patient specimens. ATCC does not conduct nor has a
olved in research on human subjects, but does erican Type Culture Conferica Repositories specimens are support to Leidos Biomedi
specimens are stored in secure, limited access facilities with sufficient security, back up is the intent and purpose of ATCC to accept only de-identified samples and sample information.  To the limit of our ability, every
fort will be made to ensure that protected es.
Their process that arceimes and interpret interpret interpret interpret interpret interpret section
ceess sectivitimes arceiment interpret interpret interpret sectivity i rsion Date: 8/8/18
breviated Title: Docetaxel & PROSTVAC in mCSPO
quest. Vials are labeled with a unique BSI ID which is printed in both eye readable and bar coded format.  No patient specific
formation is encoded in this ID.  
poetimens for which they have not been authority only for their specimens. They may not view specimen data or access
positories are escorted by repository staff at all times aples and associated will be excluded form dissimples be inall coooses to dissimples form issimples form in the cooses to destrood by a wildraw hisher
poses. Samples will ass ice primary research objectives for the protocol are achieved, intramural researchers can request access to remaining sample.
The ovided they have an IRB-approved protocol an Protocol Completion/Sample Destruction
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!"  
-  
ion Date: 8/8/18
reviated Title: Docetaxel & PROSTVAC in mCSPO
gnant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in short axis when
will be measured and followed.  
e
ine dianeers with better harreceive had her had her her her her her her her her her her her her her her her her her her her her her her her her
her her her her her her her ote:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions
either measurable nor non-measurable) sinc measurable disease.  All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological
al/pricardial effusions, lymphangitis culmoniti surability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection get lesions.  
lisease.  
target lesions.  All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should
noce, absence, or in rare cases unequivoc l measurements should be taken and recorded in metric notation using a ruler or calipers.  All baseline evaluations should be lethods for Evaluation of Measurable Disease ion Date: 8/8/18
reviated Title: Docetaxel & PROSTVAC in mCSPO
ical lesions:  Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lym
ography, including a ruler to estimate the s ame method of assessment and the same technique should be used to characterize each identified and reported lesion at baseli
uring folow-up. Imaging-based evaluation is prefe x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated
However, CT is preferable.  
ess is 5 mm or less.  If CT scans have slicethickness greater than 5 mm, the minimum size for a measurable lesion should
the slice thickness.  MRI is also acceptable in certa T-CT:  At presents an be used interchangeably with oran contract that the CT portion filte PET-C canner time. Note,  
of the same as seed even an ARI in the important on the same as sequines equition in be on-de simines equines.
of the same as dide involve and the exant in the e-mane a c formed rasound.  Ultrasound in the same to lesion size and should not be used as a method of measurement.  Ultrasound
aminations cannot be reproduced in their entime and measurement
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!  
-  
rsion Date: 8/8/18
Previated Title: Docetaxel & PROSTVAC in mCSPO  
| Iverall Respons                                                 |                                                                     |     |    |    |
|-----------------------------------------------------------------|---------------------------------------------------------------------|-----|----|----|
| cumented at least once
wks. from baseline**                                                                 | ee RECIST 1.1 manuscript for further details on what is evidence of | Patients with a global deterioration of health status requiring
deterioration at that time should be reported as "symptomatic
deterioration."  Every effort should be made to     |    |    |
| prior SD, PR or Cl                                              | sions may be accepted as disease progression in non-targe
sions may be accepted as disease progression.                                                                     |     |    |    |
| aly for non-randomized trials with response as primary endpoint | New Lesions                                                         |     |    |    |
| Patients with Non-Measurable Disease (i.e., Non-Target Disease) |                                                                     |     |    |    |
| SD                                                              | PD                                                                  | PD  | PD | 57 |
| Non-Target Lesions                                              |                                                                     |     |    |    |
| NO
IO S3                                                                 | es or
No                                                                     |     |    |    |
| No                                                              | Yes                                                                 |     |    |    |
| PD/not
evaluated                                                                 | evaluated                                                           |     |    |    |
| Non-
R/Non                                                                 | PD***                                                               |     |    |    |
| Any                                                             | Any                                                                 |     |    |    |
| Any                                                             |                                                                     |     |    |    |
| SD                                                              | PD                                                                  | Any | ** |    |
| *                                                               |                                                                     |     |    |    |  
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-  
sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO
PSA has risen above 4 ng/ml or an increase in PSA of more than 50% above nadir (lowest PSA on ADT) or confirme me to Serologic Progression will be defined as interval between initiation of ADT and date of PSA progression or death from an omplete Serological Response:  PSA level less than 0.2 ng/ml measured for 2 consecutive measurements at least 4 weeks app ogical Partial Response:  decline of PSA at least 50% measured for 2 consecutive measurements at least 4 weeks apa ues must be measured for 2 consecutive measurements at least 2 weeks apart he date of the first increase will be recorded as progression ise in PSA.  
erological Progression:
ause.  
OXICITY C RITERIA
et following adverse event management guidelines are intended to ensure the safety of each patient while on the state the state the state the state the centure adverse to a c ANTIGEN SPREAD SCORING
As described in section 1.2.5 of the background, antigen spread will be evaluated using CD4 and CD8 analysis of CD107a express
specifically by the vaccine (MC1 and Brachyry)
or PSA:
point each of the four CD4 parameters (CD107a, IFN- γ , IL-2 and TNF- α ) - max total of 4 point each of the four CD8 parameters (CD107a, IFN- γ , IL-2 and TNF- α ) - max total of
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!"  
-  
sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO
must be received within 7 days of PI awareness via iRR
l Unanticipated Problem n-compliance NIH-IRB Requirements for PI Reporting at Continuing Revi ne protocol PI will report to the NIH-IRB
ummary of all protocol deviations in a tabular format to include the date the deviation occurred, a brief description of the
iation and any corrective action.
bular summary o Grade 2 unexpected events that are possibly, probably or definitely related to the research;
Grade 5 events regardless of attribution;
Serious Events regardless of attributi
.3 OTE: Grade 1 events are not required to be reported IND Safety Reports that meet the definition of an unanticipated problem will need to be reported to the NIH IR
IH-IRB Reporting of IND Safety Reports IND SPONSOR REPORTING CRITERIA
ring the first 30 days after he subject receives investince an more that of whether the rithe rithe rithe rithe rithe rine dug rela
ressiblity that the end the event. Form th equired timing for reporting per the above guidelin
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-  
\#$%&'$( )%*+,$)&*-.'/0)11$' . 2$,034.5)4'$%604$'. *789:;<=>?@ABCDEFGHIJEKALMDNHOCP QAINHMRSDIEOMDTUJVWOTHEUXAYGFMQTHMIOCDTAZM@CHEDNAYGCDEFHLOFDHMAQSDM@ AXLOTB[\]?^_WHLOEHLGO D`IAXMDE OAKEMIHAC@HEaFHIAEQC ULOTDEMHICAFDGMOT@ADETOCbHMDOEc]ACDOXLHQKACLAKEML@H CAXEYGFMQHE LOFDHMAQSDM@ AXLOTM@AB[\]?^_Wd`XMHCAEOMTH IOCDTAZM@CHEDNdbXLM`ACGOMQO@AeJfVWHLOEHLGO D`IAdXMEOIHAC@HEg FHIAEQC ULTMAC@ DEKLMDNHOChLDEMHICAFDGMOT@ADETOCbHMDOEc_QKACLAKEMLbHU`ACGOMQ`UXLDENM@Aij_ OCbk lHc789m:
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!"  
-
rsion Date: 8/8/18
breviated Title: Docetaxel & PROSTVAC in mCSPO
Progress Report and Data Analysis any deaths have occurred, the number of participants who died during participation in the investigation and causes of de ummary of serious adverse events that were expected or considered to have causes not associated with the use of the g
nsfer product such as disease progression or concurrent orief description of any information obtained that is pertinent to an understanding of the gene transfer product's actio
bavailability.  
arrative or tabular summary showing the most frequent and most serious adverse experiences by body system rmation obtained during the previous year's clinical and non-clinical investigations, includin ummary of all serious adverse events submitted during the past year ATA AND SAFETY MONITORING PLAN
Principal Investigator/Research Teat ne clinical research team will meet on a regular basis weekly when patients are being actively treated on the trial to discuss e atients.  
l data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Adverse
Induct of the trial, or protocol deviations w The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The
ther members of the research staff.  
Sponsor Monitoring Plan as a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring program. The CCR's program allows for sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSP
ulations, and SOPs; and human subjects protection. This is done through independent verification of study data with sources.  
rmed consent prod s trial will be monitored by personnel employed by an NCI contractor. Monitors are qualified by training and experience
nitor the progress of clinical trials. Personnel monit ntoring program also extends to multi-site research when the CCR is the coordinating center bility confirmation
g administration and accountability rse events monitoring ponse assessmen Safety Monitoring Committee (SMC)
ent reviewed as loon as soon as possible annually, as looned as coon reviewed as coons will as soons to annually as soons to annually as the quarterie
Hivities and submitted
untitled h1
tatistical consideration rms a and

weeks formmmm  to 3 a adosribed in setting PROSTVAC  combined by sequaling posting
weeks forming forming the intential sion Date: 8/8/18
Previated Title: Docetaxel & PROSTVAC in mCSPO  
h d or the arent will be terrified for the disease at defined as: Will or the disease is defined as: Will between the will be
n done scers on the would be two-bine (extrant her secondary objectives will beconted include primary time the oppression on PET
dition, as a secondary evaluation, patients' response scores will be compared between the two arms at 39 weeks in the contaced by
onese sores after 9 weeks in the doctaxed th
untitled h1
arm c

Forecorea sim to the sing of a sing the content perin will be on the contine the ether all be the the to the the the the the the the the the the the the the timpecifie be th 68 sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO
omized arms, the results should at least offer a suggestion of whether there is a difference or not with respect to the score
might be shown to be associated with the magnitu domized comparison, the subset consisting of previously untreated patients on the superior randomized arm viously untreated patients on the number of previously untreated pa ACCRUAL
ments will be added in Amm C asweed in the fune. In order to allow for the possibile in A amm A and D ineedluable  
peeced to enroll onto the trial. A s a result, including th ears.  
LLABORATIVE AGREEMENT
REEMENT T YPE
laterial Transfer Agreement (Agreement \# 36562-13) is in place with Epic Sciences for the studies discussed in section 5.  
tudy is conducted under a CRADA with Bavarian Nordic, Inc. (CRADA \# 02377 operative Research and Development Agreement (CRADA):
Material Transfer Agreemen
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!  
-
sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO
nbined effective dose of 1.2 rem. This is below the guideline of 5.0 rem per year allowed for research subjects by the NIH
diation Safety Committee.  
RISKS/BENEFITS ANALYSIS
study involves clinical research with an experimental vaccine designed to generate an immune response against antigens found.
state cancer. Patients will undergo mantaly pred ticipation may be discontinued at any time without penalty, and the patient will be encouraged to discuss any concerns estions r the optional biopsy and imaging for research in the protocol, the patient will consent at the time of the procedure.  If the patient
gues the optional biopsy at that time, rve procedure will require a separate consent form. All associate Informed consent obtained. Any experime
ove procedure will require a separate consent form. All Associate I
CONSENT AND ASSENT PROCESS AND DOCUMENTATION
Telephone Re-Consent Procedure Reconsent formed date the subject he subject will signant date the informed consent. A will signand date the consent will be subject' vill be refunced vill be refunced vil b
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!"  
-  
ion Date: 8/8/18
reviated Title: Docetaxel & PROSTVAC in mCSP(  
pose of waste materials as hazardous biological waste, with incineration according to local institutional policy and according
birds for at least 72 hours after working with An example of the content of the content and an antice had no many tends and the content and the content of the content and successfullers.
An example of the content of the e the biological safety cabing, th
leak proof bag oor container labeled with a biohazard bag and decontaminate the biological safety cabing, th
ing down with sterrile gauze s port the agent from the freezer to the work area in leak proof bag.
Insport the agent from the freezer to the work area in leak proof bag.
The agent from the freezer to the w Iandle accidental spills similarly to antineoplastic spills and/or according to local, state, and federal regulation.
Handle accidental spills similarly to antineoplastic spi uration, Handling and Disposal Recommendation azard safety bag.  
generated.  
nfectants.  
on Date: 8/8/18
reviated Title: Docetaxel & PROSTVAC in mCSPo e and the complete of the common and the common and common and common and common and common allow and common and t ent Care Implications and Contraindications r
caution sites the recomber cation site or ult succarile nu ha serile narion who may be
unocompromised by direct contacto othe injection site outh succing a child for vaccin e to the method of manufacturing (virus grown in primary chicken embryo dermal cells), patients with a history of aller
ggs or egg products should not receive the vaccine.  
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-
ion Date: 8/8/18
reviated Title: Docetaxel & PROSTVAC in mCSPO  
eration and consideration in the subsequent of the consideration in the status.
The consideration is the consideration in the consideration in the consideration of the consi nfectants.  
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!"  
-  
ion Date: 8/8/18
reviated Title: Docetaxel & PROSTVAC in mCSP
s a nore or server accor indivaned services.
Image sprovision inver service individuals faceins for adidisesse (e.g., hyprensions choleterolmia,
operating, stree or TiVo wh h CDC is the only source of the licensed vaccinia vaccinia vaccinia vaccinia related orthopoviruses,
theare promnel, whose occupation shor instructions on obtainia and the lic id exposure to the recombinant vaccine, any contaminated dressings, or other infectious materials from patients, or th
e cers can be obtained from http://www.cole.gov/mmwr/pr ecombinant Vaccinia Vaccine Patient Care Implications, Contraindications and Potential Complication ent Care Implications and Contraindication ve active eczema or a history of eczema or atopic dermatitis, or Darier's disease.
ve  other acute,  chronic,  or exfoliative  skin  conditions  (e.g.,  burns,  impetigo,  va r vaccination sites with a sterile dry dressing (e.g., Tellings on deessing  sterile  assination site as  incections waster  weeks
nation, their close household contacts (c sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO
: a moderate or severe actions resolves.
muse unpression increasers is for vaccinated cecemined, it is recommended that patients with known CHF or
elopment of myocarditis and pregnant or intend to become pregnant (due to the potential risk of fetal vaccinial virus or antibodies are excreted in the immunodeficient or immunocompromised (by disease or therapy), including individuals with HIV infection onally, do not administer the recombinant vaccinia vaccine if the vaccined ompoination  vaccines frontice in the commercially for the exalle for the commercial for being immunised forth the CDC commer
the worth anning with worth is ue to the method of manufacturing (virus grown in primary chicken embryo dermal cells), do not administer the recombinant vaccine have not previously been vaccinated with vaccination for vaccination against smallpox, expected local reactions in individular ential Complications Associated With Recombinant Vaccinia Vaccination sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO
sons, regional local local occuration the vaccinations since forma e appearant of definithat may be an ulcer or seemation of the response to re-vacination depends on the degree en recombinant vaccinia vaccines are administered by intradermal, intralesional, subcutaneous or intramuscular routes of injection.
The state of the state of the state of th ere have been a number of complications reported in the literature associated with vaccination of vaccination for smallpox. Reported
ectate surey, cases of these complication  
| evaccination      | 4.5          | 6.8   | 4.5                      |
|-------------------|--------------|-------|--------------------------|
| 25                | 9.1          |       |                          |
| rimary Vaccinatio | one reported |       |                          |
| ne reporte        |              |       |                          |
| 606.1             | 212.1        | 30.3  | ostvaccinial encephaliti |
| ressive vaccin    |              |       |                          |
| ralized vaccin    | ma vaccinatu |       |                          |
| inoculatio        |              |       |                          |  
83 sion Date: 8/8/18
previated Title: Docetaxel & PROSTVAC in mCSPO
aed on a 1968 national survey, the number of deaths in primary vaccinees was approximately 1 per million and the number.
cephalitis or progressive vaccinia.  
ration has been reported by the US Department of Defense (Don recenation Program for the period oppulation
riabes, estimated cases (number of these rillion vacinations bese o  
| one reported             |              |     |
|--------------------------|--------------|-----|
| n reporte                |              |     |
| 07                       | 80           | 2.2 |
| ostvaccinial encephaliti |              |     |
| ressive vaccin           |              |     |
| eralized vaccin          | ma vaccinatu |     |
| inoculatio               |              |     |  
  
erally, self-limited adverse reactions that can be serious, but not life-threatening include progressive vaccinia, eczema
ccinatum, and post-vaccinial encephalitis/encephalom on specific econics within 2-4 days. Errichmed by a ple on are of econic cerrichment ther
ess, esterics, pullican centric (Stever
hnson synthemei) these beni e.
inations , early staations have investigated the report those individuals who received staalling 2003-December 2000
e identified but only 2 reports met the case definition on Date: 8/8/18
reviated Title: Docetaxel & PROSTVAC in mCSP  
ut of a total of 540,824 military personnel vaccinated with a New York City Board of Health strain of vaccina f
ecember 2002 through December 2003, 67 developed sympomatic my
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The  most  common  adverse  reactions  across  all  docetaxel  indications  are  infections,  neutropenia,  anemia,  febrile  neutropenia,
pain, nausea, diarrhea, vomiting, m lersion Date: 8/8/18
Abbreviated Title: Docetaxel & PROSTVAC in mCSPC
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rsion Date: 8/8/18
breviated Title: Docetaxel & PROSTVAC in mCSPO
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