A Single Arm Study of 6-Months Neoadjuvant Apalutamide Prior to Radical Prostatectomy in Intermediate Risk Patients to Reduce the Frequency of Pathologic Features That Drive Post-Operative Radiation Therapy
Phase: PHASE2
Conditions: Prostate Adenocarcinoma, Stage IIB Prostate Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center

2015-0693 
June 10, 2022 
 
 
Page 1 
MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2015-0693/MODCR003 
Protocol Title 
A Single Arm Study of 6-months Neoadjuvant Apalutamide Prior to Radical 
Prostatectomy in Intermediate Risk Patients to Reduce the Frequency of 
Pathologic Features that Drive Post-Operative Radiation Therapy 
Protocol Phase 
2 
Protocol Version 
2 
Version Date 
 6/10/2022 
Protocol PI 
John Davis 
Department 
Urology 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
137461 
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A Single Arm Study of 6-months Neoadjuvant Apalutamide Prior to Radical 
Prostatectomy in Intermediate Risk Patients to Reduce the Frequency of 
Pathologic Features that Drive Post-Operative Radiation Therapy 
 
Version: 
 
 
2 
 
Study: 
 
 
Collaborative, Phase 2 
 
Sponsor: 
 
 
MD Anderson Cancer Center 
 
Supporter: 
 
Janssen Scientific Affairs, LLC 
Drug and Funding Support 
 
Product Name: 
 
Apalutamide 
 
Principal Investigator: 
John W. Davis, MD 
 
 
 
 
MD Anderson Cancer Center—Urology 
 
 
 
 
1515 Holcombe Blvd, Unit 1373 
 
 
 
 
Houston, Texas 77030 
 
 
 
 
Phone: (713)-792-3250 (Off); (713)-794-4824 (F) 
 
 
 
 
Email: johndavis@mdanderson.org  
 
Co-Principal: 
Brian Chapin, MD  
Investigators: 
 
Patricia Troncoso, MD 
Christopher Logothetis, MD 
 
  
Statistician:  
 
Xuemei Wang 
 
Contact: 
 
 
Marisa Lozano: mllozano@mdanderson.org 
 
Correlative 
Studies Collaborator: 
Janssen R&D - Translational Medicine 
 
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1. INTRODUCTION 
 
1.1. Background.  Approximately 50% of patients who undergo radical 
prostatectomy for intermediate risk prostate cancer will have one or more risk 
features that predict for increased risk of biochemical failure and the need for 
subsequent radiation and/or hormonal therapy.  In 35%, the specific risk 
features—positive surgical margins, extra-prostatic extension, and seminal 
vesicle invasion--have been studied in randomized clinical trials as indications 
for adjuvant radiation therapy.  A recent guideline by the American Urological 
Association states that all men with these risk features should be offered and 
counseled on the known benefits of adjuvant radiation to prevent disease 
progression and improve survival.  However, there is toxicity associated with 
adding radiation to a previous surgery patient as well as the risk for over-
treatment, i.e. many with these risk features will not fail, or possibly could 
undergo successful salvage therapy at the time of a known PSA recurrence.  
Given that traditional endpoints of study for novel systemic agents can take a 
minimum of 3-5 years of follow-up, it may be reasonable and a significant 
strategic advantage to examine a much earlier surrogate endpoint found in post-
operative histopathology.  If the aggregate finding of a positive surgical margin, 
extraprostatic extension, and/or seminal vesicle invasion should now trigger 
post-operative radiation, then a novel systemic agent given in the neoadjuvant 
space could be measured by its ability to reduce this risk, and thereby save cost 
and morbidity.  Although LH/RH agonist and/or abiraterone acetate neoadjuvant 
could decrease the risk for post-operative XRT, the effects on sexual function 
would not be practical.  Therefore apalutamide monotherapy may be the best 
candidate agent to test this hypothesis. 
 
 
1.2. Study Outline: Single center, phase II, open label, 6 months (24 weeks)  
neoadjuvant apalutamide, intermediate risk prostate cancer selected for 
extended node dissection, comparison to contemporary (last 4 years) of similar 
inclusion criteria 
 
2. FULL PROTOCOL BACKGROUND 
 
2.1. The Challenge of Predicting Treatment Failure 
In the era of PSA screening, dying of prostate cancer is less common than 
Incidence [1], and better predicted through recognition of high-grade disease and 
absence of short to intermediate term other threats to survivorship [2].  
Intermediate risk prostate cancer is the most common driver of recurrent disease 
because it is so common in incidence [3], and more likely to undergo immediate 
treatment. 
 
On the low risk end of the scale, many patients are now selected for active 
surveillance, and future treatment may be triggered by increase in volume of low 
risk, or upgrading to intermediate risk [4].  Higher volume Gleason 6 pattern on 
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biopsy contributes to the risk of finding higher grades at radical prostatectomy, 
along with multiple clinical parameters [5] and it is therefore often selected for 
treatment.  Therefore the ratio of Gleason 6 cancer taken for surgery has 
decreased [6]. 
 
A review of a recent MDACC cohort of radical prostatectomy cases, stratified by 
risk category, demonstrated 15% low risk, 70% intermediate risk, and 15% high 
risk.  If one assumes PSA recurrence rates are 3%, 15%, and 30% [7-8], 
respectively, then in absolute terms, the number of failures per 1,000 cases 
would be 5 low risk, 105 intermediate risk, and 45 high risk (even if high risk 
failed 50%, then 75 recurrences/1,000 RPs).   
 
Intermediate risk pathology may seem favorable with 15% biochemical 
recurrences; however, many higher risk features are noted at prostatectomy 
pathology.  Of a typical cohort of 100 intermediate risk cases, 10% will have 
positive lymph nodes if an extended template is performed [9].  Of the remaining 
90% N0, approximately 30-40% will have other higher risk features such as 
upgrading to Gleason 8-10, tertiary  5 Gleason pattern, upstaging to pT3, or 
lymphovascular invasion (MDACC—internal data, unpublished).  Therefore, only 
approximately half of intermediate risk patients come out of surgery without an 
unexpected higher risk factor for recurrence.  Table 1 shows a larger breakdown 
of these metrics from 2 surgeons over a 4 year period and over 500 cases of 
confirmed clinically intermediate risk cancer that underwent Robot Assisted 
Radical Prostatectomy (RARP) with extended pelvic lymphadenectomy (PLND) - 
a good measure of the pool of patients available at MDACC, as 5 more surgeons 
are present now. 
 
Table 1: 519 Clinically Intermediate Risk RARP’s from 2 surgeons performing 
extended pelvic lymph node dissection from 1/1/09 to 11/30/12.  As many as 
48% will have a higher risk feature on final pathology and the remaining having 
organ confined Gleason 7 with no additional risk findings. 
Pathologic Finding 
Number 
Percent 
N1 
54 
10% 
N0 pT3 stage 
132 
25% 
N0 Gleason 8-10 
24 
5% 
N0 Tertiary 5 pattern 
50 
10% 
Lymphovascular 
Invasion 
 
Estimated 
10% 
No high risk features 
270 
52% 
Total with higher risk 
features 
249 
48% 
 
Nomograms, such as Partin Tables, can be used for prediction of high-risk 
features.  For typical cases with a PSA 2.6-4.0, Gleason 4+3, cT1c, predicted risk 
features for failure are pT3a 27%, pT3b 4% [10].  In addition, positive surgical 
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margins may be present in up to 10% of pT2 cases with quality surgeons, up to 
25% for pT3a, and higher for pT3b (Table 2—MDACC, internal data).  Taken 
altogether, one could project that as many as 50% of intermediate risk patients 
may have a pathologic higher risk features, and 35% would trigger radiation 
therapy consideration in the adjuvant setting.  
 
Table 2: Standard Reporting of Risk for Intermediate Risk Prostate status post 
RARP and pN0 staging. 
 
Pathologic Stage 
Negative Margin 
Positive Margin (%) 
pT2 
303 
30 (9%) 
pT3a 
77 
15 (16%) 
pT3b 
33 
7 (18%) 
 
To give another estimate that may be more applicable to a broader population of 
patients and surgeons, we changed the assumptions of the cohort for multiple 
surgeons, any lymph node dissection, including Nx cases (thus skews the risk 
more favorable), and excluding the lymphovascular invasion metric which is not 
uniformly reported.  Of 879 cases, we noted 23% that would clearly meet 
guidelines for triggering an ART recommendation—Table 3.  If we eliminate the 
Nx cases, under the assumption that they represent the lower tumor volume of 
the spectrum, then the ART risk rises to 30%.  If one includes another 5% of 
patients with N1 stage, but local features that trigger ART, then the figure is 35%.  
Therefore, depending upon surgeon selection (i.e. PSA values, volume of 
biopsies, dominant 4+3), ART risk at baseline may vary from 23-40%, and 35% 
may be the best assumption. 
 
Table 3: Intermediate Risk Prostate Cancer—879 Surgical Pathology Findings 
that indicate: 1) Small risk of relapse (organ confined, GS 7, N0R0), 2) ART 
Trigger—R1, +SV, +EPE, 3) early metastatic N1, 4) higher risk of relapse but no 
obvious adjuvant trigger (upgrading, tertiary 5) 
 
Category 
Number 
Percent 
1: Low risk/No 
adjuvant 
562 
64% 
2: ART Risk 
203 
23% 
3: Metastatic N1 
56 
6% 
4: High risk/ No 
adjuvant 
58 
7% 
 
2.2. Standard Therapy for Intermediate Risk Prostate Cancer 
Radical prostatectomy is a standard option [8].  Whether open versus robotic 
surgery produces better outcomes is discussed in many publications [11-14]. 
Favorable differences are clear in large datasets that look at objective events 
captured by billing codes—blood loss, hospital stay, complications, and urinary 
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strictures [11-14].  However, differences in pathologic results and functional 
outcomes are either similar or difficult to separate from surgeon experience [15].  
Use of hormonal agents is not recommended—no difference in randomized trials 
[8].  In current practice, robotic technique is the majority utilized at centers with 
access to the technology and having completed the learning curve [16]. 
 
Radiation therapy is a standard option—techniques included external and 
brachytherapy [8].  Shown by high quality studies, hormonal therapy is standard 
for 6 months (2 before, 2 during, 2 after) for external beam therapy to reduce 
PSA recurrences.  For brachytherapy, hormonal therapy is not 
studied/recommended, and noteworthy that the modality is comparatively 
selective for patients with smaller prostate, no urinary obstructive symptoms, and 
favorable pelvic bone anatomy [17].  Some practitioners either do not offer 
brachytherapy for intermediate risk, or would offer it in conjunction with external 
beam boost—a combination that increases morbidity [17]. 
 
2.3. Management of High Risk Pathology after Radical Prostatectomy 
Three randomized clinical trials have compared adjuvant radiation therapy to 
varying strategies of observation/delayed radiation [18].  In all three studies, 
adjuvant therapy was superior in preventing various outcomes such as PSA 
relapse, progression to bone metastases, use of hormonal therapy, and survival.  
However, in common practice, there is resistance to using adjuvant therapy due 
to the overtreatment, and potential side effects.  Many have argued that the 
randomized trials did not compare adjuvant therapy to immediate salvage (i.e. 
PSA 0.2), and such a study is underway [19-20] and it will take several years 
before the results are available.  Although high-risk features are commonly 
lumped together for study, sub-set analysis show that positive surgical margins 
are present in the majority of patients who benefited from the radiation.  
Nevertheless, even if surgery/radiation are not curative, there is increasing 
interest in achieving maximum local control, now that multiple agents are 
approved for managing castrate resistant disease, i.e. the oncologic principle of 
minimizing disease burden for systemic treatments [21]. 
 
Although adjuvant radiation is well tolerated compared with salvage 
prostatectomy, it does result in irritative bowel and urinary side effects and may 
inhibit recovery of sexual function.  The cost is not insignificant in addition to 
inconvenience to the patient [18].   
 
The AUA and ASTRO 2013 guidelines on post-RP radiotherapy now give a more 
forceful language to the use of ART for high risk findings [18].  They do not imply 
that ART must be done, but that it should be offered, and the evidence rationale 
carefully explained.  The cornerstone statement: “Physicians should offer 
adjuvant radiotherapy to patients with adverse pathologic findings at 
prostatectomy including seminal vesicle invasion, positive surgical 
margins, or extraprostatic extension because of demonstrated reductions 
in biochemical recurrence, local recurrence, and clinical progression. 
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(Standard; Evidence Strength: Grade A).”  The complete list of guidelines 
statements is in appendix A 
 
2.4. Integration of Neoadjuvant apalutamide into the MDACC Prostate Cancer 
Progression Model 
Morphologic assessment of prostate cancer using the Gleason Score system 
drives most of our thinking about tumor biology [22], and leaves us with a scale 
that ranges from insignificant to lethal.  Yet the cumulative clinical experience 
and published high impact trials clearly indicate the need for a better model to 
explain the heterogeneous behavior of this disease.  Illustrative examples 
include: 
 
• The PCPT trial demonstrated decreased risk of developing prostate cancer, but 
only in low risk disease [23]. 
• Androgen ablation, but not chemotherapy works better at early cancer 
progression [24]. 
• Chemotherapy is more effective at late stages, i.e. castrate resistant [25-27]. 
• Metastases to bone versus lymph nodes have different treatment resistance 
patterns [28-29] 
• Although average survival response to abiraterone acetate in CRPC is 4 months, 
the array of responses ranges from none to > 12 months [30], and some patients 
also fail to respond to enzalutamide [31] 
• Certain late-stage tumors exhibit anaplastic and/or neuroendocrine features, 
which cause bulky tumor growth and visceral metastases without significant 
change in PSA [32]. 
 
As a construct for piecing together these multiple observations, Logothetis et al have 
proposed a new biology-based prostate cancer classification [33].  The visual 
construct is a spiral image, which starts with the early DHT dependent phase, and 
proceeds through multiple turns towards the cell autonomous stage.  The spiral 
image is also meant to explain the variations observed in progression chronology: 
some patients have a tightly wound spiral and go through each turn of the spiral at a 
rapid pace, while others have stretched out spiral that generates much slower 
progression turns.   
 
The MDACC molecular classification of prostate cancer progression has 3 major 
categories: endocrine-driven, microenvironment-dependent, and tumor cell 
autonomous, and androgen signaling plays a key role in each category.  The 
endocrine-driven stage basically represents the PCPT and REDUCE trial findings 
that DHT depletion inhibits certain low-grade/low-volume tumors.  The critical step 
relevant to this proposal, is the subsequent “escape” into paracrine-driven 
progression, and the beginning of the proposed “progression spiral” model.   
 
The central observation of the endocrine-to-paracrine transition is that response to 
androgen ablation (e.g. Lupron) is heterogeneous, ranging from months to years.  
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Therefore there must be biologically meaningful differences in the role of AR 
signaling.  At this point, the numerous changes observed in oncogenes and tumor 
suppressor genes enter the model, leading to the acquired resistance to androgen 
deprivation and disease progression to its preferred sites—bone and lymph nodes.  
Each turn of the spiral will represent different alterations in the microenvironment, 
and we hope will be characterized in the future by biomarkers, but for the time being 
are best represented by response to therapy observations.  For example, a tumor 
responsive to abiraterone acetate, would be its own Cyp17 sensitive turn.  But 
abiraterone acetate is never curative in metastatic disease, indicating that patients 
will eventually turn out of sensitivity—some immediate, but others after a significant 
interval.  Apalutamide’s activity at the AR signaling step make it an attractive area for 
this study, to ask the biological question as to whether early use of the drug can pull 
certain tumors out of the progression.  
 
 
2.5. Current Status of Androgen Receptor Inhibition Therapy in Prostate 
Cancer 
Enzalutamide is a novel, potent inhibitor of the androgen receptor and is 
approved in the metastatic castration-resistant prostate cancer (CRPC) space.  
In the multinational PREVAIL study, a phase 3, double-blind, placebo-controlled, 
randomized trial, 1717 chemotherapy-naïve patients with asymptomatic or mildly 
symptomatic metastatic prostate cancer that progressed on androgen deprivation 
therapy were randomly assigned to receive 160 mg/day of enzalutamide or 
placebo.  At the time of interim analysis, enzalutamide was shown to significantly 
reduce the risk of death by 29% and the risk of radiographic progression by 81% 
(35). The AFFIRM study [36], a phase 3, double-blind, placebo-controlled trial, 
1199 men with CPRC and post chemotherapy were stratified according to 
performance status and pain, and then randomized 2:1 to enzalutamide at 160 
mg daily (n=800) versus placebo (n=399).  The study was stopped after 520 
deaths, and the median overall survival (primary endpoint) was 18.4 months for 
enzalutamide versus 13.6 months placebo.  Other endpoints were met such as 
PSA reduction, soft-tissue response, time to PSA progression, radiographic 
progression-free survival, time to first skeletal-related event, and quality of life.   
 
Enzalutamide 160 mg daily was generally well tolerated in the AFFIRM trial.  
Adverse events reported by those treated with enzalutamide (160 mg daily) with 
an incidence of at least 5% and by at least 2% greater than by those who 
received placebo included fatigue (33.6% v 29.1%), diarrhea (21.4% v 17.5%), 
hot flush (20.3% v 10.3%), musculoskeletal pain (13.6% v 10.0%), headache 
(11.6% v 5.5%), insomnia (8.6% v 6.0%), anxiety (6.4% vs. 4.0%), hypertension 
(6.1% v 2.8%), and nasopharyngitis (5.1% v 3.0%).  Other adverse events 
reported less commonly than 5% but that may be associated with enzalutamide 
treatment after careful assessment of the adverse events include: falls (4.0% vs. 
1.3%), dry skin (3.6% vs. 1.3%), and pruritus (3.5% vs. 1.3%). A greater 
proportion of patients in the enzalutamide-treated group (4.1% vs. 1.8%) 
reporting the following adverse event terms: memory impairment, cognitive 
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disorder, amnesia, disturbance of attention, and dementia. In addition, event 
terms related to hallucination (visual hallucination, tactile hallucination) were 
reported more frequently in the enzalutamide-treated group (1.6% vs.0.3%). 
 
Seizure is a known potential toxicity of enzalutamide. In vitro studies have shown 
that enzalutamide and its metaboliteM2 bind to the GABA-gated chloride channel 
with IC50 values of 1.2 μg/mL and 3.3 μg/mL, respectively and in a cell-based assay 
inhibit the channel’s activity with IC50 values of 1.4 μg/mL and 1.07 μg/mL, 
respectively. Some compounds that inhibit the GABA-gated chloride channel are 
associated with seizures. 
 
In the first clinical study of enzalutamide (S-3100-1-01), a dose-escalation study in 
men with CRPC with and without prior exposure to chemotherapy, the following 
doses were evaluated: 30, 60, 150, 240, 360, 480 (as 240 mg twice per day [BID]), 
and 600 (as 300 mg BID) mg/day. Three patients were reported to have dose-
limiting toxicities of seizure, one each at doses of 360, 480, and 600 mg/day. The 
results of this study led to the selection of the clinical dose of enzalutamide of 160 
mg/day.  As reviewed in MDACC 2013-0332, 7 patients out of 1100 (0.6%) on 
clinical trials for castrate resistant disease and exposed to enzalutamide 160 mg/day 
reported a seizure. 
 
Table 4: Summary of Study Drug Exposure, Adverse Events, and Deaths in Castrate 
Resistant Prostate Cancer (cited in from Table 3 MDACC 2013-0332, reference 
AFFIRM trial [31]). 
Treated (Safety Population) 
Enzalutamide 
n=800 
Placebo 
n=399 
Discontinued treatment 
569 (71.1%) 
380 (95.2%) 
Treatment Duration (median months) 
8.3 
3.0 
Patients with ≥ treatment emergent AE 
785 (98.1%) 
390 (97.7%) 
Patients with ≥ treatment emergent AE 
(Grade 3 or higher) 
362 (45.3%) 
212 (53.1% 
Patients with ≥ 1 serious treatment 
emergent AE 
23 (2.9%) 
14 (3.5%) 
Patients with adverse events leading to 
study drug discontinuation 
61 (7.5%) 
39 (9.8%) 
Deaths 
308 (38.5%) 
212 (53.1% 
 
 
Enzalutamide is an FDA-approved option for CRPC in the post-chemotherapy and 
pre-chemotherapy space The PREVAIL trial [35] has now been completed.  At the 
ASCO GU presentation in 2014, the results were presented that enzalutamide 
reduced risk of death by 29%, and delayed the time to chemotherapy initiation.   
 
In both of these pivotal studies, patients had demonstrated CRPC with metastases, 
and were kept on LHRH agonist therapy per standard of care.  In another study 
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more analogous to this proposal, a phase II cohort of patients with any stage 
hormone-naïve prostate cancer were treated with enzalutamide monotherapy, i.e. 
instead of standard LHRH agonist therapy.  They enrolled 63 patients (38.8% with 
metastases at entry), and 94% completed 25 weeks and 81% completed 49 weeks 
of enzalutamide.  As expected, testosterone levels increased 73% from baseline by 
week 25, and luteinizing hormone 120%.  Meanwhile PSA levels decreased from 
baseline—80%of all patients, and 100%by week 49.  The median maximum decline 
in PSA was 100% and mostly occurred in the first 5 weeks, while maintaining 
throughout 49 weeks with or without metastases.   
 
In terms of toxicity, 9 patients discontinued treatment between weeks 25 and 49—4 
due to AEs including 2 deaths, 1 protocol violation, 2 to progressive disease, and 2 
withdrawn. Overall there were 7 SAE’s but none drug related, and 3 deaths, none 
drug related.  There were no seizures reported.  The most frequent treatment-
emergent AEs were gynecomastia (47.8%), fatigue (38.8%), nipple pain (19.4%), 
and hot flash (17.9%)—grade 1 or 2 severity.  Others included diarrhea (11.9%), 
hypertension (11.9%), nausea (10.4%, and pain in extremity (10.4%).  The overall 
rate of treatment associated AE’s was 95.5%.  Global health status by EORTC QLQ-
C39 was unchanged from baseline to week 49, however fatigue was increased from 
11.3 (SD-17.2) to 14.0 (SD-14.3) with a moderate deterioration of sexual activity 
functional scale of -9.8 (SD-18.0) from 28.6 (SD-24.6) baseline. 
 
The overall conclusions were that: 1) large reductions in PSA were maintained 
beyond 25 weeks, 2) PSA control maintained in patients continuing to 49 weeks, 3) 
bone mineral density and other metabolic variables (fat body mass, lipid, glycemic 
profile) were not impacted, and 4) hormone level changes and common drug related 
AE’s were consistent with potent AR inhibition.  In this setting, of course, the risks 
and benefits would be compared to standard LHRH agonist therapy which carries 
risks of hot flashes and loss of libido in nearly all patients, and other side effects 
such as depression, fatigue, decreased bone mineral density, increased fracture 
risk, obesity, risk of diabetes, and risk of cardiovascular disease.  
 
In the setting of high risk, non-metastatic prostate cancer, ongoing research is being 
conducted at MDACC in the investigator initiated study 2013-0332: “A Pre-Operative 
Study to Assess the Effects of Abiraterone acetate plus LHRH Agonist and 
Abiraterone acetate plus LHRH and Enzalutamide for Six Months for Prostate 
Cancer Patients at High-risk for Recurrence.”  The P.I. is Christopher Logothetis, 
and Co-PIs John Davis and Eleni Efstathiou.  The primary objective of this actively 
enrolling study is to assess the difference in pathologic stage ≤ pT2 at prostatectomy 
between group A abiraterone acetate plus prednisone and LHRH plus enzalutamide 
for 6 months versus group B abiraterone acetate plus prednisone and androgen 
ablation for 6 months.  Therefore, the GU center has an ongoing interest and 
expertise in delivering this drug in the pre-surgical patient, and in this protocol will be 
the monotherapy variation as more appropriate to the intermediate risk group. 
 
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Apalutamide is a novel agent acquired by Janssen Scientific Affairs, LLC.  
Apalutamide is FDA approved for non-metastatic castration resistant prostate 
cancer, however, is still considered investigational in this trial setting.  It is in the 
class of enzalutamide, and also causes competitive AR inhibition through 
antagonistic properties that inhibits nuclear translocation of AR.  It is possibly more 
efficacious than enzalutamide in a mouse xenograft model [37]. It has less 
penetration of the blood brain barrier with possibly less seizure risk.  It also causes 
grade 1-2 fatigue and nausea.  The dose from phase II trials is 240 mg [38]. 
 
Apalutamide is a new generation AR antagonist that has been developed to 
overcome the potential therapeutic deficiencies of first generation AR antagonists 
(e.g. bicalutamide). 
 
Apalutamide is an orally available, potent and selective AR antagonist that acts by 
inhibiting the action of androgen, nuclear translocation of the AR and DNA binding to 
androgen response elements and unlike bicalutamide, it exhibits no significant 
agonist activity in AR-overexpressing prostate cancer cells. 
 
2.6. Summary of Unmet Needs 
Although at face value, a 15% failure rate for curative local treatments may seem 
too low for integrating systemic strategies, there may be potential contributions 
for an agent with low impact on perioperative morbidity.  Beyond PSA 
recurrences, 25-50% of intermediate risk cohorts may have a risk feature for 
recurrence, and a simple method of reducing this rate, may be worthy of study for 
this purpose as well as long-term disease stability.  Given the new AUA/ASTRO 
guidelines, the endpoint of ART avoidance may be a novel centerpiece of trial 
design—substituting neoadjuvant systemic therapy for postoperative 
radiotherapy. 
 
Prostate cancer in advance stages demonstrates significant temporal 
heterogeneity in terms of optimal timing of events.  Therefore if an agent such as 
apalutamide reduced the risk of needing postoperative radiation, that would be a 
modest benefit, but if the agent truncates some tumors from shifting into 
progressive disease biology, then additional benefits may be possible.  The 
ongoing theory is that lethal potential disease will shifts from endocrine regulation 
to paracrine regulation.  In intermediate risk disease, this shift may be pre-
destined but not yet engaged, and AR blockade at this early phase may 
potentially add to the cure fraction of localized disease.  
 
2.7 Biologic Rationale 
Neo-adjuvant androgen ablation with radiation has demonstrated complementary 
response but no equivalent benefit with surgery.  Several possibilities may 
account for these discordant observations: 1) the duration of androgen ablation in 
the surgical studies was insufficient, 2) the benefit reported with the combination 
of androgen ablation and   radiation is attributed specific synergy between the 
modalities that do not exist with surgery and androgen ablation. Recent evidence 
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suggests that paracrine/intracrine androgen signaling is often a driver of 
resistance to   androgen ablation, and not inhibited by androgen ablation.  
Therefore the absence of specific synergies between androgen ablation and 
surgery as exists with radiation may account for the apparent paradox. We wish 
to gain evidence in support of the hypothesis that inhibition of paracrine/intracrine 
androgen signaling with apalutamide will improve the efficacy of surgery in some 
men with prostate cancer and reduce the need for postoperative radiation.  
 
3. STUDY OBJECTIVES 
 
3.1. Primary: To determine whether 6 months (24 weeks) of neoadjuvant 
apalutamide prior to prostatectomy for intermediate risk prostate cancer results 
in a reduction of aggregate post-operative radiotherapy risk from 35% to 15%.  
 
3.2. Secondary: 
 
3.2.1. To determine the safety and tolerability of 6 months (24 weeks)  
neoadjuvant apalutamide followed by radical prostatectomy for intermediate 
risk prostate cancer 
3.2.2. To estimate the frequency of clinical complete responses and “near” 
complete responses (currently defined as <6mm total tumor volume) 
3.2.3. To characterize the molecular features of the treated prostate cancers and 
link them to morphologic characterization 
3.2.4. To measure the 3-5 year biochemical recurrence rate and quality of life of 
treated patients as a baseline to inform a larger phase III trial.  
 
4. INVESTIGATIONAL PLAN 
 
This is a single center, phase II, open label, pre-operative study of apalutamide in 
patients with intermediate risk prostate cancer. The study period will consist of 
screening, treatment, and follow-up visits to 12 months post-operative.  Additional 
follow-up onsite or via remote contact will determine disease-free and treatment-free 
status at yearly intervals 2-5.  Surgery will occur within 2 weeks of completing 24 
weeks of apalutamide.  At the mid-way evaluations (weeks 9 or 12), patients who fail 
to reach a ≥50% decrease in PSA, or demonstrate suspicious changes in DRE will 
be considered non-responders and recommended for early surgery.  For 
responders, the plan calls for 5 pre-operative PSA measurements that will be 
analyzed for rate of decline and nadir.  In the post-treatment evaluation, patients will 
be off formal protocol at 12 months, however the investigating team will track PSA 
measurements for biochemical failure rates at 2, 3, 4 and 5 years (outside or inside 
measurements) using >0.2 ng/mL as the failure definition. 
 
5. PATIENT POPULATION 
 
5.1. Inclusion Criteria 
 
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• 
Willing and able to provide written informed consent 
• 
Male, age > 18 years 
• 
Histologically confirmed adenocarcinoma of the prostate 
• 
A minimum of 10 core biopsies have been performed at baseline and 
available. A prostate biopsy within 6 months from screening is allowed for 
entry requirements.  Biopsies performed within 6-12 months from screening 
are acceptable if the treating physician would allow treatment without further 
biopsy.  Patients must meet intermediate risk criteria from Gleason score, T 
stage, and PSA value by NCCN criteria: cT2b-T2c or Gleason 7 (3+4 or 
4+3) or PSA 10-20 ng/mL.  In addition, the Gleason 3+4 or 4+3 must be 
present.  
• 
Pathology review at MD Anderson Cancer Center.  The volume of disease 
must be high enough for the surgeon to agree to include an extended 
template pelvic lymph node dissection.  
• 
Serum testosterone > 200 ng/mL 
• 
Patient and urologist must agree that patient is suitable for prostatectomy 
• 
No evidence of metastases on imaging.  This risk group does not require 
metastatic studies, but if performed they must be negative (as determined 
by urologist or radiologist).  Suspicious lymph nodes permissible if < 10 mm.  
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1. 
• 
Hemoglobin ≥ 10.0 g/dL  
• 
Platelet count ≥ 100,000 x 109/microliter,  
• 
GFR >45 mL/min  
• 
Serum potassium ≥ 3.5 mmol/L 
• 
Serum albumin ≥ 3.0 g/dL 
• 
Able to swallow the study drug whole as a tablet 
• 
Liver function test with serum bilirubin < 1.5x ULN and ALT and AST < 2.5 x 
ULN  Note: In subjects with Gilbert’s syndrome, if total bilirubin is >1.5 × 
ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤1.5 × 
ULN, subject may be eligible 
• 
Normal coagulation profile and no history of substantial non-iatrogenic 
bleeding diathesis 
• 
Agrees to use a condom (even men with vasectomies) and another effective 
method of birth control if he is having sex with a woman of childbearing 
potential or agrees to use a condom if he is having sex with a woman who is 
pregnant while on study drug and for 3 months following the last dose of 
study drug. Must also agree not to donate sperm during the study and for 3 
months after receiving the last dose of study drug. 
 
5.2. Exclusion Criteria 
 
• 
Histological variants in the primary tumor, other than adenocarcinoma; for 
example: neuroendocrine tumor, small cell or sarcomatoid 
• 
Serious or uncontrolled co-existent non-malignant disease, including active 
and uncontrolled infection 
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• 
PSA is > than 20 ng/mL (NOTE: unless other valid PSAs were ≤ 20 and the 
treating physician considers a value > 20 related to the biopsy or other non-
malignant cause.  The treating physician must consider the patient 
intermediate risk in aggregate.) 
• 
Uncontrolled hypertension.  Patients with a history of hypertension are 
allowed provided blood pressure is controlled by anti-hypertensive therapy. 
Note that this is NOT a criterion related to particular BP results at the time of 
assessment for eligibility, nor does it apply to acute BP excursions that are 
related to iatrogenic causes, acute pain or other transient, reversible causes.  
• 
Active or symptomatic viral hepatitis or chronic liver disease. 
• 
Clinically significant heart disease as evidenced by myocardial infarction, 
arterial thrombotic events in the past 6 months, severe or unstable angina, 
or Class III-IV New York Heart Association heart failure.   
• 
Other malignancy, except non-melanoma skin cancer, that is active or has a 
≥ 30% probability of recurrence within 12 months 
• 
History of gastrointestinal disorders (medical disorders or extensive surgery) 
which may interfere with the absorption of the study drug 
• 
Known history of pituitary and/or adrenal disease (or dysfunction) 
• 
Prior hormone therapy for prostate cancer including orchiectomy, 
antiandrogens, ketoconazole, or estrogens (5-α reductase inhibitors 
allowed), or LHRH agonists/antagonists 
• 
Severely compromised immunological state, including being positive for the 
human immunodeficiency virus (HIV) 
• 
Patients who are not appropriate surgical candidates for radical 
prostatectomy based on the evaluation of co-existent medical diseases and 
competing potential causes of death (such as but not limited to, unstable 
angina, myocardial infarction within the previous 6 months, or use of 
ongoing maintenance therapy for life-threatening ventricular arrhythmia, 
uncontrolled hypertension) 
• 
History of seizure, seizure disorder, or any condition that may predispose to 
seizure including, but not limited to underlying brain injury, stroke, primary 
brain tumors, or brain metastases. Also, history of loss of consciousness or 
transient ischemic attack within 12 months of enrollment (Day 1 visit). Drugs 
may not be used which are known to decrease the seizure threshold. 
 
6. STATISTICAL METHODS 
 
 
The primary objective of the study is to determine whether 6 months of neoadjuvant 
apalutamide prior to prostatectomy for intermediate risk prostate cancer can result in 
a reduction of “aggregate pathologic risk features” (APRF) that drive post-operative 
radiotherapy recommendations. We hypothesize a reduction of 20% (i.e., from 35% 
to 15%) in terms of the rate of APRF among intermediate risk patients.  Using a one-
sample exact binomial test and with a two-sided type I error of 0.05, a sample size of 
41 patients would provide 84% power to detect this change.  We would factor up to 
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10% additional enrollment for compliance issues, thus the total enrollment from 
MDACC will be up to 45 patients.    
 
 
 
 
6.1. Endpoints of Study 
 
6.1.1. Primary Endpoint 
The primary endpoint, aggregate pathologic risk features, is defined as any of the 
3 pathologic staging features on a radical prostatectomy specimen that indicate 
elevated future risk of a patient needing pelvic radiation therapy.  It can be any 
single or combination of the three.  The three drivers per AUA/ASTRO guidelines 
are positive surgical margins, extraprostatic extension, and/or seminal vesicle 
invasion.  These will be determined by a single expert genitourinary pathologist. 
The primary objective is to show a 20% decrease in these aggregate pathologic 
features. 
 
6.1.2. Secondary Endpoints 
• To determine safety and tolerability of 6 months neoadjuvant 
apalutamide followed by radical prostatectomy for intermediate risk 
prostate cancer 
• To estimate the frequency of clinical complete responses (pT0) and 
“near” complete responses (<6mm total tumor volume) 
• To characterize molecular features of treated prostate cancer and link 
them to morphologic characterization 
• To measure 3-5 year biochemical recurrence rate and quality of life of 
treated patients as a baseline to inform a larger phase III trial. 
 
6.2 Analysis Plan 
 
All patients who receive at least 9 weeks of neoadjuvant therapy of apalutamide 
and undergo radical prostatectomy will be evaluable for the primary endpoint of 
APRF.  The proportion of patients with APRF will be estimated by the number of 
patients with APRF divided by the total number of evaluable patients. As a 
primary analysis, we will estimate this proportion along with the exact 95% 
confidence interval. All patients who receive any dose of apalutamide will be 
evaluable for safety. Toxicity data will be summarized by category, grade and 
attribution. Frequency distributions, graphical techniques and other descriptive 
measures will form the basis of the analysis of safety data.  
 
The proportion of patients having clinical complete responses and “near” 
complete responses will be estimated, along with the exact 95% confidence 
interval. The molecular features of the treated patients will be characterized using 
descriptive statistics and their association with the primary endpoint, APRR, or 
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clinical response will be assessed through logistic regression analyses. The 
Kaplan-Meier method will be used to assess time to biochemical recurrence and 
to estimate the rate of biochemical recurrence at various time points. The EPIC 
quality of life data will be summarized by domains and will be compared pre- and 
post-treatment using paired t-test or Wilcoxon signed rank test as appropriate.  
 
6.3 Interim Analysis 
 
The standard therapy for intermediate risk prostate cancer patients is radical 
prostatectomy. In the current trial, we are treating patients with apalutamide for 6 
months in the neoadjuvant setting followed by the standard radical 
prostatectomy, thus we do not anticipate the rate of APRF(aggregate pathologic 
risk features) to be higher than the 35% rate with radical prostatectomy alone. 
Therefore, no interim analysis for futility is planned.  
 
Monitoring for safety will be implemented in this single arm trial with the 
benchmark of avoiding extreme toxicities (TOX), defined as any adverse event 
preventing surgery or treatment-related death before surgery.  Patients who 
voluntarily leave the trial for any reasons, or are successfully treated with dose 
reductions and proceed with surgery will not be counted as having a TOX.  
Denote the probability of TOX by θT and a beta(0.6, 1.4) distribution was 
assumed for the prior. Our stopping rule is given by the following probability 
statement: Pr (θT > 0.30 | data) >0.90. That is, we will stop the trial if, at any time 
during the study, we determine that there is more than a 90% chance that the 
TOX rate is more than 30%. The corresponding stopping boundaries are shown 
in Table 1 below and the operating characteristics of the toxicity monitoring are 
illustrated in Table 2. Multc Lean Desktop (v2.1.0) was used for generating the 
stopping boundaries and the OC table.  
 
Table 1. Interim toxicity stopping boundaries in cohort size of 5.  
Among These Number of 
Patients  
Stop the trial if these many 
patients with toxicities 
5 
4-5 
10 
6-10 
15 
8-15 
20 
9-20 
25 
11-25 
30 
13-30 
35 
15-35 
40 
16-40 
45 
18-45 
 
Table 2. The operating characteristics of toxicity monitoring.  
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True Toxicity 
Rate 
Prob (stop early) 
Average number 
of patients 
0.1 
0.0006 
44.98 
0.2 
0.02 
44.32 
0.3 
0.21 
39.70 
0.4 
0.66 
28.55 
0.5 
0.95 
17.57 
 
 
 
 
An Efficacy/Toxicity Summary will be submitted after the first five evaluable 
patients complete 24 weeks of study treatment, and every five patients 
thereafter.  The Investigator is responsible for completing the summary report 
and submitting it to the IND Office Medical Monitor for review. 
 
 
 
7. OUTLINE OF PATIENT ASSESSMENTS 
 
7.1. Visit Schedule 
 
A. Screening Phase: 
 
1) Screening (day -30 to -1):  
• Signed Informed Consent 
• Medical history 
• Physical exam with Digital Rectal Exam (DRE) 
• Vital signs 
• ECOG Performance Status 
• Laboratories (Serum chemistry and hematology): 
o albumin, calcium, lactate dehydrogenase (LDH), sodium, 
potassium, chloride, magnesium, carbon dioxide, creatinine, BUN, 
AST, ALT, alkaline phosphatase, total bilirubin, total protein, 
glucose.  Complete blood count. 
• Blood Coagulation profiles: 
o Prothrombin Time (PT) 
o Partial Thromboplastin Time (PTT) 
• Thyroid Stimulating Hormone (TSH) (T3 and T4 only to be done if TSH is 
abnormal) 
• Prostate-Specific Antigen (PSA) Test and Testosterone 
• Blood collection for Correlative Studies 
• EKG 
• MRI of the pelvis (as per physician discretion) 
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• Optional—Repeat prostate biopsy at MDACC if the initial biopsy was 
performed outside—per treating Urologist discretion, and optional tissue 
collection. 
• Concomitant Medications Review 
• Adverse Events 
• EPIC Quality of Life (QOL) Questionnaire 
 
B. Treatment Phase: 
 
 
1)  Week 1 Procedures: (If week 1 occurs within 2 weeks after screening visit, these 
procedures will not need to be repeated) 
• Physical exam with DRE if indicated by the treating physician 
• Vital signs 
• ECOG Performance Status 
• Laboratories (Serum chemistry and hematology) 
• Thyroid Stimulating Hormone (TSH) (T3 and T4 only to be done if TSH is 
abnormal) 
• Prostate-Specific Antigen (PSA) Test and Testosterone 
• Concomitant Medications Review 
• Adverse Events  
• Medication Dispensing (neoadjuvant apalutamide) 
  
2) Week 5 Procedures (± 3 days): 
• Medication dispensing (neoadjuvant apalutamide) 
• Dosing compliance 
• Physical exam with DRE if indicated by treating physician 
• Vital signs 
• ECOG Performance Status 
• Laboratories (Serum chemistry and hematology)  
• Thyroid Stimulating Hormone (TSH) (T3 and T4 only to be done if TSH is 
abnormal) 
• Prostate-Specific Antigen (PSA) Test and Testosterone 
• Concomitant Medications Review, Adverse Events 
• Adverse Events 
 
3) Week 9 Procedures (± 3 days):  
• 
Medication dispensing (neoadjuvant apalutamide) 
• 
Dosing compliance 
• 
Physical exam with DRE 
• 
Vital signs 
• 
ECOG Performance Status 
• 
Laboratories (Serum chemistry and hematology)  
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• 
Thyroid Stimulating Hormone (TSH) (T3 and T4 only to be done if 
TSH is abnormal) 
• 
Prostate-Specific Antigen (PSA) Test and Testosterone 
• 
Concomitant Medications Review 
• 
Adverse Events 
 
Note:  At the mid-way evaluation (week 9), patients who fail to reach a 50% 
decrease in PSA, or demonstrate suspicious changes in DRE will be 
considered non-responders and recommended for early surgery. 
 
4) Week 12 Procedures (± 3 days):  
Optional: Repeat prostate biopsy per urologist’s discretion.  Acceptable to perform at 
the week 9 or week 17 visit if requested for patient travel needs.   
 
 
5) Week 17 Procedures (± 3 days):  
• 
Medication dispensing (neoadjuvant apalutamide) 
• 
Dosing compliance 
• 
Physical exam with DRE if indicated by treating physician  
• 
Vital signs 
• 
ECOG Performance Status 
• Laboratories (Serum chemistry and hematology) 
• Thyroid Stimulating Hormone (TSH) (T3 and T4 only to be done if TSH 
is abnormal) 
• 
Prostate-Specific Antigen (PSA) Test and Testosterone 
• 
Concomitant Medications Review 
• 
Adverse Events 
• 
EPIC Quality of Life (QOL) Questionnaire  
• 
Blood collection for Correlative Studies 
 
 
 
6) Week 24/ Pre-op/ End of Treatment Visit Procedures (± 3 days):  
• 
Dosing compliance 
• 
Physical exam with DRE 
• 
Vital signs 
• 
ECOG Performance Status 
• Laboratories (Serum chemistry and hematology) 
• Thyroid Stimulating Hormone (TSH) (T3 and T4 only to be done if TSH 
is abnormal) 
• 
Prostate-Specific Antigen (PSA) Test and Testosterone 
• 
Concomitant Medications Review  
• 
Adverse Events 
• 
EPIC Quality of Life (QOL) Questionnaire  
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• 
Blood collection for Correlative Studies 
 
7) Radical Prostatectomy (2 weeks (+/-7 days) after last dose of study drug):  
• 
Perioperative data collection 
• 
Pathology  Tissue Collection 
 
 
C. Follow-up Phase: 
 
1) Post Radical Prostatectomy: (within 30 days post-op +/- 3 days) 
• 
Physical exam and DRE if indicated by treating physician 
• 
Assess complications from surgery at 30 days using Clavien 
methodology (Table 5). 
• 
Adverse Events 
• 
Epic Quality of Life (QOL) Questionnaire  
• 
PSA, testosterone  
 
2) Six Months Post-Radical Prostatectomy: (+/- 4 weeks) 
a. Update complications to 90 day window 
b. Use of adjuvant/salvage therapies 
c. EPIC  Quality Of Life (QOL) Questionnaire 
d. PSA, testosterone 
 
3)  Twelve Months Post Radical Prostatectomy—Last on-site Study Visit: (+/- 4 
weeks) 
a. EPIC  Quality Of Life Questionnaire 
b. PSA, testosterone 
c. Use of adjuvant/salvage therapies 
d. Update complications 
 
4) Post Study Follow-up Data Collection (on-site or remote):(+/- 4 weeks) 
a. Intervals 24, 36, 48, 60 months 
b. PSA/biochemical relapse-free status 
c. Use of adjuvant/salvage therapies 
d. Update complications 
e. Epic Quality of Life (QOL) Questionnaire 
 
7.2 Details of Assessment Methods: 
 
7.2.1 QOL assessments per above: may be written or via tablet.  Surveys will 
consist of the Expanded Prostate Cancer Index (EPIC), including the SF-12.  
As an alternative, the data may be collected using an electronic tablet 
method.  Any post-operative surveys occurring after the incidence of 
additional post radical prostatectomy radiation or hormonal therapy will 
continue but be so designated for analysis. 
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7.2.2 Complications: use Clavien reporting system shown in Table 5. 
 
 
Table 5: Classification of Surgical Complications [34] 
 
 
 
 
 
Grades 
Definition 
Grade I 
Any deviation from the normal postoperative course 
without the need for pharmacological treatment or 
surgical, endoscopic and radiological interventions.  
Allowed therapeutic regimens are: drugs such as 
antiemetics, antipyretics, analgesics, diuretics and 
electrolytes, and physiotherapy. This grade also 
includes would infections opened at the bedside.  
Grade II 
Requiring pharmacological treatment with drugs other 
than such allowed for grade I complications. Blood 
transfusions and total parenteral nutrition are also 
included. 
Grade III 
Requiring surgical, endoscopic or radiological 
intervention 
    Grade IIIa 
Grade IIIb 
Intervention not under general anesthesia. 
Intervention under general anesthesia. 
Grade IV 
Life-threatening complication (including CNS 
complications)* requiring IC/ ICU management. 
Grade IVa 
Grade IVb 
Single organ dysfunction (including dialysis) 
Multiorgan dysfunction 
Grade V 
Death of a patient 
Suffix “d” 
If the patient suffers from a complication at the time of 
discharge, the suffix “d” (for “disability”) is added to 
the respective grade of complication. This label 
indicates the need for a follow-up to fully evaluate the 
complication.     
*Brain hemorrhage, ischemic stroke, subarachnoid bleeding, but 
excluding transient ischemic attacks, CNS, central nervous system; IC, 
intermediate care; ICU, intensive care unit. 
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Table 6: Study Calendar 
 
Evaluation 
Screeninga 
Wk 1 
Wk 
5 
Wk 
9 
Wk 
12 
Wk 
17 
Wk 24/ 
Preoph 
Surgery 
30 d 
post op 
6 mo 
12 
mo 
2 yr 
3 yr 
4 yr 
5 yr 
 
 
 
+/- 3 
days 
+/- 3 
days 
+/- 3 
days 
+/- 3 
days 
+/- 3 
days 
 
+/- 3 
days 
+/- 4 
wks 
+/-4 
wks 
+/-4 
wks 
+/-4 
wks 
+/- 4 
wks 
+/-4 
wks 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
w/DRE 
X 
Xb 
Xb 
X 
 
Xb 
X 
 
Xb 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
ECOG PS 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI Pelvis 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medication 
X 
X 
X 
X 
 
X 
X 
 
 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
AE 
X 
X 
X 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
Dosing 
compliance 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
Serum chemistry/ 
hematologyd 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
PT/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSHe 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
PSA 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Testosterone 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
 
 
 
 
EPIC QOL 
X 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood Correlative 
 Studiesi 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
Tissue 
procurement 
Xf 
 
 
 
Xf 
 
 
X 
 
 
 
 
 
 
 
Complications, 
post op therapyg 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
a: Within 30 days prior to initiation of study treatment 
b: Physical exam and DRE if indicated by treating physician 
c: Use of adjuvant/salvage therapies only, such as hormones or radiation 
d: albumin, calcium, lactate dehydrogenase (LDH), sodium, potassium, chloride, magnesium, carbon 
dioxide, creatinine, BUN, AST, ALT, alkaline phosphatase, total bilirubin, total protein, glucose, complete 
blood count with differential 
e: T3/T4 testing to be done if abnormal TSH or clinically indicated 
f:  Optional collection of tissue for research purposes at time of prostate biopsy at baseline and week 12, if 
indicated by treating physician. If patient is not available to return to clinic on week 12 for repeat biopsy, this 
could be done either during week 9 or week 17 visits. Please note that tissue collection at time of radical 
prostatectomy is mandatory 
g: Record post-operative complications using Clavien method within 30 days and 90 days, and any long-
term complications related to surgery.  
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h: Early treatment discontinuation patients will complete all the pre-op assessments within 30 days post 
treatment discontinuation as their last study visit 
i: Including plasma, whole blood and serum samples as indicated in section 9.1 
j. As per physician discretion 
 
 
8. TREATMENT PLANS 
 
8.1. Six-Months Neoadjuvant apalutamide (24 weeks) 
8.1.1. Subjects will be instructed to take 240 mg per day orally of apalutamide, 4 
tablets (60 mg each).  Apalutamide may be taken with or without food and 
close to the same time each day as possible. 
8.1.2. Study Drug Procedures 
8.1.2.1. 
Apalutamide has the chemical name (4-[7-(6-Cyano-5-
trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-
fluoro-N-methylbenzamide) 
8.1.2.2. 
Apalutamide will be provided packaged in individual bottles for 
patient assignment at corresponding study visits.  Information on labels 
will comply with applicable local regulations.  Site pharmacist or 
medically qualified staff will dispense the study treatment to each 
patient in accordance with the protocol. 
8.1.2.3. 
The study treatment must be stored in a secure area and 
administered only to patients entered into the clinical study in 
accordance with the conditions specified in this protocol. Bottles of 
study treatment should be stored at 20°C to 25°C (68°F to 77°F); 
excursions are permitted to 15°C to 30°C (59°F to 86°F) in the original 
container/closure with the cap on tightly; it should never be refrigerated. 
Additional information is provided in the apalutamide Investigator’s 
Brochure. 
8.1.2.4. 
Current ICH GCP Guidelines require the investigator to ensure that 
study drug deliveries are received by a responsible person (e.g. 
pharmacist), and  
• 
that such deliveries are recorded  
• 
that study drug is handled and stored safely and properly, and should 
explain the correct use/handling of the investigational product to each 
subject.  
• 
that study drug is only dispensed to study subjects in accordance with 
the protocol that any unused study drug is returned or standard 
procedures for the alternative disposition of unused study drug are 
followed.  
 
Drug inventory and accountability records for the study drugs will be kept 
by the investigator/ pharmacist. Study drug accountability throughout the 
study must be documented. The following guidelines are therefore 
pertinent:  
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• 
The investigator agrees not to supply study drugs to any persons 
except the subjects in this study.  
• 
The investigator/pharmacist will keep the study drugs in a pharmacy or 
other locked and secure storage facility under controlled storage 
conditions, accessible only to those authorized by the investigator to 
dispense these test drugs.  
• 
A study drug inventory will be maintained by the 
investigator/pharmacist. The inventory will include details of material 
received and a clear record of when they were dispensed and to which 
subject.  
• 
At the conclusion or termination of this study, the 
investigator/pharmacist agrees to conduct a final drug supply inventory 
and to record the results of this inventory on the Drug Accountability 
Record. It must be possible to reconcile delivery records with those of 
used and returned medication. Any discrepancies must be accounted 
for. Appropriate forms of deliveries and returns must be signed by the 
person responsible.  
• 
Returned or expired study drug will be destroyed on site per MDACC 
Investigational Pharmacy policies.  
 
Apalutamide will be provided by Janssen Scientific Affairs, LLC and will 
be stored and handled according to the manufacturer specifications and 
the pharmacy standards of operation. 
 
8.1.3. Study Drug Dose Reductions or Discontinuation of Study Drug 
In subjects who experience toxicity who cannot be ameliorated by the use of 
adequate medical intervention, dose reductions can be performed.  Patients 
who experience a Grade 3 or greater toxicity considered to be related to 
apalutamide that cannot be ameliorated by the use of adequate medical 
intervention should have their treatment interrupted until the toxicity 
improves to a Grade 1or baseline. Patients may subsequently be re-started 
on study drug at a reduced dose as per the discretion of the Principal 
Investigator. If study drug needs to be discontinued for more than 30 days 
due to toxicities, the patient should be discontinued from the study treatment 
phase, all pre-op visit procedures should be followed, and the patient 
scheduled to undergo surgery as soon as recommended by medical team. 
 
Apalutamide Dose Levels 
Dose Level 
Total Daily Dose 
Number of 60 mg Tablets (QD) 
0 
240 mg 
4 
-1 
180 mg 
3 
-2 
120 mg 
2 
 
 
 
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8.1.4. Medications—Drugs and Therapies 
8.1.4.1. 
Medication taken within four weeks prior to treatment initiation must 
be captured in the medical record. All concomitant medications will be 
documented at each visit while patient is taking apalutamide, and at the 
time of early study treatment discontinuation. Only adjuvant/salvage 
therapies will be documented during the follow-up phase of the study. 
Standard concomitant medications associated with surgery and post-op 
care will not need to be captured for the purpose of this study unless it 
is given to treat a reportable AE. 
8.1.4.2. 
No other new systemic therapy or new radiotherapy for treatment of 
prostate cancer is permitted while subject is on the active phase of 
study treatment or prior to surgery. Adjuvant/salvage therapies after 
surgery could be initiated if necessary at the discretion of the treating 
physician. 
8.1.4.3. 
As a class effect, AR antagonists have been associated with 
seizures due to an off-target mechanism of action (gamma amino 
butyric acid chloride channel [GABAA] inhibition). Drugs known to lower 
the seizure threshold or cause seizures are prohibited and a 
representative list is included below.  A medication list review must be 
done by the clinical team if the patient is on medications from the below 
class list:  
• Atypical antipsychotics (e.g. clozapine, olanzapine, risperidone, 
ziprasidone) 
• Bupropion 
• Lithium 
• Meperedine and pethidine 
• Phenothiazine antipsychotics (eg, chlorpromazine, mesoridazine, 
thioridazine) 
• Tricyclic antidepressants (eg, amitriptyline, desipramine, 
doxepin, imipramine, maprotiline, mirtazapine. 
 
8.1.4.4. 
Medications/Supplements, which are NOT RECOMMENDED while 
on study (monitor for increased toxicity/potential drug interactions): 
 
• Apalutamide (and its main metabolite, ARN000308) are 
metabolized primarily by human CYP3A4 or CYP2C8, thus co-
administration with any of the following agents has the potential 
to affect the PK of apalutamide and alternative therapies should 
be used when available: 
o Strong CYP3A4 inhibitors: itraconazole, clarithromycin, 
erythromycin, diltiazem, verapamil, delavirdine, 
atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, 
saquinavir, telithromycin, voriconazole, grapefruit; co-
administration with any of these agents may increase 
apalutamide plasma concentrations 
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o Strong CYP3A4 inducers: phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentin, phenobarbital, efavirenz, 
tipranivir, St. John's wort; co-administration with any of 
these agents may decrease apalutamide plasma 
concentrations 
o Strong CYP2C8 inducers: rifampin 
o Apalutamide may also induce CYP3A4; therefore, caution should 
be taken when administered in conjunction with CYP3A4 
substrates that have a narrow therapeutic index 
o Apalutamide may also induce other PXR-regulated enzymes and 
transporters such as CYP2C8, CYP2C9, CYP2C19, UDP 
glucuronosyl transferase (UGT), and P-glycoprotein. 
Coadministration of apalutamide withsubstrates of CYP3A4, 
CYP2B6 (eg, efavirenz, bupropion), CYP2C8 (eg, repaglinide, 
pioglitazone), CYP2C9 (eg, warfarin, tolbutamide), CYP2C19 
(eg, omeprazole, lansoprazole), UGT (eg, levothyroxine, valproic 
acid) and P-glycoprotein (eg, digoxin, dabigatran etexilate, 
colchicine) may result in decreased concentrations and loss of 
efficacy. 
o The potential for drug-drug interaction between apalutamide and 
warfarin (e.g., Coumadin) is unknown at present. If a patient is 
taking warfarin, re-assess PT/INR as clinically indicated and 
adjust the dose of warfarin accordingly. 
o Due to possible resistance mechanisms which may be 
contributed by glucocorticoid receptor signaling, concurrent use 
of corticosteroids during the study is not recommended; short 
term use (≤ 4 weeks) will be allowed if clinically indicated, 
however, its use must be tapered off as soon as possible. 
o Avoid pomegranate 
 
Reference for a comprehensive list of potential drug to drug 
interactions: 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
 
8.1.4.5. 
Treatment Compliance: Study drug accountability will be performed 
to document compliance with the dosing regimen. Subjects will be 
asked to bring back all remaining study drug at each study visit for drug 
accountability. 
 
8.1.4.6. 
Emergency Procedures and Overdose: There is no specific 
antidote for an overdose of apalutamide. Patients who develop adverse 
reactions from a suspected overdose should receive appropriate 
symptomatic treatment. 
 
 
 
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8.2. 
ADVERSE EVENTS 
 
Timely, accurate, and complete reporting and analysis of safety information from 
clinical studies are crucial for the protection of subjects, investigators, and the 
sponsor, and are mandated by regulatory agencies worldwide.  
 
8.2.1. Adverse Event Definitions and Classifications 
 
Adverse Event 
 
Adverse Event (AE) – Any untoward or unfavorable medical occurrence in a 
human subject, including any abnormal sign (for example, abnormal physical exam 
or laboratory finding), symptom, or disease, temporally associated with the 
subject’s participation in the research, whether or not considered related to the 
subject’s participation in the research in which a subject is administered a 
medicinal (investigational or non-investigational) product.  An adverse event does 
not necessarily have a causal relationship with the treatment. 
 
This includes any occurrence that is new in onset or aggravated in severity or 
frequency from the baseline condition, or abnormal results of diagnostic 
procedures, including laboratory test abnormalities. 
 
 Expected AE - Any AE with specificity or severity that is consistent with the current 
Investigator Brochure (IB) or consistent with the risk information described in the 
Informed Consent Document (ICD) or general investigational plan.  
 
 
Serious Adverse Event 
 
Serious Adverse Event (SAE) – Any AE associated with the subject’s participation 
in research that:   
• results in death;  
• is life-threatening, (places the subject at immediate risk of death from the event 
as it occurred). An adverse event or suspected adverse reaction is considered 
‘‘life-threatening’’ if, in the view of Principal Investigator, its occurrence places 
the patient or subject at immediate risk of death. It does not include an adverse 
event or suspected adverse reaction that, had it occurred in a more severe 
form, might have caused death; 
• results in inpatient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability/incapacity;  
• is a suspected transmission of any infectious agent via a medicinal product 
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• results in a congenital anomaly/birth defect; or 
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
o Important medical events as defined above may also be considered serious 
adverse events. Any important medical event can and should be reported as 
an SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, 
the IND Office. 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS 
ADVERSE EVENT. 
 
Hospitalization 
 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization that is the serious event for which details must be provided. 
 
Any event requiring hospitalization or prolongation of hospitalization that occurs during 
the study must be reported as a serious adverse event, except hospitalizations for the 
following: 
• Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term care facility) 
• Surgery or procedure planned before entry into the study. [Note: 
Hospitalizations that were planned before the start of data collection and 
where the underlying condition for which the hospitalization was planned has 
not worsened will not be considered serious adverse events. Any adverse 
event that results in a prolongation of the originally planned hospitalization is 
to be reported as a new serious adverse event.] 
 
 
Life-Threatening Conditions 
 
Disease progression should not be recorded as an adverse event or serious 
adverse event term; instead, signs and symptoms of clinical sequelae resulting 
from disease progression/lack of efficacy will be reported if they fulfill the serious 
adverse event definition. 
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Unexpected (Unanticipated) AE - Any AE, with specificity or severity that is not 
consistent with the current IB, or the applicable product reference safety 
information, or not consistent with the risk information described in the informed 
consent document or general investigational plan. 
 
8.2.2. Attribution Definitions 
 
The following classification will be used to determine whether an AE is related to 
the study drug, CT-011:  
• Definite - It is clearly related  
• Probable - It is likely related  
• Possible - It may be related  
• Unlikely - It is doubtfully related  
• Unrelated - It is clearly NOT related  
 
Definitely related – Events directly or indirectly attributed to study drug, and/or 
study participation. Events occurring with sufficient frequency to suggest that they 
are not random. The event follows a temporal sequence from the time of drug 
administration and follows a known response pattern to the study drug.  It occurs 
immediately following the study drug administration, improves on stopping the 
drug, or reappears on repeat exposure. 
 
Probably related – The event follows a reasonable temporal sequence from the 
time of drug administration, and follows a known response pattern to the study 
drug and cannot be reasonably explained by other factors. There is a reasonable 
response to withdrawal of the drug. Rechallenge information is not available or 
advisable. 
 
Possibly related – The event has a reasonable temporal relationship to the study 
drug administration and follows a known response pattern to the study drug.  
However, a potential alternate etiology may be responsible for the event. The effect 
of drug withdrawal is unclear. Rechallenge information is unclear or lacking. 
 
Unlikely – The adverse event is doubtfully related to the investigational agent. 
 
Unrelated – Events that would occur regardless of study participation, including 
events that are clearly random occurrences. If the frequency of the event suggests 
a possible connection to the study intervention, then it should be considered 
related. If the event is clearly related to other factors, such as a patient's clinical 
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state, therapeutic interventions, or concomitant medications, the event would be 
considered unrelated to therapy. 
 
 
 
8.2.3. Special Reporting Situations 
 
When a report contains a Janssen product, an identifiable patient, and identifiable 
reporter, the following events represent Special Reporting Situations: 
• 
Drug exposure during pregnancy (maternal and paternal) 
• 
overdose of a Janssen medicinal product  
• 
pregnancy exposure (maternal and paternal) 
• 
exposure to a Janssen medicinal product from breastfeeding  
• 
suspected abuse/misuse of a medicinal Janssen product 
• 
inadvertent or accidental exposure to a medicinal Janssen medicinal product  
• 
any failure of expected pharmacological action (i.e., lack of effect) of a Janssen 
medicinal product 
• 
unexpected therapeutic or clinical benefit from use of a Janssen medicinal 
product 
• 
medication error involving a Janssen product (with or without patient exposure 
to the medicinal Johnson & Johnson product, e.g., name confusion) 
• 
suspected transmission of any infectious agent via a medicinal product. 
 
These safety events may not meet the definition of an adverse event; however, from 
Janssen Scientific Affairs, LLC perspective, they are treated in the same manner as 
adverse events. Special situations should be recorded on the Adverse Event page of 
the Department of Urology database. 
 
Any special situation that meets the criteria of a serious adverse event should be 
recorded on a Serious Adverse Event Report Form and be reported to Janssen 
Scientific Affairs, LLC within 24 hours of becoming aware of the event. 
 
8.2.4. Adverse Events Reporting 
 
All Adverse Events 
 
General guidelines – Toxicity will be scored using CTC AE Version 4.0 for toxicity 
and adverse event reporting. A copy of the CTCAE Version 4.0 can be downloaded 
from the CTEP homepage (http://ctep.info.nih.gov). All appropriate treatment 
areas should have access to a copy of the CTC AE Version 4.0. All adverse clinical 
experiences must be recorded according to the table “Recommended Adverse 
Events Recording Guidelines”, after they were documented in the treating 
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physician’s clinic note, utilizing the NCI CTC v 4.0 to determine terminology and 
grade. Adverse events will be recorded following the first exposure to study drug 
until 30 days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. For discontinued patients, follow 
up on serious adverse events will be conducted up to 30 days from last treatment 
of study drug. 
 
 
When an adverse event occurs, the following information and assessments should 
be recorded: 
i) 
The signs, symptoms, or diagnosis of the event. 
ii) 
The date of the event. 
iii) 
The adverse event severity, using the criteria outlined above. 
iv) 
The relationship of the event to the study drug as outlined above. 
v) 
The description of any action taken regarding study drug disposition. 
vi) 
Any required therapy, medication, treatment, or diagnostic procedure. 
 
The Principal Investigator (PI) or physician designee is responsible for the 
appropriate medical management of all adverse events. The PI or physician 
designee must evaluate each adverse experience for its seriousness and 
determine attribution to study drug. 
 
The investigator must appraise all abnormal laboratory results for their clinical 
significance. If any abnormal laboratory result is considered clinically significant, 
the investigator must provide details about the action taken with respect to the test 
drug and about the patient’s outcome. 
 
The investigator must appraise all evaluation test results for their clinical 
significance. If any abnormal evaluation test result is considered clinically 
significant, the investigator must provide details about the action taken with 
respect to the test drug and about the patient’s outcome.  Any evaluation test that 
is not considered clinically significant will not be captured as an adverse event 
(AE). 
 
Serious Adverse Events 
 
All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
Institutional Review Board Policy for Investigators on Reporting Unanticipated 
Adverse Events for Drugs and Devices”. Unless stated otherwise in the protocol, 
all SAEs, expected or unexpected, must be reported to the IND Office, 
regardless of attribution (within 5 working days of knowledge of the event). 
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All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next working 
day) of knowledge of the event to the Safety Project Manager in the IND Office.  
 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB.  
 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical 
recovery is complete and laboratory tests have returned to baseline, progression 
of the event has stabilized, or there has been acceptable resolution of the event.  
Additionally, any serious adverse events that occur after the 30 day time period 
that are related to the study treatment must be reported to the IND Office. This 
may include the development of a secondary malignancy. 
 
 
Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, 
and Institutional Review Board policy. 
 
Maintenance of Safety Information: 
 
Safety information will be maintained in a clinical database/repository in a 
retrievable format. At a minimum, at the end of the treatment phase (=”last patient 
off treatment”) as well as the end of the follow-up phase (=”last patient out”) of the 
Study, the Principal Investigator shall provide all adverse events, both serious and 
non-serious, in report format. However, in certain circumstances more frequent 
review of the safety data may be necessary, e/g/ to fulfill a regulatory request, and 
as such the data shall be made available within a reasonable timeframe at Janssen 
Scientific Affairs’ request. 
 
 
Individual Case Safety Report (ICSR) 
 
A valid ICSR must contain the four minimum criteria required to meet regulatory 
reporting requirements. 
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• an identifiable subject (but not disclosing personal 
information such as the subject’s name, initials or 
address) 
• an identifiable reporter (investigational site) 
• a Janssen medicinal product 
• an adverse event, outcome, or certain special situations 
 
The minimum information required is: 
• suspected Janssen medicinal product (doses, indication) 
• date of therapy (start and end date, if available) 
• batch or lot number, if available 
• subject details (subject ID and country) 
• gender 
• age at AE onset 
• reporter ID 
• adverse event detail (AE verbatim in English), onset date, relatedness, 
causality, action taken, outcome, (if available) 
• Janssen protocol ID 
 
Product Quality Complaint (PQC) 
 
A product quality compliant is defined as any suspicion of a product defect 
related to a potential quality issue during manufacturing, packaging, release 
testing, stability monitoring, dose preparation, storage or distribution of the 
product, or delivery system.  Not all PQCs involve a subject.  Lot and batch 
numbers are of high significance and need to be collected whenever available. 
 
Examples of PQC include but not limited to: 
• Functional Problem: e.g., altered delivery rate in a controlled release 
product 
• Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
• Potential Dosing Device Malfunction: e.g.,  autoinjector button not working, 
needle detaching from syringe 
• Suspected Contamination 
• Suspected Counterfeit 
 
Procedures for Reporting Safety Data and Product Quality Complaints 
(PQCs) for Janssen Medicinal Products to Janssen Scientific Affairs, LLC 
 
All adverse events and special situations, whether serious or non-serious, related 
or not related, following exposure to a Janssen medicinal product are to be 
documented by the investigator and recorded in the Department of Urology 
database and in the subject’s source records. Investigators must record in the 
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Department of Urology database (REDCap) their opinion concerning the 
relationship of the adverse event to a Janssen medicinal product.  
All (serious and non-serious) adverse events reported for a Janssen medicinal 
product should be followed-up in accordance with clinical practice. 
 
SAEs and Special Reporting Situations 
 
All serious adverse events that have not resolved by the end of the study, or that 
have not resolved upon discontinuation of the subject's participation in the study, 
must be followed until any of the following occurs: 
• The event resolves 
• The event stabilizes 
• The event returns to baseline, if a baseline value/status is available 
• The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct 
• It becomes unlikely that any additional information can be obtained (subject or 
health care practitioner refusal to provide additional information, lost to follow-
up after demonstration of due diligence with follow-up efforts) 
 
The PRINCIPAL INVESTIGATOR will transmit all SAEs and special situations 
following exposure to a Janssen product under study in a form provided by 
Janssen Scientific Affairs, LLC in accordance with an acceptable transmission 
method, in English within 24-hours of becoming aware of the event(s). 
 
 
All follow-up information for serious adverse events that are not resolved at the 
end of the study or by the time of patient withdrawal must be reported directly by 
the PRINCIPAL INVESTIGATOR, within 24 hours becoming aware, to 
Janssen Scientific Affairs, LLC using the Janssen/MedWatch ’s Serious Adverse 
Event Form  
 
All available clinical information relevant to the evaluation of a related SAE, 
serious ADR or special situation is required. 
 
• The PRINCIPAL INVESTIGATOR is responsible for ensuring that these 
cases are complete and if not are promptly followed-up. A safety report is not 
considered complete until all clinical details needed to interpret the case are 
received. Reporting of follow-up information should follow the same timeline 
as initial reports. 
 
• Copies of any and all relevant correspondences with regulatory authorities 
and ethics committees regarding any and all serious adverse events, 
irrespective of association with the Janssen Product under study, are to be 
provided to Janssen Scientific Affairs, LLC using an acceptable transmission 
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method within 24 hours of such report or correspondence being sent to 
applicable health authorities. 
 
PQC Reporting 
 
A PQC may have an impact on the safety and efficacy of the product. Timely, 
accurate, and complete reporting and analysis of PQC information from studies 
are crucial for the protection of patients, investigators, and Janssen Scientific 
Affairs, LLC, and are mandated by regulatory agencies worldwide. Janssen 
Scientific Affairs, LLC has established procedures in conformity with regulatory 
requirements worldwide to ensure appropriate reporting of PQC information. Lot 
and/or Batch #s shall be collected or any reports failure of expected 
pharmacological action (i.e., lack of effect). The product should be quarantined 
immediately and if possible, take a picture. 
 
All initial PQCs involving a Janssen medicinal product under study must be 
reported to Janssen Scientific Affairs, LLC by the PRINCIPAL INVESTIGATOR 
within 24 hours after being made aware of the event. The Janssen contact 
will provide additional information/form to be completed. 
 
If the defect for a Janssen medicinal product under study is combined with either 
a serious adverse event or non-serious adverse event, the PRINCIPAL 
INVESTIGATOR must report the PQC to Janssen Scientific Affairs, LLC 
according to the serious adverse event reporting timelines.  A sample of the 
suspected product should be maintained for further investigation if requested by 
Janssen Scientific Affairs, LLC.  
 
Pregnancy 
 
All initial reports of pregnancy must be reported to Janssen Scientific Affairs by the 
study-site personnel within 24 hours of their knowledge of the event. Abnormal 
pregnancy outcomes (eg, spontaneous abortion, stillbirth, and congenital 
anomaly) are considered serious adverse events and must be reported as a 
Serious Adverse Event.  
 
Because the effect of the study drug on sperm is unknown, pregnancies in partners 
of male subjects included in the study will be reported by the study-site personnel 
within 24 hours of their knowledge of the event.  
 
Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required. 
 
Transmission Methods 
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The following methods are acceptable for transmission of safety information to 
Janssen Scientific Affairs, LLC: 
• Electronically via Janssen SECURE Email service (preferred) - RA-OMPUS-
COBS_Cen_E@its.jnj.com 
 
Please use the contact information and process information provided by Janssen.  
 
 
Abnormal Laboratory Results 
 
The criteria for determining whether an abnormal laboratory test result should be 
reported as an adverse event are as follows: 
 
1. Test result is associated with accompanying symptoms, and/or 
2. Test result requires additional diagnostic testing or medical/surgical 
intervention (merely repeating an abnormal test, in the absence of any of the 
above conditions, does not meet criteria for reporting and an AE), and/or 
3. Test result leads to a change in study dosing or death from the study, 
significant additional concomitant drug treatment or other therapy, and/or 
4. Test result leads to any of the outcomes included in the definition of a serious 
adverse event, and/or 
5. Test result is considered to be an adverse event by the investigator 
 
Any abnormal test result that is determined to be an error does not require 
reporting as an adverse event, even if it did meet one of the above conditions 
except for condition #4. Clinically significant laboratory results must be recorded 
in the Department of Urology database. 
 
Dose Modification/Toxicity Management 
 
Subjects who experience a Grade 3 or greater toxicity considered to be related to 
apalutamide that cannot be ameliorated by the use of adequate medical 
intervention should have their treatment interrupted until the toxicity improves to 
a Grade 1 or baseline. Subjects may subsequently be re-started on study drug at 
a reduced dose follow a discussion between the Principal Investigator.  Dose 
modifications are provided as guidance and should not replace the investigator’s 
own clinical judgment. 
 
 
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Toxicity 
Dose of JNJ-56021927 (assuming 240 mg/day dosing) 
Grade 1 or 2 
If a Grade 2 Toxicity has not resolved to Grade≤1 after 30 
days, study drug will be discontinued.  For all other Grade 
1 or 2 Toxicities there will be no change. 
(First Occurence) 
≥Grade 3  
Hold until Grade 1 or baseline, resume at full dose 
First Recurrence ≥Grade 3 
Hold until Grade 1 or baseline, resume at 180 mg (3 
tablets)  
Second Recurrence ≥Grade 3 
Hold until Grade 1 or baseline, resume at 120 mg (2 
tablets) 
Third Recurrence ≥Grade 3 
Discontinue 
First occurrence of seizure of any grade 
or Grade 4 neurotoxicity 
Discontinue 
 
 
Rash 
Dose modifications for rash are allowed only for apalutamide and are summarized in below table. 
If the skin rash has any component of desquamation, mucosal involvement, or pustules, stop 
dosing with apalutamide, refer to dermatologist for evaluation, and a skin biopsy is 
recommended (in addition to the interventions listed in below Table) If the skin rash is Grade 3 or higher, 
asking the subject to consent to documentation by a photograph and further evaluation by a dermatologist 
should also be considered. 
 
 
Severity 
Intervention 
Grade 1 
• 
Continue apalutamide at current dose 
• 
Initiate dermatological treatmenta 
o 
Topical steroid cream AND 
o 
Oral Antihistamines 
• 
Monitor for change in severitya 
Grade 2 (or symptomatic 
Grade 1)b 
• 
Hold apalutamide for up to 28 days 
• 
Initiate dermatological treatmenta 
o 
Topical steroid cream AND 
o 
Oral Antihistamines 
• 
Monitor for change in severitya 
o 
If 
rash 
or 
related 
symptoms 
improve, 
reinitiate 
apalutamide when rash is Grade≤1. Consider dose 
reduction at a 1 dose level reductionc. 
Grade ≥3d 
• 
Hold apalutamide for up to 28 days 
• 
Initiate dermatological treatmenta 
o 
Topical steroid cream AND 
o 
Oral Antihistamines AND 
o 
Consider short course of oral steroids 
• 
Reassess after 2 weeks (by site staff), and if the rash is the same 
or has worsened, initiate oral steroids (if not already done) and 
refer the subject to a dermatologist 
o 
Reinitiate apalutamide at a 1 dose level reductione when 
rash is Grade≤1. 
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o 
If the dose reduction will lead to a dose less than 120mg, 
the study drug must be stopped (discontinued) 
• 
If after 28 days, rash has not resolved to Grade≤1, contact 
Janssen 
to 
discuss 
further 
management 
and 
possible 
discontinuation of study drug.  
 
Note: Rash may be graded differently according to the type of rash and associated symptoms. For 
example, maculo-papular rash is graded by body surface area covered and not severity of the rash. 
Please consult NCI-CTCAE Version 4.03 for specific grading criteria for other types of rash. 
a Obtain bacterial/viral cultures if infection is suspected 
b Subject presents with other rash related symptoms such as pruritus, stinging, or burning 
c 1 dose level reduction = 60mg (1 apalutamide tablet) 
d If there is blistering or mucosal involvement, stop apalutamide dosing immediately and contact 
Janssen 
e If a subject previously started oral corticosteroids, continue for at least 1 week after resumption 
of reduced dose of apalutamide. If the proposed total oral steroid use will exceed 28 days, 
contact Janssen. 
 
Criteria for Discontinuation of Study Treatment 
 
To discontinue Study Treatment, either of the criteria below must be met: 
• 
The patient completed 24 weeks of study treatment; 
• 
Patients who fail to reach a 50% decrease in PSA or demonstrate suspicious 
changes in DRE at mid-way evaluation (week 9);  
• 
Sustained side effects: patients who have sustained toxicities, such as 
hyperglycemia or hypertension that do not return to NCI CTCAE (version 4.0) 
grade 1 or less within 30 days despite appropriate medical management, 
should be discontinued from the study treatment phase. All end-of-study 
treatment procedures should be conducted. The patient will be followed to the 
pre-op visit; 
• 
Dosing noncompliance: study treatment administration and dosing 
compliance will be assessed on Day 1 of all cycles, and at Pre-surgery/End of 
Treatment Visit. A count of study treatment will be conducted during this visit 
and patient dosing compliance will be assessed. If dosing compliance is not 
>75% in the absence of toxicity, patient should be re-instructed regarding 
proper dosing procedures and continue in the protocol. Subsequent dosing 
compliance procedure will be conducted at each study visit. If a patient 
misses 14 or more doses within 4 weeks, the patient should be discontinued 
from the study treatment phase. All end-of-study treatment procedures should 
be followed. The patient will be followed to the pre-op visit 
• 
Initiation of new anticancer treatment: patients will be discontinued from the 
study treatment when investigator, in his or her judgment, determines new 
treatment for prostate cancer is warranted. All end-of-study treatment 
procedures should be conducted and the patient will be followed to the preo-
op visit 
• 
Administration of prohibited medications: the patient will be discontinued from 
the protocol treatment when prohibited drug is administered (Section 8.1.4.3). 
All end-of-study treatment procedures should be conducted and the patient 
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will be followed to the pre-op visit. Supportive care medications are permitted 
with their use following institutional guidelines. The concurrent administration 
of other anticancer therapy, including cytotoxic, hormonal (except LHRHa), or 
immunotherapy is prohibited during study treatment phase. Use of other 
investigational drug therapy for any reason is prohibited 
• 
Patient met Grade 4 criteria for elevated Liver Function Tests or the criteria 
for dose discontinuation of non-mineralocorticoid based side effects. 
• 
Subjects experiencing toxicity considered to be related to the use of for which 
more than two dose reductions areneeded will require discontinuation of 
study drugs. 
 
Withdrawal from Study 
 
An investigator may withdraw a patient from the study at any time based on 
clinical judgment or if a patient withdraws consent. In this event, the reason(s) for 
withdrawal must be documented and clarification if withdrawal of consent 
includes Post-Radical Prostatectomy Evaluation data collection. A patient’s 
decision to take part in the study is voluntary and he may choose not to take part 
in the study or to stop taking part at any time. If he chooses not to take part or to 
stop at any time, it will not affect his future medical care or medical benefits. A 
patient may withdraw from study treatment phase for any reason. In general, 
subjects who withdraw will not be replaced unless the number of completed 
subjects falls below the estimated sample size required to provide the desired 
precision. 
 
 
Radical Prostatectomy 
 
Within 2 weeks of stopping apalutamide, patients will undergo planned radical 
prostatectomy.  The surgical access is per the attending surgeon discretion such 
as open or robot-assisted.  The extent of primary surgery such as 
inclusion/exclusion of the neurovascular bundles and bladder neck is per 
attending surgeon discretion.  The seminal vesicles should be completely 
removed if possible.  The lymph node dissection should attempt to consist of an 
extended template, specifically: a) obturator fossa, b) external iliac from the 
medial aspect of the external iliac artery and clearing the triangular space at the 
junction of the external and internal arteries, c) hypogastric artery to include a 
continuation of the obturator fossa beneath the obturator nerve.  The protocol 
does not require the surgeon to deviate from his/her common practice and 
judgment in the event unexpected grossly enlarged lymph nodes are 
encountered. 
 
9. CORRELATIVE STUDIES 
 
The specimens collected in the context of this protocol are blood and tissue. These will 
be stored in a manner that will allow us to address the secondary aims in this protocol. 
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Any future additional analyses not specified in this protocol will be agreed upon by prior 
approval from Janssen Scientific Affairs, LLC.   
 
All specimens will be prospectively encoded with de-linked numbers such that the 
receiving lab will not have access to patient identifiers. Investigators involved in this 
project will ensure confidentiality of patients by restricting access to the GU Research 
Laboratory database in which the unique identification numbers cross-referenced to the 
MDACC patient medical record number will be kept. Clinical information will be 
accessed by investigators using the institutional electronic medical record, which stores 
clinical information and care reports of patients who are being treated at MDACC. 
Access to the MDACC electronic medical record is restricted with a security password. 
Any individual patient's information will not be reused or disclosed to any other person 
or entity, or for other research. All requests for use of this material must be in the 
context of IRB approved protocols.   
 
Caveolin-1 (Cav-1), a major structural component of caveolae, is secreted by prostate 
cancer cells and associated with malignant progression through multiple mechanisms 
and signaling pathways (Thompson TC et al. Prostate Cancer Prostatic Dis 13:6, 2010). 
We have shown that Cav-1 is implicated in the transition from high-grade prostatic 
epithelial neoplasia to prostate cancer through c-Myc regulation and Akt signaling 
induction (Yang G et al. Mol Cancer Res 10:218, 2012). Other studies show that Cav-1 
levels rise during prostate cancer progression and mediate resistance to hormone 
therapy (Nasu et al. Nat Med 4:1062, 1998, Karantanos T et al. Oncotarget 7: No. 29, 
2016) by inducing glycolytic activities in prostate cancer cells and promoting hormone 
resistance under androgen deprivation through upregulation of acetyl-CoA carboxylase 
1 and fatty acid synthase (Karantanos T et al. Oncotarget 7: No. 29, 2016, Tahir SA et 
al. Cancer Res 73:1900, 2013). Finally, investigations show serum Cav-1 associated 
with high-risk prostate cancer (Gumulec J et al. Oncol Rep 27:831, 2012); biochemical 
recurrence after prostatectomy (Tahir SA et al. Clin Cancer Res 12:4872, 2006); and, 
when levels are high, with castration-resistant prostate cancer rather than with 
hormone-naive disease (Sugie S et al. Anticancer Res 33, 1893, 2013). 
 
Sample Logistics 
Prostatectomy tissue from surgery follows standard pathology procedures including 
room temperature transportation to pathology (attached to MDACC OR) for fresh cut by 
GU pathologist.  Serum samples drawn in the clinic will be transported by MDACC 
clinical research staff to the Eckstein lab—Mays Clinic, 7th floor, MDACC inside GU 
medical oncology clinic. Blood will be stored in the Eckstein lab; and tissue in Alexander 
lab, Tan zone on MDACC main campus.  Samples will be stored approximately for 10 
years after following protocol completion.    
 
 
9.1 Biomarker Plan 
 
A. Blood and Derivatives  
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1. Blood (PAXgene) will be collected from all subjects at time points indicated in the 
T&E schedule to assess mRNA for ARv7 and other high risk molecular markers 
such as SRD5A1, FOXA1, HOXB13, KLK3 (Labcorp) 
2. Blood will be collected for assessment of germline DNA repair gene mutations 
(Futreal Lab – MDACC)  
3. Plasma will be collected for CAV-1 assessment at pretreatment and prespecified 
timepoints (Thompson Lab- MDACC)  
B.   Formalin-fixed paraffin-embedded (FFPE) tumor blocks or tumor slides from 
biopsy and radical prostectomy specimens will be collected from all subjects in this 
study to evaluate expression of markers using prespecified methods: Radical 
Prostatectomy specimens will be also employed.  
1. A custom mRNA panel includes markers previously identified as markers 
predictive of response to abiraterone acetate in AA-302 study (Ricci D. 2014 
ASCO). This will be conducted on pretreatment specimens (biopsies) (Labcorp) 
2. Protein assessment of markers of interest by  immunohistochemistry (IHC) These 
markers include but will not be limited to the following: AR-N, AR (C19), AR-V7, 
PSA-GR, Ki67, p-cMET, pSrc, CD56, Chromogranin A, NKX3.1, Rb p53, ATM, 
PTEN, and immune markers. Additional markers assessment will be assessed 
based on available data and findings at the time of analysis and will be dependent 
on tissue availability.  Protein assessment will be performed both on biopsy and 
radical prostatectomy specimens based on availability (Alexander Lab – MDACC) 
3. DNA sequencing will be performed for assessment of somatic DNA repair gene 
alterations. This will be conducted on pretreatment specimens unless unavailable 
in which case radical prostatectomy specimens will be used (Alexander /Futreal 
Labs-MDACC). 
 
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