Clinical trial NCT03093272
Conditions: Prostate Cancer
Keywords: Prostate Cancer
Sponsor: Dana-Farber Cancer Institute
Start date: 2017-06-23; Completion date: 2019-12-31
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying a combination of drugs as a possible treatment for castration-resistant prostate cancer.

The interventions involved in this study are:

* Docetaxel (a type of chemotherapy)
* Apalutamide (the study medication, also known as ARN-509)
* Prednisone (a corticosteroid given to prevent reactions to docetaxel).
* Leuprolide acetate (also known as Lupron, a GnRH agonist or similar drug which is standard of care, causes chemical castration which greatly lowers the level of testosterone in the body)

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

Apalutamide is considered an investigational product, which is believed to reduce the growth of prostate cancer cells. The FDA (the U.S. Food and Drug Administration) has not approved apalutamide as a treatment for any disease, but it is being studied in prostate cancer. Docetaxel is an approved therapy for this type of cancer. The FDA has not approved the combination of the two drugs in any use.

In this research study, the investigators are evaluating the combination of two drugs, docetaxel with apalutamide. The investigators will keep track of participants' prostate-specific antigen (PSA), scans, and overall health to determine how well this drug combination works at treating this type of cancer.

Arms: arm 1: * Apalutamide (ARN-509) will be taken orally at home daily
* Docetaxel will be administered every 3 weeks intravenously
* Prednisone will be taken orally twice daily
* Leuprolide Acetate will be administered at the specification of the physician
Interventions: intervention 1: Leuprolide Acetate intervention 2: Prednisone intervention 3: Docetaxel intervention 4: Apalutamide
Intervention descriptions: intervention 1: a GnRH agonist intervention 2: Prednisone is a corticosteroid intervention 3: Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. intervention 4: The apalutamide drug substance is an almost white to slightly brown powder. The tablet formulation of apalutamide is an immediate release oral tablet containing 60-mg of drug substance, with a non-functional green film coat

Protocol documents:
Prot_SAP_000.pdf: 
Title: A Phase 2 Study of Docetaxel plus Apalutamide in Castration-Resistant Prostate 
Cancer Patients Post Abiraterone Acetate 
 
 
NCT Number: NCT03093272    
 
 
 
IRB Approval Date: 16-Jan-2017 
 


 
Page 1 
 
DF/HCC Protocol #: 16-485  
 
TITLE: A Phase 2 Study of Docetaxel plus Apalutamide in Castration-Resistant Prostate 
Cancer Patients Post Abiraterone Acetate 
 
Coordinating Center/Sponsor:  
Dana-Farber Cancer Institute 
 
 
Principal Investigators (PI): 
 
Lauren C. Harshman, MD 
 
 
Dana-Farber Cancer Institute 
 
 
The Lank Center for Genitourinary Oncology 
 
450 Brookline Ave, DANA 1230 
 
Boston, MA 02215 
 
Phone: 617-632-2429 
 
Fax: 617-632-2165 
 
 
 
LaurenC_Harshman@dfci.harvard.edu 
 
Co-principal investigator 
 
Christopher J. Sweeney, MBBS  
 
Other Investigators: 
 
Mary-Ellen Taplin, MD  
 
 
Jeffrey G. Supko, PhD 
 
Statistician: 
 
P. Kathryn Gray, PhD 
 
 
Department of Biostatistics and Computational Biology 
 
 
Dana Farber Cancer Institute 
 
 
Harvard School of Public Health 
 
 
450 Brookline Ave., CLSB-11047 Boston, MA 02215  
 
 
Phone: 617-582-7145  
 
 
Fax: 617-632-5444 
 
 
 
 
Drug Support & Funding:   
 
Janssen Scientific Affairs, LLC 
 
 
 
Agents: 
Apalutamide: Supplied by Janssen Research & Development, LLC 
Docetaxel: Commercial Supply 
Prednisone: Commercial Supply 
GnRH antagonist or agonist: Commercial Supply 
 
 
 
IND #: 130853 
IND Sponsor: Lauren C. Harshman, MD 
 


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SCHEMA 
 
 
Safety Lead In Phase  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Cycle: 21 days +/- 3 days. 
Start at 
dose level 1 
Treat cohort 
(3 participants) 
Number 
of DLTs 
Halt accrual. 
Review toxicities 
to assess for 
need to start 
apalutamide at 
lower dose 
going forward 
Recruit 3 more 
participants 
Further 
DLTs? 
Complete 
accrual of 33 
total patients 
≥ 2 of 6 with 
DLTs 
No 
<1 
2 or 3 
Halt accrual. 
Review toxicities 
to assess for 
need to start 
apalutamide at 
lower dose 
going forward 


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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Study Design ............................................................................................................6 
1.2 
Primary Objectives...................................................................................................6 
1.3 
Secondary Objectives...............................................................................................6 
1.4 
Exploratory Objectives ............................................................................................6 
2. 
BACKGROUND .................................................................................................................6 
2.1 
Study Disease(s).......................................................................................................6 
 
 
2.3 
Rationale ................................................................................................................13 
2.4 
Correlative Studies Background ............................................................................13 
3. 
PARTICIPANT SELECTION ...........................................................................................13 
3.1 
Inclusion Criteria ...................................................................................................13 
3.2 
Exclusion Criteria ..................................................................................................14 
3.3 
Inclusion of Women and Minorities ......................................................................16 
4. 
REGISTRATION PROCEDURES ...................................................................................16 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...................................16 
4.2 
Registration Process for DF/HCC Institutions .......................................................16 
5. 
TREATMENT PLAN ........................................................................................................16 
5.1 
Treatment Regimen ................................................................................................16 
5.2 
Laboratory Studies .................................................................................................17 
5.3 
Agent Administration.............................................................................................18 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................20 
5.5 
Criteria for Taking a Participant Off Protocol Therapy .........................................21 
5.6 
Duration of Follow Up ...........................................................................................22 
5.7 
Criteria for Taking a Participant Off Study ...........................................................22 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................23 
6.1 
Toxicity Management ............................................................................................23 
6.2 
General Guidelines for Dose Modifications and Delays for apalutamide 
and docetaxel .........................................................................................................24 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................33 
 
 
 
7.2 
Expected Adverse Event List for Docetaxel ..........................................................34 
 
 
 
 
 
 
 
 


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7.11 
Adverse Event Characteristics ...............................................................................43 
 
 
7.13 
Expedited Adverse Event Reporting ......................................................................44 
7.14 
Expedited Reporting to the Food and Drug Administration (FDA) ......................44 
7.15 
Expedited Reporting to Hospital Risk Management .............................................44 
7.16 
Routine Adverse Event Reporting .........................................................................44 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................48 
 
 
8.2 
Docetaxel 41 ............................................................................................................50 
8.3 
Prednisone ..............................................................................................................53 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................53 
9.1 
Pharmacokinetic Studies (Supko Laboratory) .......................................................53 
9.2 
Blood Collection for PD assays for Biomarker Testing ........................................56 
10. 
STUDY CALENDAR .......................................................................................................59 
11. 
MEASUREMENT OF EFFECT........................................................................................62 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................62 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................68 
12.1 
Data Reporting .......................................................................................................68 
12.2 
Data Safety Monitoring..........................................................................................68 
13. 
STATISTICAL CONSIDERATIONS...............................................................................69 
13.1 
Study Design/Endpoints.........................................................................................69 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................70 


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13.3 
Definition of Study Population/ Stratification Factors ..........................................71 
13.4 
Interim Monitoring Plan of Safety Lead in Phase .................................................72 
13.5 
Analysis of Primary Endpoints ..............................................................................72 
13.6 
Analysis of Secondary Endpoints ..........................................................................72 
13.7 
Safety Considerations ............................................................................................73 
13.8 
Reporting and Exclusions ......................................................................................73 
 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................75 
APPENDIX B 
INFORMATION ON POSSIBLE DRUG INTERACTIONS ...................76 
Appendix C 
 Prohibited Medications .........................................................................................78 
Appendix D 
PCWG2 Criteria .....................................................................................................80 
 
 
 


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1. OBJECTIVES 
 
1.1 
Study Design 
 
A single arm, open label phase 2 design will evaluate the combination of docetaxel with 
apalutamide (ARN-509). Up to 33 patients with metastatic castration-resistant prostate cancer 
(CRPC) will be enrolled. A 6-patient safety lead in phase will be undertaken prior to open 
enrollment. If 0 to 1 of 6 patients have no dose limiting toxicities (DLTs) as defined in Section 
6.1, the study will open to full enrollment. With 30 evaluable patients, there is a 90% power to 
detect a significant improvement in median progression-free survival (PFS) from 4 months 
(anticipated with docetaxel alone post abiraterone acetate) to 6.5 months with the combination.  
 
1.2 
Primary Objectives 
 
To evaluate progression-free survival on the combination of docetaxel plus apalutamide 
 
1.3 
Secondary Objectives 
 
To assess the following outcomes with the combination of docetaxel plus apalutamide: 
• Safety 
• Tolerability 
• Dose-limiting toxicities in the safety lead in group 
• Evaluate the effect of apalutamide on docetaxel pharmacokinetics 
• Radiologic time to progression (rTTP)  
• Time to disease progression 
• Time to prostate-specific antigen (PSA) progression (TTPP) 
• Time to treatment failure (progression plus intolerability) 
• Objective response rate 
• PSA (biochemical) response 
• Percent change in PSA from baseline 
• Overall survival (OS) 
 
1.4 
Exploratory Objectives 
 
• To assess for changes in efficacy (e.g., PFS, PSA response, OS) in patients based on 
presence or absence of variants of the androgen receptor (AR) as assessed by ctDNA in 
plasma and mRNA by qtPCR in whole blood. 
 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
Castration-resistant prostate cancer is a fatal disease from which nearly 30,000 men die annually 
in the United States.1 Docetaxel has long been the backbone of treatment after initial resistance 
to androgen deprivation therapy with a median OS of 18 months.2 More recently, docetaxel was 


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proven to increase OS when given in combination with androgen deprivation therapy (ADT) at 
the time of diagnosis of hormone-sensitive metastatic prostate cancer, eliciting a greater than 12 
month OS benefit compared to ADT alone (CHAARTED).3 The last several years have 
witnessed significant improvements in our treatment armamentarium for CRPC with the 
introduction of the next generation biosynthesis inhibitor abiraterone acetate and the androgen 
antagonist enzalutamide. Both agents significantly increase progression-free survival (PFS), PSA 
response rates, and overall survival in the chemotherapy naïve and post-chemotherapy settings.4-7 
This efficacy underscores the ongoing dependence on the androgen receptor (AR) pathway 
despite resistance to the first line hormonal blockade.  
 
In the US, almost all CRPC patients will receive abiraterone acetate, enzalutamide, and docetaxel 
at some point during their disease course. Given the easy oral administration and tolerability the 
second line hormonal maneuvers are often prescribed prior to docetaxel. Several retrospective 
series have reported the efficacy results of either abiraterone acetate administered after 
enzalutamide or enzalutamide given after abiraterone acetate and have shown only modest PSA 
and PFS results, when compared to the results leading to approval of either drug. In patients who 
received abiraterone acetate after enzalutamide, PSA responses ranged from 4-8% and PFS from 
2.7 to 3.9 months.8,9 In patients who received enzalutamide after abiraterone acetate, PSA 
responses ranged from 21-28%, and in one study, median PFS was around 3.0 months.10,11 In 
patients treated with both prior docetaxel and abiraterone acetate, median time on enzalutamide 
was 3.2 months with 18% having a PSA response ≥50%.12 Pertinent to this study, several studies 
have retrospectively analyzed the response to docetaxel after abiraterone acetate, with PSA 
declines ≥50% in 26-63%, median time to PSA progression of 4.1-4.6 months, median PFS 3.7-
5.1months, and median OS of 11.7 -12.5 months just over a year.13-18 No abiraterone acetate-
refractory patients responded to docetaxel.  
 
Reasons for these lower responses in the third and fourth line setting are likely the transition to a 
more androgen autonomous disease state and various resistance mechanisms. To investigate this, 
we should consider the recent results of the ECOG led trial, E3805, which showed that docetaxel 
given at the time of starting ADT for metastatic hormone-sensitive prostate cancer (HSPC) 
improved overall survival by 13 months from 44 to 57 months.3 Moreover, for patients with a 
pre-specified definition of high volume disease, the overall survival was further increased from 
32 months to 49 months. It is unknown why docetaxel deployed when the prostate cancer is 
hormone sensitive improves overall survival to such a dramatic degree. Preclinical and clinical 
experience has documented minimal activity of taxane therapy without ADT.19,20  
 
On the other hand, the observations from the preclinical work21 and E3805 showing marked 
activity of ADT with taxane therapy at time of starting ADT suggests concurrent AR inhibition 
may modulate the expression of AR regulated genes, which in turn enhances docetaxel 
sensitivity. One well characterized mechanism of docetaxel resistance in prostate cancer cells is 
up-regulation of transporters which protect the cancer cell by facilitating efflux of docetaxel 
from the cells. Notable preclinical reports include the finding that the ATP-binding cassette 
(ABC) transporter family, ABCB1, was one of the top up-regulated genes in a taxane resistant 
variant of C4-2B22. Knockdown of ABCB1 by shRNA re-sensitized the cells to docetaxel 
treatment. Others have implicated another ABC transporter, BCRP/ABCG2, after they observed 
that expression of Pim-1L and BCRP are upregulated in mitoxantrone and docetaxel-resistant 


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prostate cancer cell lines23. Furthermore, knocking-down Pim-1L blocked multimer formation of 
endogenous BCRP and also re-sensitized the resistant cells to docetaxel. The ATP-cassette 
binding protein 4 (ABCC4) is another transporter implicated in prostate cancer resistance to 
docetaxel preclinically24. The docetaxel-resistant MLL cells had higher levels of ABCC4 than 
the docetaxel sensitive PC3 cells, which had no detectable ABCC4 expression and inhibition of 
ABCC4 resulted in MLL cells becoming sensitive to docetaxel. Based on our RNA Seq data of 
the prostate cancer cell lines we have noted ABCC4 was induced by the androgen, 
dihydrotestosterone (DHT) by more than 2 fold in LNCaP while in LAPC4 we observed 
androgen induced up-regulation of other ABC transporters, ABCC11, ABCC1 and ABCA5. The 
latter adds plausibility to the notion that AR inhibition could decrease the levels and function of 
these transporters in metastatic HSPC and be the basis of the enhanced activity of docetaxel 
when given in conjunction with ADT in metastatic HSPC. 
Another line of evidence suggesting transporters may impact docetaxel activity in prostate cancer 
is germline variants of these efflux genes are associated with improved overall survival when 
patients are treated with docetaxel in CRPC. Specifically, although the mechanism is unclear, 
SNPs in ABCB1 and ABCG2 have been shown to be associated with improved overall survival 
in men with CRPC treated with docetaxel.25,26  
 
AR splice variants such as AR-V7 may play a role in such resistant states. AR-V7 is an AR 
isoform that lacks the ligand binding domain to which abiraterone and enzalutamide bind. 
Patients with this isoform have a constitutively active AR leading to resistance.27 Recent work 
published by Antonarakis et al demonstrated that patients with the AR-V7 isoform measured in 
their circulating tumor cells (CTCs) had resistance to enzalutamide and abiraterone.27 No AR-V7 
positive patients achieved a PSA response to either agent compared to 53% and 68% of AR-V7 
negative patients respectively. Similar significantly improved outcomes were seen in PSA-PFS, 
radiologic PFS, and OS in AR-V7 negative patients compared to those whose CTCs expressed 
the positive variant. 
Another line of evidence linking AR activation with docetaxel activity is the observation that the 
ARv7 splice variant, which lacks the hinge region of the AR does not co-sediment with 
microtubules or coprecipitate with the dynein motor protein. This was associated with the ARv7-
expressing LuCap23.1 tumor xenograft being docetaxel resistant28. In contrast, the microtubule-
interacting splice variant ARv567 is sensitive to taxane-induced microtubule stabilization and the 
ARv567-expressing LuCap86.2 tumor xenografts are sensitive to docetaxel. This body of work 
suggests the interactions between docetaxel, androgen receptor and microtubule proteins are 
inter-related and impact the ability to kill prostate cancer cells. As such the findings of 
concurrent ADT and docetaxel having a profound effect in E3805 may be due to more 
pronounced blockade of AR transportation to nucleus secondary to ADT leading to ligand 
depletion and docetaxel blocking AR transportation. As such, hormone sensitive metastatic 
prostate cancer cells may be more reliant on microtubule mediated trafficking of AR. It is also 
recognized that cancer cell resistance to taxanes can be seen with microtubule mutations 
decreasing affinity for taxanes, which results in less cytotoxicity29,30. The potential for the AR-
docetaxel-microtubule interaction observations being associated with outcomes will be explored 
as part of the exploratory studies detailed below. 


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To support the tenet that AR activation can impact the cytotoxicity of docetaxel we can draw 
from recent work, which has elucidated biological insights as to how AR modulation enhances 
another cytotoxic, radiation. Specifically, ADT plus radiation improves cancer control and 
overall survival when administered to patients with localized disease compared to either alone31-
33. Recent preclinical insights have shown that AR regulated DNA repair genes are decreased 
with AR blockade and that this reduction enhanced radiation sensitivity34,35.  
This body of work adds plausibility that AR modulation may alter genes and enhance activity of 
another cytotoxic agent such as docetaxel. These findings could be relevant to decreasing AR 
signaling with ARN509 plus ADT in the CRPC and hormone sensitive metastatic prostate cancer 
setting.34,35 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.3 
Rationale 
 
To combat potential resistance mechanisms of chemoresistance and AR autonomous clones in 
patients with metastatic CRPC who have received prior abiraterone, we propose to study the 
combination of docetaxel and apalutamide. Because both agents are metabolized (substrates) of 
CYP3A4 and apalutamide may also be an inducer of CYP3A4, we will perform a safety lead in 
phase with a pharmacokinetic evaluation of the two agents.  
 
2.4 
Correlative Studies Background 
 
Preclinical and clinical studies have shown AR targeted therapies are less effective if the AR 
is mutated. For example, enzalutamide was less effective if ARv7 was present in CTCs or if 
mutations in AR DNA were seen in ctDNA from plasma. An alternative strategy to assess the 
presence of AR splice variants is with qtPCR of whole blood. As such, we will assess the 
efficacy of docetaxel with apalutamide by assessing PFS, PSA response and OS in patients 
with and without evidence of variants of the AR as assessed by ctDNA in plasma and mRNA 
by qtPCR in whole blood. We anticipate the use of a cytotoxic chemotherapy in combination 
with AR targeting will address clones both responsive to AR inhibition and not responsive to 
AR inhibition and that the efficacy outcomes will be better for the combination in patients 
with variants of the AR receptor treated with the combination than with enzalutamide alone 
or docetaxel alone. We will also assess whether the combination is associated with greater 
efficacy in the patients without aberrations in the AR than when treated with docetaxel or 
enzalutamide alone. 
 
 
3. PARTICIPANT SELECTION 
 
All screening assessments must be performed within 30 days prior to the date of registration.  
 
3.1 
Inclusion Criteria  
 
• Histologically confirmed adenocarcinoma of the prostate 
• Castration-resistant prostate cancer requires the following criteria:  
 
A castrate level of testosterone (< 50ng/dL) 
 
Prostate cancer progression on or since last treatment as documented by PSA rise 
or bone progression according to PCWG239 or soft tissue radiographic 
progression according to RECIST criteria Version 1.1 


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 
If on anti-androgen, will need to show no PSA decline after at least a 6-week 
withdrawal period from the last dose of bicalutamide or nilutamide or 4 weeks 
from last flutamide dose 
 
Will require a 2-week washout period from last dose of ketoconazole, abiraterone 
acetate or radiation 
• Treatment with abiraterone acetate for CRPC in the past is required. It does not need to 
be the last treatment prior to enrollment. 
• There is no limit to number of prior therapies 
• Metastatic disease by bone scan or other nodal or visceral lesions on CT or MRI  
• Age ≥ 18 years 
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (See 
Appendix A)  
• Adequate organ function as evaluated by the following laboratory criteria: 
 
Hemoglobin ≥ 9g/dL; no transfusions and erythropoietin supplementation 
permitted within the last 3 months 
 
Absolute neutrophil count (ANC) ≥ 1500/µL 
 
Platelet count ≥ 100 x 109/L 
 
Total bilirubin ≤ upper limit of normal (ULN) (Note: In subjects with Gilbert’s 
syndrome, if total bilirubin is > ULN, measure direct and indirect bilirubin and if 
direct bilirubin is ≤ ULN, subject may be eligible) 
 
AST and ALT < 2.5 x ULN or < 5x the ULN if liver metastasis 
 
Serum creatinine < 2.0 × ULN or creatinine clearance > 30cc/min 
 
Serum albumin ≥ 3.0 g/dL 
 
Serum potassium ≥ 3.5 mmol/L (if < 3.5, can be repleted and reassess for 
eligibility as long as stable off potassium supplementation for > 48 hrs) 
• Ability to swallow the study drug as a whole tablet 
• The effects of apalutamide and docetaxel on the developing human fetus are unknown. 
For this reason and because chemotherapeutic agents are known to be teratogenic, men 
must agree to use adequate contraception. Specifically, they must agree 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 agree 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. They must also agree not to donate sperm during the study and for 3 
months after receiving the last dose of study drug. 
• Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
• Pathology consistent with majority of specimen having small cell carcinoma of the 
prostate (prostate cancer with neuroendocrine features is acceptable). 
• Prior treatment with enzalutamide for CPRC; non-CRPC use is allowed (e.g., 
neoadjuvant, combined with radiation for localized disease and didn’t progress while on 
it in those settings) 
• Prior treatment with docetaxel chemotherapy in the castration-resistant setting. Prior 
treatment with docetaxel in either the neoadjuvant or adjuvant setting or for hormone 


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sensitive disease (e.g., CHAARTED population) is allowed, as long as therapy was 
completed > 12 months prior to study registration  
• Presence of untreated brain metastasis 
• Seizure or known condition that may pre-dispose to seizure (including but not limited to 
prior stroke or transient ischemic attack within 1 year prior to first dose, brain 
arteriovenous malformation; or intracranial masses such as schwannomas and 
meningiomas that are causing edema or mass effect). Loss of consciousness within 12 
months may be permitted upon discussion with study PI. 
• Medications known to lower the seizure threshold (see list under prohibited medications, 
Appendix C) must be discontinued or substituted prior to study treatment initiation. 
• Current, recent (within 4 weeks of the first dose of this study), or planned participation in 
an experimental drug study with an experimental agent. 
• Persistent grade > 1 (NCI CTCAE v4.0) AEs due to investigational drugs that were 
administered more than 14 days before registration. 
• Radiation within 2 weeks prior to registration. 
• Peripheral neuropathy ≥ Grade 2. 
• Current evidence of any of the following: 
o Uncontrolled hypertension despite addition or adjustment of antihypertensive 
regimen 
o Gastrointestinal disorder affecting absorption 
o Active infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis) or 
other medical condition that would make prednisone/prednisolone (corticosteroid) 
use contraindicated 
• Uncontrolled intercurrent illness including, but not limited to, severe or unstable angina, 
myocardial infarction, symptomatic congestive heart failure (defined as New York Heart 
Association Grade II or greater), arterial or venous thromboembolic events (e.g., 
pulmonary embolism), or clinically significant ventricular arrhythmias, significant 
vascular disease (e.g. aortic aneurysm, aortic dissection), or symptomatic peripheral 
vascular disease within 6 months prior to registration. 
• Psychiatric illness/social situations that would limit compliance with study requirements. 
• Any condition that in the opinion of the investigator, would preclude participation in this 
study 
• History of allergic reactions or severe hypersensitivity reactions to drugs formulated with 
polysorbate 80 or antisense oligonucleotides. 
• History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to apalutamide or docetaxel 
• Participants receiving any medications or substances that are strong inhibitors or inducers 
of CYP3A4 are ineligible. Because the lists of these agents are constantly changing, it is 
important to regularly consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the 
Physicians’ Desk Reference may also provide this information. As part of the 
enrollment/informed consent procedures, the patient will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or 
if the patient is considering a new over-the-counter medicine or herbal product.  
• Inability to comply with study and/or follow-up procedures 


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3.3 
Inclusion of Women and Minorities 
 
Men of all races and ethnic groups are eligible for this trial. 
Women are not eligible for this trial as they do not have prostates and as such do not get prostate 
cancer. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
Apalutamide will be taken orally once daily. Apalutamide dosing will start on Cycle 1 Day 2 for 
the PK cohort and on Cycle 1 Day 1 for the rest of the patients. Docetaxel will be administered 
every 3 weeks intravenously in the infusion center of each site for a maximum of 10 cycles. 
Quantities of apalutamide have been predetermined at the start of the study. On average, patients 
may receive up to two years’ worth of treatment. The amount of time on therapy is subject to 
change and any patients wishing to continue past two years should discuss with their treating 
physician and overall PI. A treatment cycle is defined as 21 consecutive days. Treatment will be 
administered on an outpatient basis. Reported adverse events and potential risks are described in 
Section 7. Appropriate dose modifications are described in Section 6. No investigational or 
commercial agents or therapies other than those described below may be administered with the 
intent to treat the participant's malignancy. 


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Of note, if 2 or more patients of the first 6 experience a dose limiting toxicity (DLT), the dosing 
of the study drugs will be reviewed and the protocol amended as necessary. 
 
Table 1: Treatment Regimen 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Apalutamide Take with food 
consistently at 
approximately the 
same time each 
morning.  
Starting dose of 
240mg  
(four 60mg 
tablets) 
 
Orally 
Daily 
21 days  
(3 weeks) 
(+/- 3 
days) 
 
 
 
Docetaxel 
Premedicate with 
corticosteroids 
per institutional 
guidelines 
75mg/m2 in 250 
cc NS 
IV over 1 hr +/- 
10 min 
Day 1 of 
each cycle; 
for up to 10 
cycles max 
 
Prednisone 
Refer to the 
package insert 
5mg tablet 
Orally  
 
Can be dose 
reduced after 
cycle 1 per 
standard of care 
(SOC).  
Twice daily 
(may hold 
on days 
receiving 
steroid 
premeds 
for chemo) 
 
The participant will be requested to maintain a medication diary of each dose of medication. The 
medication diary should be completed by the participant each cycle and returned to study staff. 
 
5.2 
Laboratory Studies 
 
5.2.1 Pre-Treatment Criteria for C1D1. Subsequent Day 1 dosing criteria should follow section 
6 guidelines: 
 
C1D1 labs should meet the following criteria prior to treatment: 
 
Hemoglobin ≥ 9g/dL: no transfusions and erythropoietin supplementation 
permitted within the last 3 months 
 
ANC ≥ 1500/µL 
 
Platelet count ≥ 100 x 109/L 
 
Total bilirubin ≤ ULN (Note: In subjects with Gilbert’s syndrome, if total 
bilirubin is > ULN, measure direct and indirect bilirubin and if direct bilirubin is 
≤ ULN, subject may be eligible) 
 
AST and ALT < 2.5 x ULN or < 5x the ULN if liver metastasis 
 
Serum creatinine < 2.0 × ULN or creatinine clearance > 30cc/min 
• If screening labs have been done within 72 hrs of C1D1, they may be used in lieu of 


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18 
 
repeat C1D1 labs. 
 
• Day 1 labs must be reviewed by study staff prior to treatment to ensure they meet criteria 
as detailed in Section 6 
 
• For cycle 2 and onward, if assessments due on day 1 of the cycle are completed within 72 
hours prior to day 1 treatment, they do not need to be repeated (unless a toxicity or 
assessment parameter needs to be re-assessed in order to meet criteria to treat) 
 
5.2.2 Serial thyroid function monitoring 
 
• Thyroid function tests to include thyroid stimulating hormone (TSH), total T3 and free 
T4 should be evaluated at screening. The TSH should subsequently be evaluated 
throughout the study (with T3 and T4 done only if TSH is abnormal). These labs do not 
need to be reviewed prior to dosing on D1 and subsequent cycles, but once results have 
returned, the subsequent dosing should be adjusted as needed per the dosing modification 
guidelines in section 6.  
 
 Screening: TSH, total T3, free T4 
 Day 1 of each cycle for the first 4 cycles: TSH; only if abnormal at prior assessment: 
total T3 and free T4. Once T3 and FT4 normalize, they do not need to continue to be 
checked unless TSH becomes abnormal again  
 Every 12 weeks starting after Cycle 5: TSH; only if abnormal at prior assessment: total 
T3 and free T4. Once T3 and FT4 normalize, they do not need to continue to be checked 
unless TSH becomes abnormal again    
 
5.3 
Agent Administration 
 
5.3.1 Apalutamide 
 
• Apalutamide will be given at a fixed dose of 240 mg orally daily: four 60 mg tablets 
taken all at once. 
• The drug should be taken with food at the same time each day within 30 minutes after a 
meal for consistency. It will be advised that patients both on the PK cohort and in the 
non-PK cohort take apalutamide with food. 
• In the PK cohort, the first dose of apalutamide in cycle 1 will be given on day 2 after 
the 24 hour PK sample has been collected. On day 1 of cycle 2, the dose of 
apalutamide should be taken after the pretreatment PK sample is collected, 
coincident with starting the docetaxel infusion. 
• For the non-PK cohort, the first dose of apalutamide will start on cycle 1, day 1 or 
day 2 if logistical issues with scheduling. The drug should be taken at approximately 
the same time each day. 
• The drug should not be crushed, dissolved, or chewed.  
• A drug diary will be supplied   
• A missed dose should be taken as soon it is remembered. If twelve or more hours have 
lapsed since a missed dose, participants should not take the missed dose; rather the 


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participant should resume dosing at the next scheduled dose. Participants should not 
double up or take more than one dose of apalutamide per day.  
• Vomited doses should not be made up.  
• Caregiver Precautions - Pregnant women and women of childbearing potential should not 
handle apalutamide without protection, e.g. gloves. No need to wear gloves or use 
extraordinary caution when cleaning up vomited or fecal matter. 
 
5.3.2 Docetaxel 
 
5.3.2.1 
Steroid pre-medication 
 
All participants should be premedicated with corticosteroids per institutional standards in order to 
reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity 
reactions. Refer to institutional standards for recommendations on premedication prior to 
docetaxel chemotherapy. Additional premedications (e.g.: antihistamines) may be administered 
as needed per institutional standards. 
 
5.3.2.2 
Docetaxel plus prednisone 
 
Intravenous docetaxel plus oral prednisone will be administered according to the Docetaxel 
package insert or institutional standards for advanced prostate cancer. Docetaxel will be 
administered by a constant-rate intravenous (IV) infusion over 1 hour on Day 1 of each cycle of 
the Treatment Period.  
 
Prednisone (5 mg) will be taken orally twice daily on days 1-21 of each cycle. On the days the 
patient receives steroid premedication for chemotherapy, prednisone may be held. However, 
prednisone dose can be modified as needed per standard of care or physician preference 
after cycle 1. 
 
Dose reductions or delays with docetaxel should be determined according to section 6 and at the 
discretion of the Investigator.  
 
Prednisone may be tapered and discontinued after completion of docetaxel chemotherapy per 
investigator discretion. 
 
If docetaxel is discontinued, patients may still be eligible to receive apalutamide. This 
continuation should be discussed with the PI. 
 
5.3.3 GnRH agonist or antagonist 
 
Patients will be maintained on their existing GnRH agonist or antagonist and schedule unless 
they were intolerant or have been surgically castrated 
 
5.3.4 Order of Administration – No specific order of administration is required  
 


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5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
5.4.1 Seizure risk 
 
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:  
 
• 
Atypical antipsychotics (e.g. clozapine, olanzapine, risperidone, ziprasidone) 
• 
Bupropion 
• 
Lithium 
• 
Meperedine and pethidine 
• 
Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine) 
• 
Tricyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, imipramine, 
maprotiline, mirtazapine 
• 
Prochlorperazine maleate (Compazine) should be avoided given potential interactions 
with apalutamide due to seizure risk. 
See Appendix C for a representative list. 
 
5.4.2 Potential CYP450 isoenzyme interactions 
 
Because there is a potential for interaction of apalutamide with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies. The Overall PI Dr. 
Harshman should be alerted if the participant is taking any agent known to affect or with the 
potential to affect selected CYP450 isoenzymes.    
 
Apalutamide is metabolized primarily by human CYP3A4, thus co-administration with strong 
inhibitors or inducers of CYP3A4 should be avoided as much as possible. Apalutamide may also 
induce CYP3A4; therefore, caution should be taken when administered in conjunction with 
CYP3A4 substrates that have a narrow therapeutic index. Docetaxel is a CYP3A4 substrate. In 
vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant 
administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4. 
Examples of the strong CYP3A4 inhibitors and inducers that should be avoided if possible (some 
allowances per PI discretion) and alternatives used include the following:  
• 
Co-administration with any of these strong CYP3A4 inhibitors may increase 
apalutamide plasma concentrations and potentially lead to increased toxicity. 


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21 
 
• 
Itraconazole, 
clarithromycin, 
erythromycin, 
diltiazem, 
verapamil, 
delavirdine, 
atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
voriconazole, grapefruit juice (or grapefruits), ketoconazole, dexamethasone (with the 
exception of dexamethasone given as premedication for docetaxel) 
• 
Co-administration with any of these strong CYP3A4 inducers decrease apalutamide 
plasma concentrations and may lead to decreased efficacy. 
• 
Phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, efavirenz, 
tipranavir, St. John's wort 
 
5.4.3 Anticoagulation 
 
• The potential for drug-drug interaction between apalutamide and warfarin (e.g., 
Coumadin) is unknown at present. If a subject is taking warfarin, re-assess PT 
(prothrombin time)/international normalized ratio (INR) as clinically indicated and adjust 
the dose of warfarin accordingly. 
• Patients on stable doses of other anticoagulants such as lovenox or fondaparinux are 
permitted if they have been on it for >6 months. 
 
5.4.4 Supportive care medications 
 
• Drugs needed for supportive care such as anti-emetics are permitted  
 
• Steroids for nausea: prednisone is permitted but dexamethasone is not due to its CYP3A 
interaction, which may increase the levels of apalutamide. Dexamethasone is permitted as a 
docetaxel premedication. 
 
• We do not anticipate patients will require growth factors but if they are on them prior to trial 
for other reasons and meet other eligibility criteria they will be permitted. Growth factors 
may be started during treatment if clinically indicated. 
 
• Bone strengthening agents such as denosumab and zoledronic acid are permitted. 
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue until 
one of the following criteria applies: 
 
Patients will be discontinued from the study drug but continued to be followed for toxicity if: 
• They have evidence of confirmed progressive disease as defined by new bone metastases, 
progression of existing osseous disease (i.e., appearance of 2 or more new lesions by 
PCWG2 criteria), new visceral metastases as defined by traditional RECIST 1.1 criteria,40 or 
symptomatic disease. New visceral metastases and symptomatic disease do not require 
confirmatory scans. Per PCGW2 bone progression, confirmatory scans are only required if 
progression on first restaging scans.   


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• They have evidence of compromised organ function or performance status 
• Unacceptable adverse event(s) or toxicity 
• General or specific changes in the participant's condition render the participant unacceptable 
or unsafe for further treatment in the judgment of the treating investigator 
• Patient requests to withdraw from study therapy 
• If apalutamide is discontinued per the protocol, per investigator or patient request, the patient 
will be withdrawn from the study. They may continue to receive docetaxel as it is standard of 
care.  
• Participant demonstrates an inability or unwillingness to comply with the oral medication 
regimen, documentation, or comply with study requirements 
• Clinical need for concomitant or ancillary therapy that is not permitted in the study 
• Unrelated intercurrent illness that, in the judgment of the investigator, will affect assessments 
of clinical status to a significant degree 
 
It is the right and duty of the investigator to interrupt the treatment of any patient whose health or 
well-being may be threatened by continuation in this study. 
 
Participants will be removed from the protocol therapy when any of these criteria apply. The reason 
for removal from protocol therapy, and the date the participant was removed, must be documented 
in the case report form (CRF). Alternative care options will be discussed with the participant. 
 
An ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the ODQ website or obtained from the ODQ 
registration staff. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI Lauren C. Harshman MD at 617-632-4524.  
 
5.6 
Duration of Follow Up 
 
Participants will be followed for adverse events for 30 days after cessation of protocol therapy or 
until death, whichever occurs first. Participants removed from protocol therapy for unacceptable 
adverse event(s) greater than grade 2 deemed related to the study drug will be followed until 
resolution to a grade <2 or until stabilization (as determined by the investigator) of an irreversible 
adverse event. 
 
After the 30-day post study drug period is complete, patients will be followed approximately every 
3-6 months for up to 36 months (from the patient’s last treatment on study) for progression and 
survival data, either by clinic visit if they are still being treated at the study center or by phone, 
medical record, referring or subsequent treating physician, or publicly available records such as 
the Social Security Death Index (SSDI) if the patient cannot be reached by phone or in person. 
 
5.7 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 


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23 
 
• Withdrawal of consent for data submission 
• Death 
• 36 months from the patient’s last treatment on study  
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
For Decentralized Subject Registrations, the research team updates the relevant Off Treatment/Off 
Study information in OnCore. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Toxicity Management 
 
Good clinical practice with supportive care measures and the dose modifications as listed below 
will be instituted. Toxicity will be graded according to CTCAE grading version 4. Investigators 
are encouraged to institute preemptive supportive care and patient education (e.g. anti-diarrheals, 
anti-emetics, anti-hypertensive agents) at early signs of toxicities emerging to prevent grade 2 
and 3 occurrence). 
 
All clinically important abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return either to baseline or to a level deemed acceptable by the 
investigator and study monitor, or until a diagnosis is made that explains them. 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 discontinuation 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 or sponsor 
 
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 (e.g., hyperkalemia 
due to hemolysis). Hypocalcemia or hyponatremia that correct to normal or a lesser grade when 
accounted for hypoalbuminea and hyperglycemia should be counted as the grade based on the 
corrected level. Clinically significant laboratory results must be recorded on the patient’s Adverse 
Event CRF. 
 


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24 
 
6.2 
General Guidelines for Dose Modifications and Delays for apalutamide and 
docetaxel  
 
Dose delays and modifications will be made as indicated in the following tables. The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If toxicity occurs, the appropriate treatment will be used to ameliorate signs and symptoms 
including antiemetics for nausea and vomiting, anti-diarrheals for diarrhea and anti-pyretics and 
anti-histamines for drug fever before toxicity grade is determined. 
 
All adverse events experienced by participants will be collected from the time of the first dose 
of study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off-study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible. 
 
A decision to modify one or both agents will be based on investigator judgment.   
 
Subjects will be monitored continuously for AEs throughout the study and for 30 days after the last 
dose of study treatment, and for any serious adverse event assessed as related to study treatment or 
study procedures, even if the SAE occurs more than 30 days after the last dose of study treatment. 
Subjects will be instructed to notify their physician immediately of any and all AEs. Subjects 
experiencing one or more AEs due to the study treatment may require a dosing delay or reduction(s) 
in their dose in order to continue with study treatment. Assessment of causality (chronology and 
confounding factors such as disease, concomitant medications, diagnostic tests, and previous 
experience with the study treatment) should be conducted by the principal investigators when 
possible, before a decision is made to modify the dose or to hold dosing temporarily. As a general 
approach, it is suggested that all AEs be managed with supportive care when possible at the earliest 
signs of toxicity to avoid dose interruptions and reductions if possible.  
 
The criteria presented in this section for dose modifications and delays are meant as general 
guidelines for both study drugs: 
1. As a general approach, it is suggested that all AEs be managed with supportive care when 
possible at the earliest signs of toxicity. Should this be ineffective, a dose delay or dose reduction 
may be considered to avoid worsening toxicity. Please refer to relevant sections for the dose 
reduction levels for study treatment.  
2. If a subject develops unacceptable toxicity as defined here that is determined to be related to 
study treatment, and if supportive care measures and/or a dose reduction of the responsible agent 
fail to lessen the toxicity to acceptable levels, study treatment of one or both agents should be 
withheld until resolution and then restarted or discontinued as per the protocol.  
3. Dose reduce the drug thought to be the offending agent and modify plan based on re-challenge 
with lower dose. 
 


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25 
 
The following will define DLTs for the first cycle (i.e. first 3 weeks of therapy) and are 
examples of unacceptable toxicity that should guide dose adjustment after cycle 1: 
• Intolerable Grade 2 toxicity (except alopecia) that cannot be adequately managed with 
supportive care and/or a dose reduction 
• Intolerable rash of any grade that cannot be adequately managed with supportive care and/or a 
dose reduction 
• Any Grade 3 or Grade 4 toxicity despite optimal management that poses a significant clinical 
risk (including nausea, vomiting, diarrhea, hypertension) 
• Concurrent elevation of ALT/AST > 3x ULN with total bilirubin > 2x ULN unless due to biliary 
obstruction or other etiology other than study medications 
• Grade 4 thrombocytopenia or anemia > 7 days (transfusions permitted) 
• Grade 4 neutropenia > 7 days duration 
• Grade ≥ 3 neutropenic fever (> 38.3°C single temperature or sustained temperature ≥ 38°C for 
more than one hour)  
• Grade ≥ 3 neutropenia with documented infection  
• Seizure of any grade 
 
Dose modifications or delays may occur in the setting of lower grade toxicity than defined 
above if the investigator believes that it is in the interest of the subject’s safety and does not 
meet criteria for a DLT.  
 
• If a study drug is withheld for a treatment-related toxicity, re-initiation of study treatment cannot 
occur until toxicity decreases to ≤ Grade 1 or baseline value. 
• The minimum dose of study treatment is detailed in the dose reduction tables.  
• If the subject recovers from his or her toxicities (per the criteria above) to Grade ≤ 1 or to the 
baseline value (or lower) within 42 days, and the toxicity was deemed related to study treatment, 
then study treatment may be restarted at a reduced dose (see relevant sections for 
schedule/magnitude of dose reduction). Subjects receiving the lowest dose of study treatment 
may be restarted at the same dose at the discretion of the investigator with pre-emptive 
supportive care, unless it was a DLT event. If the toxicity was unrelated to study treatment, then 
study treatment may be restarted with no change in dose. The 42-day maximum hold applies to 
either study drug.  
• Dose interruptions for reason(s) other than toxicity, such as surgical procedures, may be allowed 
with PI approval.  
• If study treatment is interrupted, held, or skipped, the subject should be instructed not to make 
up the withheld doses, and the planned safety and tumor assessment schedule are to be 
maintained. 
• Dose reductions will be by organ system as detailed below. Unless otherwise specified in 
the table below, the maximal amount of time allowed for recovery is 42 days. The 
guidance below is listed based on potential responsible agent. Investigators can adapt 
which agent to adjust based on clinical context of patient and must document the 
rationale for the decision. 
 


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26 
 
Dose delays for reason(s) other than AEs related to the study drugs, such as surgical procedures 
with no anticancer therapy intent, may be allowed with study chair approval. The acceptable 
length of interruption will be determined by the investigator and study chair after assessing the 
risk benefit analysis. 
 
If a patient shows evidence of progression during a dose interruption, therapy can be 
restarted if the investigator considers patient was benefiting from therapy prior to therapy 
being held or was too early to determine. 
 
If a participant experiences several adverse events and there are conflicting recommendations, 
the investigator should use the recommended dose adjustment that reduces the dose to the lowest 
level. 
 
No intra-participant dose escalation or re-escalation is permitted. 
 
If one study drug is held or discontinued for toxicity, the other agent may still be given or 
restarted if they meet treatment criteria.  
 
6.2.1 In general, toxicities attributed to apalutamide, follow this modification.  
 
Table 2: Dose Modifications for Apalutamide Toxicities 
Dose Level 
Apalutamide 
Starting dose  
240mg daily 
1st dose reduction 
180mg daily 
2nd dose reduction 
120mg daily 
 
Table 3: Dose Modification Guidance for Apalutamide Toxicities  
Toxicity 
Dose of apalutamide (assuming 240 mg/day 
dosing) 
Grade 1 or 2 
No change 
≥ Grade 3 or higher 
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 ≥ 3 neurotoxicity** 
Discontinue both apalutamide and docetaxel 
*Recurrences refer to the same type of grade 3 event—i.e., grade 3 anemia and grade 3 
thrombocytopenia are different types of events 
**For peripheral neuropathy, refer to docetaxel dose modifications below as that is unlikely to be 
due to apalutamide. 
 
 
 


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Rash 
Dose modifications for rash are allowed only for apalutamide and are summarized in below table 
(Table 4). 
 
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. 
  
 Table 4: Apalutamide Dose Modification Guidance for Rash 
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. 
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 


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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. 
 
6.2.2 In general toxicities attributed to docetaxel, follow this modification.  
 
Table 5: Dose Modification Schedule for Docetaxel Toxicities 
Dose Level 
Docetaxel 
Starting dose  
75mg/m2 IV every 3 weeks 
1st dose reduction 
60mg/m2 IV every 3 weeks 
2nd dose reduction 
55mg/m2 IV every 3 weeks 
*No dose less than 55mg/m2 will be given; patients will be discontinued from trial. 
• Docetaxel may be given within a 3-day window (+/-3 days of Day1 of each cycle). If held for 
toxicity on Day 1, can reassess within that 3 days and give if meets treatment criteria. If 
cannot be given within that window from protocol scheduled time point, skip dose until day 1 
of next cycle. Day 1 of subsequent cycles will not change if docetaxel is delayed.  
• No more than two dose reductions of docetaxel should be allowed for any patient. If a patient 
who has had 2 dose reductions has toxicities requiring further dose reductions, then docetaxel 
should be stopped and they should be treated with androgen deprivation and apalutamide 
alone.   
• Dose adjustments are to be made according to the system showing the greatest degree of 
toxicity.  
• If the dose level is reduced due to toxicity, then it will not be re-escalated in subsequent 
cycles.  
 
Dose Modifications for Myelosuppression  
 
• All hematologic toxicities will be considered related to docetaxel and not apalutamide 
• Dose modifications are to be made based on the granulocyte and/or platelet count drawn 
prior to planned treatment (can be done the day prior to planned dose): 
 
 
Table 6: Dose Modifications for Myelosuppression 
Docetaxel 
Absolute neutrophils/mm3 
Day 1 of each cycle 
 
 
Platelet/mm3 
Day 1 of each cycle 
No change 
≥ 1,500                             
AND 
 
≥ 100,000 
Hold 
< 1,500                              
OR 
 
< 100,000 
NOTE: If a dose reduction is made, maintain the lower dose for all 
subsequent cycles 
• A need for three dose reductions will require that the patient discontinue 


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docetaxel and continue on androgen blockade alone. 
• The planned day 1 dose can be delayed for three days to recheck counts 
and give within the 3-day window if the patient meets the criteria above.   
• If the patient experiences febrile neutropenia or ≥ 7 days with a neutrophil 
count < 500 cells/mm3, the dose should be reduced by one dose level and 
the patient can be retreated once the neutrophil count has recovered to ≥ 
1,500/mm3 and platelet count has recovered to ≥ 100,000/mm3. The fever 
must have resolved and if an infection is identified, it must be adequately 
treated and have clinically resolved before restarting therapy. If prior 
bacteremia, blood cultures must be negative on recheck. Patient can 
continue with docetaxel while on antibiotics if no medication interactions 
found. 
• NOTE: Labs do not need to be re-checked to reassess absolute 
neutrophil count within 7-days; if absolute neutrophil count is 
incidentally found to remain <500 cells/mm3 for ≥ 7 days, the 
docetaxel dose will need to be reduced subsequently.  
• Use of growth factors is not required as the dose and schedule does not 
meet ASCO guidelines. If, however, the investigator considers it in 
patient’s best interest, growth factors can be used per investigator 
discretion. 
 
• Patients should not be retreated with subsequent cycles of docetaxel until neutrophils 
recover to a level ≥ 1500 cells/mm3 and platelets recover to a level ≥ 100,000 cells/mm3. 
If the previous cycle was held due to absolute neutrophil count <1,500 cells/mm3 or 
platelet count <100,000 cells/mm3, docetaxel may be resumed at full dose, or with a dose 
reduction, at the treating investigator’s discretion, and rationale should be documented. 
(See above for specific requirements for patients who experience febrile neutropenia or 
absolute neutrophil count <500 cells/mm3 for ≥ 7 days.) 
 
Dose Modification for Hepatic Dysfunction 
• ALT and bilirubin will be evaluated prior to each Day 1  
• Patients who develop abnormal liver function tests for any reason while on the study will have 
the following dose reductions: 
 Table 7: Dose Modifications for Abnormal Liver Function 
Bilirubin 
 ALT/ SGPT 
Action 
 
> ULN* 
 
or 
 
> 5 x ULN 
Hold 3 weeks. If recovered**, reduce docetaxel 
dose by one dose level. If not, discontinue 
docetaxel. 
 ULN* 
and 
> 3 x ULN 
Reduce docetaxel by one dose level 
* For patients with Gilbert’s Syndrome, hold if the bilirubin level is > 1.5 x its baseline 


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value 
** Recovery is < 3 x ULN for ALT/SGPT and WNL for bilirubin. For patients with 
Gilbert’s Syndrome, recovery is defined as a bilirubin level < 1.5 x its baseline value. 
Dose modifications are based on ALT/ SGPT alone due to the lack of specificity of 
AST/SGOT. 
 
Stomatitis 
• If stomatitis ≥ grade 2 is present on day 1 of any cycle, docetaxel should be held until 
stomatitis has resolved.   
• If Grade 3/4 stomatitis occurs at any time, the dose of docetaxel will be reduced one dose 
level for all subsequent doses.   
• If a second Grade 3/4 stomatitis event occurs, docetaxel will be reduced one more dose 
level.  
• If a third Grade 3/4 stomatitis event occurs, the patient will be taken off study. 
 
Peripheral Neuropathy 
• If  Grade 3, the patient will discontinue docetaxel. 
• If Grade 2, the docetaxel will be held and the patient should be retreated upon recovery to 
a  Grade 1 toxicity with a dose reduction of docetaxel by one level.   
• If Grade 2 or greater neurotoxicity persists for more than 3 weeks, the patient will 
discontinue docetaxel. Peripheral neuropathy is unlikely to be secondary to apalutamide 
and thus it may be continued if patient was receiving clinical benefit. 
 
Infusion or Hypersensitivity Reactions for Docetaxel  
• Infusion reactions (including fever, chills, diarrhea, rash, urticaria, erythema, pruritus, 
bronchospasm, hypotension, and anaphylaxis) can occur with docetaxel. 
• In the event of an infusion reaction, follow the Institutional Guidelines and/or the 
recommendations shown in the tables below, based on the grade of the reaction. 
• To identify the grade of a reaction, refer to the list below adapted from the General 
Disorders and Administration Site Conditions section of the NCI CTCAE Version 4.0: 
 
 
Table 8: Dose Modification and Management for Infusion or Hypersensitivity Reactions 
for Docetaxel 
Infusion 
Reaction 
Definition 
Management/Next Dose for Docetaxel 
≤ Grade 1 
Mild transient reaction; infusion 
interruption not indicated 
 
 
Interruption or intervention not indicated. 
Slow the rate of infusion of the drug until 
resolution of symptoms, then resume at the 
planned infusion rate. 
 
Grade 2 
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids indicated for ≤ 
Interrupt the infusion. Follow institutional 
guidelines or give steroids 
(e.g., solumedrol 40 mg IV), 
diphenhydramine 50 mg IV, and/or an H2 


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Infusion 
Reaction 
Definition 
Management/Next Dose for Docetaxel 
24 hours). 
blocker (e.g. Ranitidine 50 mg IV) after 
consultation with the attendant physician. 
Resume after recovery of symptoms at a 
slower rate, and then increase incrementally 
toward the initial rate. If the reaction 
reoccurs, stop the infusion and do not 
administer the remaining volume. 
 
Grade 3 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae Note: any 
infusion that is interrupted and not 
resumed within the visit will be 
considered a Grade 3 reaction. 
 
 
Stop the infusion. Treat the participant as per 
grade 2 reaction above. 
 
Remove the participant from docetaxel 
therapy or consider desensitization after allergy 
consult review. 
 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated. 
 
ICU level care (e.g., vasopressor 
support) 
 
Stop the infusion. Treat the participant as per 
grade 2 reaction above. 
 
Remove the participant from docetaxel 
therapy. 
 
Diarrhea  
• If patients experience significant diarrhea (>3 loose stools/24hrs over baseline), they 
should be treated prophylactically in subsequent cycles with loperamide or 
diphenoxylate.   
• If patient experiences >grade 2 diarrhea despite prophylaxis, docetaxel should be reduced 
one dose level.   
• If patients experience > grade 2 diarrhea despite 36 hrs of prophylaxis AND dose 
reduction, they should discontinue docetaxel.  
• Maximal prophylactic treatment includes (e.g., loperamide, diphenoxylate hydrochloride 
with atropine, octreotide) 
 
Fluid Retention 
• There are no dose reductions for fluid retention. Participants should be treated with salt 
restrictions and diuretics. More aggressive therapy depends on the clinical situation. In 
severe situations, the Investigator, with the participant, should determine if it is in the 
participant’s best interest to continue or discontinue study treatment. 
 


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Other Toxic Effects possibly related to docetaxel: 
• If toxicities  Grade 2, manage the subject symptomatically if possible, and retreat 
without dose reduction. 
• If toxicities  Grade 3 and clinically significant (not mentioned above), docetaxel should 
be withheld (except for anemia as patients can be transfused) until resolution to  
Grade 1 or baseline and patients treated with a one dose level reduction. 
 
Delay of Therapy: 
• If docetaxel has to be delayed for more than 42 days from planned day of dosing because 
of any docetaxel-related toxicity, then docetaxel should be stopped and the patient 
should be continued on treatment with androgen deprivation therapy plus 
apalutamide as long as no contra-indications/toxicities due to apalutamide prohibit 
further dosing. 
 
6.2.3 Dose Modification Tables for Specific Adverse Events: 
 
• Any seizure is considered a DLT and the patient will be discontinued from both study 
medications 
 
o Unless clearly due to another source or to one of the study agents (e.g., only occurs 
night/week of docetaxel or only occurs 3rd week of cycle when only on apalutamide), 
can consider nausea, vomiting, and diarrhea as ‘related’ to both docetaxel and 
apalutamide as they are known toxicities of both agents. Dose reduce both agents per 
table below if unable to tease out which agent is the source as it is likely that both 
may contribute to the toxicity. 
 
Table 9: Dose Modification and Management for Nausea, Vomiting, or Diarrhea 
Nausea, Vomiting 
or Diarrhea  
Management  
Next Dose  
≤ Grade 1 
No holding/change required 
No change in dose 
Grade 2 
No holding/change required. 
Maximize supportive care. 
Resume at same dose level 
Grade 3 
Hold* until < Grade 2 
Resume at one dose level lower, if 
indicated and per MD discretion** 
Grade 4 
Off protocol therapy 
Off protocol therapy 
*Participants requiring a delay of >42 days should go off protocol therapy. 
**Participants requiring a greater number of dose reductions than allowed per Section 6.2.1 
should go off protocol therapy. 
Recommended management:   
Nausea/vomiting: antiemetics per recommendations in section 5.4 given possible interactions 
 
Diarrhea: Loperamide antidiarrheal therapy 
Dosage schedule recommendations: 4 mg at first onset, followed by 2 mg with each loose 
movement until diarrhea-free for 12 hours (maximum dosage: 16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 


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Table 10: Dose Modification Instructions for General Non-Hematologic Toxicity 
Event 
Action 
Grade 1 
Continue current dose level 
Grade 2 
Continue current dose level 
Grade 3 
Discontinue for up to 42 days until the event is ≤ Grade 1 or baseline. Administer 
at one dose level lower for subsequent cycles, unless further dose reduction is 
required.  
Grade 4 
Discontinue for up to 42 days until the event is ≤ Grade 1 or baseline. Discuss the 
event with the PI prior to restarting. If the investigators agree, then administer at 
one dose level lower for subsequent cycles, unless further dose reduction is 
required. 
 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of reported and/or potential AEs (Sections 7.1 and 7.2) and the characteristics of an 
observed AE (Section 7.4) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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7.2 
Expected Adverse Event List for Docetaxel  
 
The most serious adverse reactions from docetaxel are (taken from the package insert): 
• 
Toxic Deaths  
• 
Hepatotoxicity  
• 
Neutropenia  
• 
Hypersensitivity  
• 
Fluid Retention  
 
The most common adverse reactions across all docetaxel indications are infections, neutropenia, 
anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, 
dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, 
vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the 
indication. 
 
The following data are based on the experience of 332 patients, who were treated with docetaxel 
75 mg/m² every 3 weeks in combination with prednisone 5 mg orally twice daily (see Table 
12). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 12: Clinically Important Treatment Emergent Adverse Reactions (Regardless of 
Relationship) in Patients with Prostate Cancer who Received Docetaxel in Combination 
with Prednisone (TAX327) 
 
 


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• Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 mg/m2 to 
100 mg/m2 of docetaxel and grade 4 neutropenia (<500 cells/mm3) occurs in 85% of 
patients given 100 mg/m2 and 75% of patients given 60 mg/m2. Frequent monitoring of 
blood counts is, therefore, essential so that dose can be adjusted. Docetaxel should not 
be administered to patients with neutrophils <1500 cells/mm3. 
 
• Febrile neutropenia occurred in about 12% of patients given 100 mg/m2 but was very 
uncommon in patients given 60 mg/m2. Hematologic responses, febrile reactions and 
infections, and rates of septic death for different regimens are dose related. 
 
• Patients should be observed closely for hypersensitivity reactions, especially during the 
first and second infusions. Severe hypersensitivity reactions characterized by generalized 
rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have 
been reported in patients premedicated with 3 days of corticosteroids. Severe 
hypersensitivity reactions require immediate discontinuation of the docetaxel infusion and 
aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be 
rechallenged with docetaxel. 
 
• Hypersensitivity reactions may occur within a few minutes following initiation of a 


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docetaxel infusion. If minor reactions such as flushing or localized skin reactions occur, 
interruption of therapy is not required. All patients should be premedicated with a 
corticosteroid prior to the initiation of the infusion of docetaxel per institutional standards. 
 
• Severe fluid retention has been reported following docetaxel therapy. Patients should 
be premedicated with oral corticosteroids prior to each docetaxel administration to reduce 
the incidence and severity of fluid retention  
 
• Patients with pre-existing effusions should be closely monitored from the first dose for the 
possible exacerbation of the effusions. 
 
• When fluid retention occurs, peripheral edema usually starts in the lower extremities and 
may become generalized with a median weight gain of 2 kg. 
 
• Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in 
patients given anthracyclines and/or cyclophosphamide 
 
• Localized erythema of the extremities with edema followed by desquamation has been 
observed. 
 
• In case of severe skin toxicity, an adjustment in dosage is recommended. The 
discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer 
patients. Among 92 breast cancer patients premedicated with 3-day corticosteroids, 
there were no cases of severe skin toxicity reported and no patient discontinued docetaxel 
due to skin toxicity. 
 
• Severe neurosensory symptoms (e.g. paresthesia, dysesthesia, pain) were observed in 5.5% 
(53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 
6.1%.  
 
• Patients who experienced neurotoxicity in clinical trials and for whom follow-up 
information on the complete resolution of the event was available had spontaneous 
reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks). 
 
• Severe peripheral motor neuropathy mainly manifested as distal extremity weakness 
occurred in 4.4% (42/965). 
 
• Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer patients but 
has led to treatment discontinuation in only 1.8%.  
 
• Symptoms of fatigue and weakness may last a few days up to several weeks and may be 
associated with deterioration of performance status in patients with progressive disease. 
 
Post-marketing experiences across all indications: (from PI)  
 
The following adverse reactions have been identified from clinical trials and/or post-
marketing surveillance. Because they are reported from a population of unknown size, precise 
estimates of frequency cannot be made. 
 
Body as a whole: diffuse pain, chest pain, radiation recall phenomenon. 


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Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities, 
thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction. 
 
Cutaneous: very rare cases of cutaneous lupus erythematosus and rare cases of bullous 
eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, 
and Scleroderma-like changes usually preceded by peripheral lymphedema. In some cases, 
multiple factors may have contributed to the development of these effects. Severe hand and foot 
syndrome has been reported. 
 
Gastrointestinal: abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, 
gastrointestinal hemorrhage, gastrointestinal perforation, ischemic colitis, colitis, intestinal 
obstruction, ileus, neutropenic enterocolitis and dehydration as a consequence to 
gastrointestinal events have been reported. 
 
Hematologic: bleeding episodes. Disseminated intravascular coagulation (DIC), often in 
association with sepsis or multiorgan failure, has been reported. Cases of acute myeloid 
leukemia and myelodysplastic syndrome have been reported in association with docetaxel 
when used in combination with other chemotherapy agents and/or radiotherapy. 
 
Hypersensitivity: rare cases of anaphylactic shock have been reported. Very rarely these cases 
resulted in a fatal outcome in patients who received premedication. 
 
Hepatic: rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing 
liver disorders, have been reported. 
 
Neurologic: confusion, rare cases of seizures or transient loss of consciousness have been 
observed, sometimes appearing during the infusion of the drug. 
 
Ophthalmologic: conjunctivitis, lacrimation or lacrimation with or without conjunctivitis. 
Excessive tearing which may be attributable to lacrimal duct obstruction has been reported. 
Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically 
occurring during drug infusion and in association with hypersensitivity reactions have been 
reported. These were reversible upon discontinuation of the infusion. 
 
Hearing: rare cases of ototoxicity, hearing disorders and/or hearing loss have been 
reported, including cases associated with other ototoxic drugs. 
 
Respiratory: dyspnea, acute pulmonary edema, acute respiratory distress syndrome, 
interstitial pneumonia. Pulmonary fibrosis has been rarely reported. Rare cases of radiation 
pneumonitis have been reported in patients receiving concomitant radiotherapy. 
 
Renal: renal insufficiency and renal failure have been reported. The majority of these cases 
were associated with concomitant nephrotoxic drugs. 
 
 


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7.11 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information, which 
is provided. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.13 
Expedited Adverse Event Reporting  
 
Investigators must report to the Overall PI Dr. Harshman any serious adverse event (SAE) that 
occurs after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form. 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy.  
  
7.14 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. Please refer to 21 CFR § 600.80 for guidance. 
 
7.15 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant safety 
reports or sentinel events that require reporting according to institutional policy.  
 
7.16 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Sections 7.1 and 7.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
             
 
 
 
 


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8.1.2 Form 
 
The tablet formulation of apalutamide will be used in this study. The apalutamide drug 
substance is an almost white to slightly brown powder. The tablet formulation of apalutamide is 
an immediate release oral tablet containing 60-mg of drug substance, with a non-functional 
green film coat. Each 60-mg tablet contains the following inactive ingredients: hydroxypropyl 
methylcellulose acetate succinate (HPMC-AS), colloidal anhydrous silica, croscarmellose 
s odium, microcrystalline cellulose, silicified microcrystalline cellulose, and magnesium 
stearate. Commercially available Opadry® coating powder is used for the film coating, which is 
comprised of polyvinyl alcohol (partially hydrolyzed), titanium dioxide, polyethylene glycol, 
talc, and colorants iron oxide yellow and iron oxide black (E172). 
 
8.1.3 Storage and Stability 
 
Apalutamide tablets (60-mg) are packaged in 120-count, 160 cc high-density polyethylene 
(HDPE) bottles with child-resistant closure (CRC) and include desiccant. For clinical 
formulation-specific and batch-specific storage instructions, see the packaging labels. At the 
clinical site and at the patient’s home, the study drug should be stored at room temperature and 
protected from heat and should not be frozen. Participants should be advised to keep all 
medications out of the reach and out of sight of children. 
 
8.1.4 Compatibility 
 
N/A 
 
8.1.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
Study treatment must only be dispensed by a Pharmacist or medically qualified staff. Study 
treatment is to be dispensed only to participants enrolled in this study. Once the study treatment is 
prepared for a participant, it can only be administered to that participant. 
 
Pregnant women and females of childbearing potential should use gloves as a precautionary 
measure.  
 
8.1.6 Availability 
 
Apalutamide will be distributed to the Dana-Farber Cancer Institute pharmacy by Janssen. The 
Dana-Farber Cancer Institute Pharmacy will distribute study drug to participating Dana-
Farber/Harvard Cancer Center sites. Apalutamide will be provided free of charge for this study. 
 
 


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8.1.7 Preparation 
 
No preparation is required. The apalutamide tablets will come fully constituted.  
 
8.1.8 Administration 
 
• Apalutamide will be administered orally. 
• The drug should be taken with food at the same time each day within 30 
minutes after the meal for consistency. It will be advised that patients both on 
the PK cohort and in the non-PK cohort take apalutamide with food. 
• The drug should not be crushed, dissolved, or chewed.  
• Missed doses should be skipped if less than 12 hours until next planned dose. 
• Vomited doses should not be made up. 
 
8.1.9 Ordering 
 
Apalutamide will be ordered from Janssen or their designee. A drug order form as well as 
instructions on how to order study drug will be distributed to study site prior to site activation.  
 
8.1.10 Accountability 
 
Accountability for study drug is the responsibility of the investigator.  
 
The study site must maintain accurate records demonstrating dates and amount of study drug 
received, to whom dispensed (participant by participant accounting), and accounts of any study 
drug accidentally or deliberately destroyed. At the end of the study, reconciliation must be made 
between the amount of study drug supplied, dispensed, and subsequently destroyed. 
 
At the time of delivery of study drug to the site, the investigator, designee, or Pharmacist (where 
appropriate) will confirm that the supplies for the study have been received. This following 
information will be confirmed: lot numbers, quantities shipped/delivered, and date of receipt. 
 
8.1.11 Destruction and Return 
 
Drug will be destroyed at the site at the end of the study. Destruction will be documented in the 
site’s drug accountability records. 
 
8.2 
Docetaxel 41  
 
Please see the prescribing information.  
 
8.2.1 Description 
 
Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by 
semisynthesis beginning with a precursor extracted from the renewable needle biomass of 
yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine, N-
tert-butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-


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acetate 2-benzoate, trihydrate.  
 
Mechanism of Action: 
Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells 
that is essential for mitotic and interphase cellular functions. Docetaxel binds to free 
tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously 
inhibiting their disassembly. This leads to the production of microtubule bundles without 
normal function and to the stabilization of microtubules, which results in the inhibition of 
mitosis in cells. Docetaxel’s binding to microtubules does not alter the number of 
protofilaments in the bound microtubules, a feature which differs from most spindle poisons 
currently in clinical use. 
 
8.2.2 Form 
 
Docetaxel Injection Concentrate is supplied in glass vials as non-aqueous, clear, viscous, 
colorless to pale yellow solution at 20mg/mL concentration. Docetaxel injection concentrate is 
sterile, non-pyrogenic, and is available in single-dose vials as 20 mg/mL or 80mg/4mL.   
 
One vial formulation (Injection Concentrate) 
 
Docetaxel injection concentrate (20mg/mL) requires no prior dilution with a diluent and is 
ready to add to the infusion solution. Docetaxel injection concentrate should be inspected 
visually for particulate matter or discoloration prior to preparation. If the injection concentrate is 
not clear or appears to have precipitation, then it should be discarded.   
 
8.2.3 Storage and Stability 
 
Store vials at 25°C (77°F); excursions permitted to 15°C to 30°C (36°F and 77°F). Retain in 
the original package to protect from bright light.  
 
Docetaxel final dilution for infusion, if stored between 2°C and 25°C (36°F and 77°F) is 
stable for 4 hours. Docetaxel final dilution for infusion (in 0.9% Sodium Chloride 
solution), diluted to a final concentration of 0.3mg/ml to 0.74mg/ml, should be used within 4 
hours (including the 1 hour intravenous administration). 
 
8.2.4 Compatibility 
 
Contact of the docetaxel injection concentrate with plasticized PVC equipment or devices used 
to prepare solutions for infusion is not recommended. In order to minimize patient exposure to 
the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion 
bags or sets, the final docetaxel dilution for infusion should be stored in bottles (glass, 
polypropylene) or plastic bags (polypropylene, polyolefin) and administered through 
polyethylene-lined administration sets. 
 
8.2.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 


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Study treatment must only be dispensed by a Pharmacist or medically qualified staff. Study 
treatment is to be dispensed only to participants enrolled in this study. Once the study treatment is 
prepared for a participant, it can only be administered to that participant.  
 
Docetaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, 
caution should be exercised when handling and preparing docetaxel solutions. The use of 
gloves is recommended.  
 
If docetaxel injection concentrate or final dilution for infusion should come into contact with 
the skin, immediately and thoroughly wash with soap and water. If docetaxel injection 
concentrate or final dilution for infusion should come into contact with mucosa, immediately 
and thoroughly wash with water. 
 
8.2.6 Availability 
 
Docetaxel is commercially available. 
 
8.2.7 Preparation  
 
Docetaxel may be prepared according to institutional standards or package insert. 
 
For one vial preparation: 
1. Docetaxel vials should be stored at room temperature, 25°C (77°F), and protected from light.  
2. Aseptically withdraw the required amount of docetaxel injection concentrate (20 mg/mL) 
with a calibrated syringe and inject into a 250-mL infusion bag of either 0.9% Sodium Chloride 
solution to produce a final concentration of 0.3 to 0.74 mg/mL. 
If a dose greater than 200 mg of docetaxel is required, use a larger volume of the infusion 
vehicle so that a concentration of 0.74 mg/mL docetaxel is not exceeded. 
2. Thoroughly mix the infusion by manual rotation. 
3. Attach non-PVC tubing with a 0.22-micron filter attached 
3. As with all parenteral products, docetaxel should be inspected visually for particulate matter 
or discoloration prior to administration whenever the solution and container permit. If the 
docetaxel injection concentrate or final dilution for intravenous infusion is not clear or appears 
to have precipitation, these should be discarded. 
 
8.2.8 Administration 
 
The final docetaxel dilution for infusion should be administered intravenously as a 1-hour 
infusion (+/- 10 min) under ambient room temperature and lighting conditions. Docetaxel may be 
administered according to institutional standards or package insert. 
 
8.2.9 Ordering 
 
Docetaxel will not be provided by the sponsor. Commercial supply will be used. 
 
 


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8.2.10 Accountability 
 
Accountability for study treatment is the responsibility of the investigator.  
 
The study site must maintain accurate records demonstrating dates and amount of study treatment 
received, to whom dispensed (participant by participant accounting), and accounts of any study 
treatment accidentally or deliberately destroyed. At the end of the study, reconciliation must be 
made between the amount of study treatment supplied, dispensed, and subsequently destroyed. 
 
8.2.11 Destruction and Return 
 
N/A for IV agent. 
 
8.3 
Prednisone 
 
8.3.1 Description 
 
Prednisone is a corticosteroid 
 
8.3.2 Form 
 
Prednisone 5-mg tablets are small, white tablets. 
 
8.3.3 Storage and Stability 
 
Prednisone will be prescribed and prescriptions may be filled at a pharmacy chosen by 
the participant. 
 
8.3.4 Compatibility 
 
We do not anticipate any excess toxicity combining prednisone with the study 
medications. 
 
8.3.5 Handling 
 
There are no specific instructions for handling prednisone. 
 
8.3.6 Availability 
 
Prednisone is commercially available. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Pharmacokinetic Studies (Supko Laboratory) 
 
9.1.1 Rationale  
 
Pharmacokinetic sampling will be performed in the first 12 patients enrolled in the clinical trial at 
Dana-Farber Cancer Institute to evaluate the possible effect of daily oral administration of 
apalutamide on the pharmacokinetics of docetaxel. The initial daily dose of apalutamide given in 
cycle 1 will be withheld until just after the 24-hour sample is collected on day 2. Serial blood 


DF/HCC Protocol #: 16-485 
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samples will be collected according to the same schedule on days 1-2 of cycles 1 and 2. The 
concentration of docetaxel will be determined in all plasma samples. Determining the drug 
concentration in a sample obtained 24 hours after dosing, just prior to taking the next daily dose 
of apalutamide, is absolutely necessary to properly define the plasma profile for a single dosing 
interval. Alterations in the pharmacokinetic behavior of docetaxel will be evaluated by comparing 
the mean pharmacokinetic parameters estimated from the plasma concentration-time profiles 
defined for the doses given on day 1 of cycles 1 and 2.  
 
The sampling schedule has been devised to accommodate treatment on an outpatient basis. 
Patients are to be instructed to take apalutamide, at approximately the same time every day 
within 30 minutes after a meal/food, at a time that will allow the patient to arrive at the clinic 
to obtain a pharmacokinetic sample before dosing and to remain for an additional 8 hours. The 
actual sampling schedule and procedures that are to be used to establish times, collect samples, 
and process specimens for storage and shipment prior to analysis are described below.   
 
9.1.2 Collection of Specimens 
 
Place a large gauge peripheral catheter (e.g., 19- or 20-gauge angiocath straight set with T-
connector, or similar IV access device) within a vein in the arm of the patient for the collection of 
pharmacokinetic blood samples on day1 of cycles 1 and 2.  Patency of the sampling catheter should 
be maintained between blood draws using either a heparin lock (e.g., 10 U/mL in normal saline) 
or a slow drip of Normal Saline for Injection, USP (e.g., 10 mL/h).  Blood may be obtained directly 
by venipuncture on days when only a single pharmacokinetic sample is scheduled for collection.  
When sampling through the peripheral catheter, begin to clear the catheter approximately 1 min 
before the specified sample time by withdrawing the lock solution and approximately 0.5 mL of 
blood into a syringe. Remove and properly dispose the syringe used to clear the catheter.   
 
A battery-powered digital timer/stopwatch programmed to operate continuously as a 24-hour clock 
must be used to accurately monitor the drug administration and sample collection times. The same 
timer must be allowed to run without interruption until the last pharmacokinetic blood specimen 
has been obtained from the subject. Timer readings will be noted at the precise time that the two 
drugs are taken on days when the patient is in the clinic and at the beginning and ending times of 
the blood sample collection intervals. Readings of the digital timer must be directly recorded on a 
copy of the Pharmacokinetic Data Form for this study. Computer files for printing the 
Pharmacokinetic Data Form and sample collection and storage tube labels will be prepared by the 
DF/HCC Cancer Pharmacology Core and distributed by e-mail to clinical research staff each study 
site.   
 
Samples are to be collected in a plastic lavender stoppered Vacutainer 4.0 mL plasma collection 
tube with spray-coated K2EDTA (Becton-Dickinson, cat. no. 367844). Blood samples will be 
obtained on day 1 of cycles 1 and 2 just before starting the docetaxel infusion (within 15-minutes 
pre-dose), at the midpoint of the infusion (30 minutes +/- 5 minutes) and at the end of the infusion 
(60 minutes +/- 5 minutes.) Post-dose samples will be obtained at 30 minutes (+/- 5 minutes), 1.0 
hour (+/- 10 minutes), 1.5 hours (+/- 10 minutes), 2.0 hours (+/- 10 minutes), 4.0 hours (+/- 15 
minutes), 6.0 hours (+/- 15 minutes), and 8.0 hours (+/- 15 minutes) after completion of the 
infusion.  On day 2 a sample will be collected at 24.0 hours (+/- 1 hour) after start of the infusion.  


DF/HCC Protocol #: 16-485 
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55 
 
The dose of apalutamide on day 1 of cycle 2 should be taken after the pretreatment sample is 
collected coincident with starting the docetaxel infusion.  It is also very important that the patient 
is aware that the morning dose of apalutamide on day 2 of cycle 1 and cycle 2 must not be taken 
before arriving at the clinic and the 24-hour pharmacokinetic sample has been collected.   
 
In the event that either study drug is held at a PK-collection time point, PK collection should be 
discussed with study PI.  In general, PK sampling will be skipped if: 
• The docetaxel infusion is not administered (e.g., cycle 2 day 1 infusion held) 
• The patient has not completed 5 consecutive days of apalutamide dosing before scheduled 
PK sampling 
• Apalutamide dose is held on the day of scheduled PK sampling 
 
9.1.3 Handling of Specimens 
 
Once collected in a plastic lavender stoppered Vacutainer 4.0 mL plasma collection tube with 
spray-coated K2EDTA (Becton-Dickinson, cat. no. 367844). Promptly mix the plasma collection 
tube by immediately inverting it 8-times gently (i.e. without agitation), then place the tube on wet 
ice until centrifuged (1,300 x g, 10 min, 4°C) within 15 min after collection. Separate the plasma 
from the blood cells using a disposable pipette and transfer the plasma into a 4.5 mL self-standing 
polypropylene cryogenic storage vial with external threads (Fisher Scientific, cat. no. 12-565-291).  
Affix a pre-printed label, with the protocol number, patient accession number, and sample number 
onto the cryovial, oriented crosswise toward the upper part of the tube, without overlapping the 
vial cap. Completely cover the label with polyester protective label tape (Fisher Scientific, cat. no. 
11-867B) to prevent the label from detaching from the vial when stored frozen. Place the tube on 
crushed dry-ice until stored in a freezer maintained at < -70°C.   
 
9.1.4 Shipping of Specimens for PK analysis 
 
Complete sets of samples from one or more patients will be sent by next day delivery to the address 
listed below. Place the sample tubes in a zip lock plastic bag. Package samples in a seamless 
styrofoam container. Place the sample bag over at least 3-4 inches of dry ice on the bottom of the 
container and completely cover with an additional 3-4 inches or more of dry-ice. Seal the 
styrofoam container within a tight-fitting cardboard shipping box. Insert copies of the 
Pharmacokinetic Data Form for each set of samples into a separate zip-lock plastic bag placed on 
top of the styrofoam container before the external shipping box is sealed. Send the samples from 
Monday to Wednesday by overnight courier for delivery on the following day. Samples should not 
be shipped on a Thursday or Friday.  Notification of the shipment and the courier tracking no. must 
be made by sending an e-mail to the following: (1) MGHCCPOSPL@partners.org; and (2) 
jsupko@partners.org. Attach a scanned copy of the Pharmacokinetic Time Record for all samples 
in the shipment to the email. Please do not attempt to charge shipping costs to Dr. Supko.  
 
 
Dr. Jeffrey G. Supko 
 
Massachusetts General Hospital 
 
55 Fruit St., GRJ 1025 
 
Boston, MA 02114 
 
Tel: 617-724-1970 


DF/HCC Protocol #: 16-485 
Protocol Version Date: 15 June 2018  
56 
 
 
9.1.5 Pharmacokinetic Analysis 
 
The concentration of docetaxel and other analytes of interest will be determined by analytical 
methods based upon reversed-phase high-performance liquid chromatography with tandem mass 
spectrometry established by the DF/HCC Cancer Pharmacology Core laboratory located at the 
Massachusetts General Hospital.  Validation of the analytical methods and their application to 
the analysis of study samples will conform to recommendations in the current FDA Guidance for 
Industry on Bioanalytical Method Validation, May 2001 
(http://www.fda.gov/downloads/Drugs/Guidances/ucm070107.pdf).   
 
Individual patient plasma concentration-time curves will be analyzed by noncompartmental 
methods using routines supplied in the WinNonlin Professional Version 4.0.1 software package 
(Pharsight Corp., Cary, NC). Pharmacokinetic parameters and variables will be calculated 
according to standard equations. Mean values of pharmacokinetic parameters will be statistically 
compared using the paired two-tailed t-test of the log-transformed data.   
 
9.2 
Blood Collection for PD assays for Biomarker Testing 
 
To be done at the Dana-Farber Cancer Institute 
 
Unused samples will be destroyed at the end of the study and will not be used for future analysis. 
 
9.2.1 cfDNA Plasma 
 
As an exploratory endpoint, plasma will be collected for genomic analysis of circulating free 
DNA (cfDNA). cfDNA will be collected at baseline, C5D1, and at time of progression or 
discontinuation of treatment. The cfDNA from each time point will be subjected to low pass 
whole genome sequencing to assess DNA quality, tumor purity (i.e. the approximate percentage 
of DNA isolated from peripheral blood originating from tumor rather than normal cells), and 
copy number profile of tumor DNA. For subjects with cfDNA of adequate quality and purity, we 
will also perform whole exome sequencing from cfDNA isolated at baseline, at best tumor 
response, and at progression. The sampling schedule and procedures that are to be used to 
establish times, collect samples, and process specimens for storage and shipment prior to 
analysis are described in the lab manual. 
 
• Time Points  
o Pre-dose Cycle 1 Day 1 (Note: Whole Blood for Germline DNA needs to only be 
collected once at pre-dose Cycle 1/Day 1) 
o C5D1 
o At time of progression or discontinuation of treatment 
 
• Method for analysis:  
o Assay Details for ultra low pass whole genome sequencing (ULP-
WGS): Frozen aliquots of plasma will be thawed at room temperature. Cell-free 
DNA is extracted from 2 mL of plasma and eluted into 60 uL of resuspension 


DF/HCC Protocol #: 16-485 
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57 
 
buffer using the Qiagen Circulating DNA kit on the QIAsymphony liquid 
handling system. Extracted cell-free DNA is frozen at -20 °C until ready for 
further processing. Quantification of extracted cfDNA and gDNA is performed 
using the PicoGreen (Life Technologies) assay on a Hamilton STAR-line liquid 
handling system. Library construction of cell-free DNA is performed using the 
Kapa HyperPrep kit with custom adapters (IDT). Generally, 5 ng of cfDNA input 
is used for ultra low-pass whole-genome sequencing (ULP-WGS). A Hamilton 
STAR-line liquid handling system is used to automate and perform this method. 
Constructed sequencing libraries are pooled (2 uL of each x 96 per pool) and 
sequenced using 100bp paired-end runs over 1 x lane on a HiSeq2500 (Illumina) 
for ULP-WGS. 
o The genome is divided into T non-overlapping windows, or bins, of 1Mb. Aligned 
reads are counted based on overlap within each bin using the tools in HMMcopy 
Suite (http://compbio.bccrc.ca/software/hmmcopy/). The read counts are then 
normalized to correct for GC-content and mappability biases using HMMcopy R 
package. This data is used to generate a Hidden Markov Model to derive copy 
number alterations and Tumor DNA purity using TitanCNA R package v1.9.0 
(https://github.com/gavinha/TitanCNA) 8. Samples must pass a quality threshold 
(median absolute deviation score < 0.115) for accurate purity estimate. 
o Assay details for whole exome sequencing: When possible, 20ng of cfDNA 
input is used to construct another cfDNA library for WES, which afforded affords 
greater library complexity and reduced the depth of sequencing required to 
achieve the desired mean target coverage. Library construction was performed 
using the Kapa HyperPrep kit with custom adapters (IDT) on a Hamilton STAR-
line liquid handling system. Libraries are then quantified using the PicoGreen 
(Life Technologies) assay on a Hamilton STAR-line liquid handling system and 
pooled up to 12-plex. Hybrid selection of cfDNA libraries is performed using the 
Nextera Rapid Capture Exome kit (Illumina) with custom blocking oligos (IDT 
and Broad Institute). Sequencing to generate 100bp paired-end reads is performed 
on the Illumina HiSeq2500 in high-output mode with 2-4 libraries per lane. Single 
nucleotide variants are identified using MuTect16 and cancer cell fractions of 
these variants are derived using ABSOLUTE. 
 
9.2.2 AR Variant Testing 
 
AR variants will be measured at RNA level by qRTPCR and by measuring circulating tumor 
DNA (ctDNA) 
 
• Time Points  
o Pre-dose Cycle 1 Day 1  
o C5D1 
o At time of progression or discontinuation of treatment 
 
• Method for analysis:  
o Total RNAs sourced from the buffy coat containing normal circulating cells (i.e. 
PBMC) as well as the circulating tumor cells (CTCs) will be used for ARv7 


DF/HCC Protocol #: 16-485 
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analysis. Droplet digital polymerase chain reaction (ddPCR) technology will be 
used.  
o DdPCR (QX200, Bio-Rad, Hercules, CA, USA) will be employed in this study. 
Droplet generation, PCR reactions, and detection will be carried out according to 
the manufacturer's instruction. Briefly, the reactions will be performed in 20-μL 
reaction volume that consists of 10 μL of 2× ddPCR Supermix for probes (No 
dUTP) (Bio-Rad), 1 μL of gene-specific primers (900 nM) and probes (250 nM) 
and 2 μL of the cDNA sample. Each reaction mix will be converted to droplets 
with the QX200 droplet generator (Bio-Rad). Droplet-partitioned samples will be 
transferred to a 96-well plate, sealed and cycled in a C1000 Touch thermal cycler 
(Bio-Rad) under the following cycling protocol: 95 °C for 10 min, followed by 40 
cycles of 94 °C for 30 s, 60 °C for 60 s, and a 10-min incubation at 98 °C. The 
cycled plates will then be read on a Bio-Rad QX200 droplet reader. At least two 
negative control wells with no cDNA template will be included in every run. The 
data analysis will be performed with QuantaSoft droplet reader software v1.7.4 
(Bio-Rad). The target mRNA concentrations will be calculated using Poisson 
statistics and the background will be corrected based on the data of the no 
template control. Absolute transcript levels will be initially presented as copies 
per μL and converted to copies per μg RNA based on the input amount of RNA. 
 
 
 


DF/HCC Protocol #: 16-485 
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10.  
STUDY CALENDAR 
 
All screening assessments must be performed within 30 days prior to the date of registration.  
 
In the event that the participant’s condition is deteriorating, laboratory evaluations should be 
repeated within 48 hours prior to initiation of the next cycle of therapy. 
 
Assessments must be performed prior to administration of study agents. Study assessments and 
agents should be administered within + 3 days of the protocol-specified date, unless otherwise 
noted. 
 
Table 13: Study Calendar 
 
 
 
Screeninga 
 
C1D1
a, b 
 
C1D8, 
C1D15 
 
C2 
D1 
 
C2 
D15 
 
C3 
D1 
 
C4 
D1 
Cycle 5,  
Day 1 
(week 
13) 
Cycles 6+, 
Day 1b 
 
 
Every  
12 
weeks 
 
30day Post-
study drug 
follow-up 
visit (+ 7 
days) 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical and cancer 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam/Clinic 
visit b, c 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
Vital signsd 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
Weight 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Performance statuse 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
CBC with differentialf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Complete metabolic 
panelg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Serum PSA 
X 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
Serum Testosterone 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
LDH 
X 
 
 
 
 
 
 
 
 
 
X 
X 
PT/PTT or INR 
X 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
PK samplesh   
 
 
X 
 
X 
 
 
 
 
 
 
 
 
Blood/plasma for ARv7 
 
X 
 
 
 
 
 
X 
 
 
Xo 


DF/HCC Protocol #: 16-485 
Protocol Version Date: 15 June 2018  
60 
 
and biomarker studiesi 
TSH, Free T4, T3 j 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
 
Bone Scan 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
MRI or CT 
chest/abd/pelvisk 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
Docetaxel 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Apalutamidel 
 
X (daily dosing while on study) 
 
GnRH 
agonist/antagonistm 
 
 
X 
 
Concomitant 
medications 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
Adverse events 
Assessment 
 
 
X 
X* by 
MD, 
NP, PA 
or RN 
X 
X* 
by 
MD, 
NP, 
PA, 
or 
RN 
X 
X 
X 
X 
 
X 
Study Drug Diary 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Progression/Survival 
Follow-upn 
 
 
 
 
 
 
 
 
 
 
X 
 
 
a  
All screening assessments must be performed within 30 days prior to the date of 
registration. If testing is performed within 72 hours of the first dose, screening 
evaluations may serve as the pre-dose Day 1 visit evaluations. All other visits must be 
done within +/-3 days and scans +/- 7 days of scheduled event. If study drugs are held, 
the assessments and cycle/day numbering should continue according to protocol 
schedule and will not be adjusted.   
b  
The physical examination, clinical laboratory tests, and ECOG performance status may 
be performed up to 72 hours before study drug administration; test results must be 
available before study drug administration.  
c  
Complete physical examination including neurologic assessment at screening, day 1 of 
cycle 1. Otherwise, brief disease- and adverse event-focused history and focused physical 
exam. 
d 
Blood pressure, heart rate, and temperature at screening, day 1 of all cycles, and at post-
study drug follow-up visit.   
e 
ECOG Performance status should be assessed 
f 
CBC with differential includes WBC, ANC, hemoglobin, hematocrit, and platelets 
g  
Serum complete metabolic panel includes sodium, potassium, chloride, bicarbonate, 
BUN/ creatinine, calcium, albumin, and liver function tests (total bilirubin, AST/ALT, 
alkaline phosphatase) 
h  
Pharmacokinetic (PK) samples will be drawn in the first 12 patients enrolled at Dana-
Farber Cancer Institute (more may be added to ensure at least 6 patients with 2 full sets of 
PK samples C1-C2D2): At each time point, 4mL of whole blood will be collected into an 
EDTA (lavender top) vacutainer.   
• C1D1: just before starting the docetaxel infusion (within 15-minutes pre-dose), at the 


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midpoint (30 min +/- 5 min) and end (60 min +/- 5 min) of the infusion; post-dose 
samples at 30 min (+/- 5 min), 1.0 hour (+/- 10 min), 1.5 h (+/- 10 min), 2.0 h (+/- 10 
min), 4.0 h (+/- 15 min), 6.0 h (+/- 15 min), and 8.0 h (+/- 15 min) after completion of 
the infusion 
• C1D2: on day 2 at 24.0 h (+/- 1 h) after start of the docetaxel infusion. Prior to first 
dose of apalutamide. 
• C2D1: just before apalutamide dose and starting the docetaxel infusion (within 15-
minutes pre-dose), at the midpoint (30 min +/- 5 min) and end (60 min +/- 5 min) of 
the infusion; post-dose samples at 30 min (+/- 5 min), 1.0 hour (+/- 10 min), 1.5 h (+/- 
10 min), 2.0 h (+/- 10 min), 4.0 h (+/- 15 min), 6.0 h (+/- 15 min), and 8.0 h (+/- 15 
min) after completion of the infusion 
• C2D2: day 2 at 24.0 h (+/- 1 h) after start of the docetaxel infusion. Prior to dose of 
apalutamide. The dose of apalutamide should be taken after the pretreatment sample 
is collected coincident with starting the docetaxel infusion.   
i 
Blood for exploratory biomarker studies. Refer to section 9.2 for further information.  
j 
TSH, total T3, and free T4 should be evaluated at screening. TSH should then be 
measured  on Day 1 of each cycle for the first 4 cycles, and then every 12 weeks starting 
after Cycle 5, at which point it can be done concomitant with the every 12 week scans.  
After screening, total T3 and free T4 should be performed only if TSH abnormal at 
previous assessment, or becomes abnormal. They should be followed until they 
normalize.   These labs do not need to be reviewed prior to dosing on D1 and subsequent 
cycles, but, once results have returned, the subsequent dosing should be adjusted as 
needed per the dosing modification guidelines in section 6.  
k 
Radiologic or symptomatic documentation must be provided for subjects who are 
removed from the study for progressive disease. Contrast CT or MRI scans of the 
chest/abdomen/pelvis are preferred but if the patient’s renal function will not permit 
contrast, non-contrast imaging will be permitted. Type of imaging should remain 
consistent throughout the study. If baseline CT chest does not demonstrate prostate 
cancer, do not need to repeat chest CT on study unless the investigator suspects new 
findings based on clinical signs/symptoms. NOTE: If bone lesions are present in the chest 
CT imaging field at baseline, chest CT is to be continued at subsequent assessments. 
 
l 
 The first dose of apalutamide will start on C1D2 for the PK cohort but C1D1 for all 
others. Apalutamide dose is to be taken in clinic on days when PKs are being collected 
(e.g., C1D2, C2D1, C2D2; unless PK collection is held per protocol.)  For the PK cohort, 
the dose of apalutamide on C2D1 should be taken after the pretreatment sample is 
collected, coincident with starting the docetaxel infusion.  
 
m 
 Patients without a history of surgical castration will be maintained on their GnRH agonist 
or antagonist per their normal schedule unless intolerant 
 n 
 Follow-up regarding progression and survival every 3-6 months for up to 36 months from 
end of treatment. This can be performed at a follow-up visit in clinic if they are still being 
treated at DF/HCC, phone, medical record, referring or subsequent treating physician, or 
publicly available records such as SSDI. 
 
o 
At 30 day Post-study drug follow-up visit (+ 7 days) or at visit when drug discontinued 
for PD. 
* Adverse assessments may be performed by MD, NP, PA or RN. 
 
 


DF/HCC Protocol #: 16-485 
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62 
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 
45:228-247, 2009] and PCWG2 criteria (see Appendix D). Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. 
 
For the purposes of this study, participants should be re-evaluated every 12 weeks. When possible, 
confirmatory scans will also be obtained at least 4-8 weeks following initial documentation of an 
objective response. The serum PSA level will be measured monthly. Continuation of study 
therapy will be encouraged in patients with PSA increases but no evidence of radiographic 
or symptomatic disease progression or unconfirmed disease progression. Bone flare 
phenomenon can occur with antiandrogens.  
 
11.1.1 Definitions 
 
Evaluable for Target Disease response. Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response. These 
participants will have their response classified according to the definitions stated below. 
(Note: Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response. Participants who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease. The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by chest 
x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam. All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 


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Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered non-
measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as target 
lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion, which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.  
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a 
digital measurement tool. All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 30 days before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 


DF/HCC Protocol #: 16-485 
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64 
 
imaged but are assessable by clinical exam.  
 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung; however, CT is preferable.  
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT thickness is 5mm or less. If CT scans have slice thickness greater than 
5 mm, the minimum size of a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible. 
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later data and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure from CT, MRI may be used instead 
of CT in selected instances.  
 
Tumor markers. Tumor markers alone cannot be used to assess response, but changes in PSA will 
be evaluated as a secondary measure of clinical outcome. 
 
 
 
Definition of PSA response: A PSA partial response is defined as a ≥ 50% decline from 
baseline and requires a confirmatory PSA at least 3 weeks or more later. Given that a favorable 
effect on PSA may be delayed for 12 weeks or more, PSA will be monitored every cycle but 
treatment will continue through early rises for a minimum of 12 weeks.39  
 
Cytology and Histology. These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ 
cell tumors, where known residual benign tumors can remain). 


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FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
(b) No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET 
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
(c) FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. 
The use of FDG-PET in this circumstance should be prospectively described in the protocol 
and supported by disease-specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity. 
 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data, which may bias an investigator if it is not routinely or serially 
performed.   
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 


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increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Existing bone metastases may be the only target lesions in some patients. Because bone lesions 
are notoriously difficult to follow, ‘progression’ in non-target lesions is defined as the 
appearance of 2 new lesions, and, for the first reassessment only, a confirmatory scan 
performed 6 or more weeks later is required that shows a minimum of 2 or more additional 
new lesions (PCWG2 criteria).   
 
Other measurable disease will be assessed according to RECIST version 1.1: 
 
Evaluation of Measurable Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator). 
 
Because bone lesions are notoriously difficult to follow, ‘progression’ is defined as the 
appearance of 2 new lesions, and, for the first reassessment only, requires a confirmatory 
scan performed 6 or more weeks later that shows a minimum of 2 or more additional new 
lesions (PCWG2 criteria).   
 
11.1.4.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning technique, 
imaging modality, or findings thought to represent something other than tumor (for example, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions). However, unless 
symptomatic or associated with laboratory abnormalities, a lesion identified on a follow-up scan 


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in an anatomical location that was not scanned at baseline will not be considered new until 
confirmed with repeat scans ≥4 weeks later. If a new lesion is equivocal (because of small size 
etc.), follow-up evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion was 
discovered. 
 
11.1.4.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Table 14: For Participants with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. As response is not 
the primary endpoint, this is not required, but encouraged. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
 
 
 
 
 
 
 


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Table 15: For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD** 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
** Because bone lesions are notoriously difficult to follow, ‘progression’ is defined as the 
appearance of 2 new lesions, and, for the first reassessment only, requires a confirmatory 
scan performed 6 or more weeks later that shows a minimum of 2 or more additional new 
lesions (PCWG2 criteria).   
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The ODQ will collect, manage, and perform quality checks on the data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the ODQ according to the schedule set by the ODQ. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 


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summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is an open-label, single-arm phase 2 study of the combination of docetaxel and apalutamide 
in patients with metastatic CRPC.  
 
There will be an initial 6 patient safety lead-in phase. The first 3 patients will be accrued to start 
the initial combination at dose level 1 and then accrual will be halted until all have completed the 
first cycle (i.e., first 3 weeks of therapy). If less than 2 patients experience a drug related dose-
limiting toxicity (DLT) as defined in section 6.1, the next 3 patients will be enrolled. Accrual 
will be halted again until this next cohort has completed their first cycle and safety assessment. If 
<2/6 patients experience a DLT, the study will open to full accrual. If 2 or more patients 
experience a DLT, the dosing of the study drugs will be reviewed and protocol amended. 
 
The primary objective is to evaluate the efficacy of the drug combination in terms of progression 
free survival. 
 
Primary endpoint 
 
Progression free survival (PFS) is defined as the time from treatment initiation until the occurrence 
of one of the following:  
1. A participant was considered to have progressed by bone scan if  
a. the first bone scan with greater than or equal to (≥) 2 new lesions compared to baseline 
was observed in less than (<) 12 weeks from study drug initiation and was confirmed 
by a second bone scan taken ≥6 weeks later showing ≥2 additional new lesions (a total 
of ≥4 new lesions compared to baseline);  
b. the first bone scan with ≥2 new lesions compared to baseline was observed in ≥12 
weeks from study drug initiation and the new lesions were verified on the next bone 
scan ≥6 weeks later (a total of ≥2 new lesions compared to baseline);  
2. Progression of soft tissue lesions measured by computerized tomography (CT) or magnetic 
resonance imaging (MRI) by RECIST v. 1.1; or  
3. Death from any cause.  
 
Patients who have not progressed or died at the time of assessment will be censored at the time of 
the last date of assessment. In the event that patients demonstrate progression based on soft tissue 
by RECIST v 1.1, and/or bone scans at differing time points, the earliest date of documented 
progression will be used to calculate PFS. 
 
 
 
 


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Secondary endpoints:  
 
• Safety and tolerability according to NCI CTCAE version 4.0 
• Dose-limiting toxicities (DLT) in the safety lead in group 
• Pharmacokinetics (Cmax and AUC) of docetaxel 
• Time to disease progression: defined as the time from treatment initiation to objective 
disease progression by imaging or by worsening symptoms but does not include by PSA 
rise alone. Death from non-prostate cancer causes are not considered as an event. The date 
of progression will be determined as described above for PFS. Patients who die for any 
reason prior to disease progression will be censored at the time of death.  
• Time to radiologic progression (rTTP): time from treatment initiation to objective 
radiologic progression on subsequent screening according to RECIST v.1.1 
• Time to PSA progression: time from treatment initiation to first rise ≥25% and >2ng/dL 
above the nadir that has been confirmed 3 or more weeks later    
• Time to Treatment Failure: time from treatment initiation to discontinuation of therapy due 
to disease progression (not by PSA rise alone), toxicity, or patient withdrawal. 
• Overall survival (OS): is defined as the time from trial treatment start to death due to any 
cause, or censored at date last known alive. 
• PSA decline ≥50% from baseline at 12 weeks of therapy and which has been confirmed 
with a second PSA at ≥ 3 weeks later. 
• Percent change from baseline in serum PSA39: the percent change from baseline in PSA 
levels after 12 weeks on study and the maximum percent change (rise or fall) from 
baseline will be recorded 
• Overall Response Rate (ORR): The ORR (%) will be calculated as the number of patients 
with best objective response via RECIST v 1.1 criteria of CR or PR divided by the 
number of patients with measurable disease at baseline. The best objective response for a 
given patient will be based on objective responses determined from data obtained up to: 
progression, the last evaluable assessment in the absence of progression, or initiation of 
subsequent anticancer therapy. Patients for whom an objective response cannot be 
determined or for who the best objective response is ‘not evaluable’ (NE) will be 
considered non-responders.   
  
13.2 
Sample Size, Accrual Rate and Study Duration 
 
The sample size calculations included the following assumptions: 
  
(1) The distribution of PFS follows an exponential distribution  
(2) The median time to disease progression under standard therapy is about 4 months 
[observed in multiple series for patients treated with prior enzalutamide after abiraterone 
for CRPC].13-18   
(3) The hypothesis to be tested is based on the median PFS time of H0: t0=4 months versus 
Ha: t1=6.5 months. The test will be one-sided. 
  
 
 


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            The following table considers a few scenarios with sample size of 30 to achieve at least 
90% power. 
 
 
 
Table 16 
 
  
 
 
 
 
 
 
 
A sample size of 30 evaluable patients achieves 90% power to detect the difference between the 
null hypothesis (Ho: 4 months median PFS from historical control or current standard therapy) 
and the alternative hypothesis (Ha: 6.5 months of median PFS from the combination therapies) at 
an alpha =0.1 significance level using a one-sided Wald test for the log failure rate parameter, 
conducted after two-year post-enrollment study duration. Anticipating that 10% of patients will 
not be evaluable due to possible adjustment in dosing from findings of safety run-in phase, 
sample size will be augmented to a total of 33 patients. 
  
The accrual is expected to be 3 patients every month for 12 months to complete enrollment with 
additional follow-up to 2 years for disease progression or survival, the study is expected to last 
approximately 36 months.  
 
Table 17: Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
0 
+ 
6 
= 
6 
Not Hispanic or Latino 
0 
+ 
27 
= 
27 
Ethnic Category: Total of all subjects 
0 
+ 
33 
= 
33 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
0 
+ 
5 
= 
5 
Black or African American 
0 
+ 
3 
= 
3 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
0 
White 
0 
+ 
25 
= 
25 
Racial Category: Total of all subjects 
0 
+ 
33 
= 
33 
 
 
  
 
 
 
 
13.3 
Definition of Study Population/ Stratification Factors 
 
Safety /Evaluable population: All patients receiving at least one dose of docetaxel with 
apalutamide will be included in analyses unless otherwise specified. 
Ho: 
median PFS 
(mos.)  
 Ha: 
median 
PFS 
(mos.) 
Number 
of PFS 
failures 
Type I error 
(one-sided) 
Power (%) 
 
3 
5 
29 
0.1 
93 
3.5 
6 
28 
0.1 
94 
4 
6.5 
28 
0.1 
90 


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No stratification factors are used in enrolling patients. 
 
13.4 
Interim Monitoring Plan of Safety Lead in Phase 
 
There will be an initial 6 patient safety lead-in phase. The first 3 patients will be accrued and 
then accrual will be halted until all have completed the first cycle. If less than 2 patients 
experience a drug related dose-limiting toxicity (DLT), the next 3 patients will be enrolled. 
Accrual will be halted again until this next cohort has completed their first cycle and safety 
assessment. If <2/6 patients experience a DLT, the study will open to full accrual. If 2 or more 
patients experience a DLT, the dosing of both study agents will be reviewed and protocol 
amended. 
 
13.5 
Analysis of Primary Endpoints 
 
Progression-free survival (PFS) will be summarized using the product-limit method of Kaplan-
Meier. Median times for PFS endpoint will be presented with two-sided 80% confidence 
intervals estimated using log-log (survival) methodology. If the lower confidence interval 
(corresponding to a one-sided 90% CI) excludes null hypothesis or historical control of 4 month 
median PFS, then there is sufficient evidence to indicate the combination therapy improves PFS. 
Kaplan-Meier estimates of PFS at 6 or 12 months after treatment initiation may also be presented 
with two-sided 80% confidence intervals. 
 
13.6 
Analysis of Secondary Endpoints 
 
Safety and Tolerability: All adverse events recorded during the trial will be summarized 
for the safety population. The incidence of events that are new or worsening from the time 
of first dose of treatment will be summarized according to system organ class and/or 
preferred term, severity (based on CTCAE version 4.0 grade), type of adverse event, and relation 
to study treatment. Deaths reportable as SAEs and non-fatal serious adverse events will be listed 
by patient and tabulated by primary system organ class, and type of adverse event. 
 
Clinical data will be summarized using descriptive statistics (number of patients, mean, median, 
standard deviation, minimum and maximum) for continuous variables and using frequency and 
percentages for discrete variables  
 
Time to event endpoints (e.g., time to radiologic progression, time to treatment failure) will be 
analyzed using the Kaplan-Meier Method.   
 
PSA response will be assessed according to Prostate Cancer Working Group 2 criteria. 
 
Serum PSA change from baseline: the maximum percent PSA change (rise or fall) from 
baseline to after 12 weeks on study. It will be summarized using box-whisker plots and waterfall 
plots for each treatment arm. For patients who discontinue on or before the 12 week assessment 
or for whom the 12 week assessment is missing, the last observation prior to the week 12 
assessment will be utilized. Patients with no post-baseline PSA data will be excluded from the 


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summaries. 
 
Objective Response Rate: The proportion of patients with ORR (as defined in section 11.1.4.4) 
will be presented with two-sided 90% confidence interval estimated using exact binomial 
methods. 
 
Pharmacokinetic (PK) analysis: 
 
The PK parameters of the first 12 patients enrolled at Dana-Farber Cancer Institute will be 
determined using noncompartmental methods with WinNonLin version 5.2. Maximum blood 
concentration (Cmax) and time of maximum blood concentration (tmax) will be determined by 
visual inspection. The area under the blood concentration-time curve (linear trapezoidal rule) will 
be determined between 0-24 hours (AUC0-24). The mean (+/- STDEM) concentration-time 
profiles of docetaxel will be presented.  
 
Exploratory /Correlative Analysis: 
 
For the subset of patients with AR-V7 expression in CTCs, the association between pre-
treatment AR-V7 expression and outcomes will be explored, e.g., the proportion of patients with 
objective response according to pre-treatment AR-V7 will be summarized with two-sided 90% 
exact binomial confidence intervals (CI). Kaplan-Meier estimates will be used to assess the 
distribution of PFS according to baseline AR-V7 expression positivity. Medians of time to event 
endpoints will be shown with two-sided 90% CIs. 
 
13.7 
Safety Considerations 
 
Patients will be monitored throughout treatment and follow-up period for occurrence of adverse 
events (AE’s; acute, delayed, and cumulative) as well as for changes in clinical status, vital 
signs, and laboratory data. NCI Common Terminology Criteria for Adverse Events (CTCAE, 
Version 4.0) will be used to grade toxicities. 
 
Safety parameters to be assessed include eligibility assessment, medical history, performance 
status, vital signs, physical examination, baseline ECG, and the following laboratories: serum 
PSA, testosterone, CBC with differential, and complete metabolic panel.  
 
13.8 
Reporting and Exclusions 
 
13.8.1 Evaluation of Toxicity 
 
All participants who received at least one dose of study treatment will be included in the 
toxicity assessment. In the safety lead in phase of 6 patients, DLTs will be summarized 
among all patients evaluable for DLT (i.e., patients are excluded if they stop therapy prior 
to receiving more than 85% of planned dosing of both agents in first 28 days for reasons 
other than DLT). Baseline toxicities will not be included/attributed to the study therapy. 
 


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13.8.2 Evaluation of the Primary Efficacy Endpoint 
 
The primary endpoint will be based on intent-to-treat population. Specifically, all eligible 
participants included in the study will be assessed for response/outcome to therapy, even 
if there are major protocol therapy deviations.   
 
Subanalyses may be performed on the basis of a subset of participants, excluding those 
for whom major protocol deviations have been identified (e.g., early death due to other 
reasons, early discontinuation of treatment, major protocol violations, etc.). However, 
these subanalyses will not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding participants from the analysis should be 
clearly reported. If applicable to the endpoint, the 95% confidence intervals will be 
provided.  
 
 
 
 
 
 
 
 
 
 
 
  


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75 
 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
 
The participant ____________________________ is enrolled on a clinical trial using the 
experimental agent apalutamide. This clinical trial is sponsored by Dana-Farber Cancer 
Institute. This form is addressed to the participant, but includes important information for others 
who care for this participant.  
 
Apalutamide interacts with many drugs that are processed by your liver. Because of this, it is 
very important to tell your study doctors about all of your medicine before you start this study. It 
is also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study. When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions. You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you. These are the things that you and they need to know:  
 
Apalutamide interacts with (a) certain specific enzyme(s) in your liver.  
• The enzyme(s) in question is CYP3A4  
• Apalutamide must be used very carefully with other medicines that need these liver 
enzymes to be effective or to be cleared from your system.   
• Other medicines may also affect the activity of the enzyme.   
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects. 
o Docetaxel is broken down by this enzyme in order to be cleared from your 
system. Thus, apalutamide may decrease the potency of docetaxel, which could 
lead to less effectiveness. 
o Co-administration with any of these strong CYP3A4 inhibitors may increase 
apalutamide plasma concentrations and potentially lead to increased side 
effects. 
▪ Itraconazole, 
clarithromycin, 
erythromycin, 
diltiazem, 
verapamil, 
delavirdine, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, 
saquinavir, telithromycin, voriconazole, grapefruit juice (or grapefruits), 
ketoconazole, dexamethasone 
o Co-administration with any of these strong CYP3A4 inducers may decrease 
apalutamide plasma concentrations and may lead to decreased effectiveness. 
▪ Phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, 
efavirenz, tipranavir, St. John's wort 


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• You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
• Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of 
CYP3A4. 
• Your prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or consult a medical reference to see 
if any medicine they want to prescribe is on a list of drugs to avoid.   
• Please be very careful! Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye. They also have a generic name—it is usually small and 
located above or below the brand name, and printed in the ingredient list. Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction.   
• Be careful:  
o If you take acetaminophen regularly: You should not take more than 4 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age. 
Read labels carefully! Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit: Avoid these until the study is over.  
o If you take herbal medicine regularly: You should not take St. John’s wort while 
you are taking apalutamide. 
o Unless prescribed by your doctor, do not take dexamethasone with the exception 
of the day before, day of, and day after docetaxel premedication.  
 
 
Other medicines can be a problem with your study drugs.  
 
• You should check with your doctor or pharmacist whenever you need to use an over-
the-counter medicine or herbal supplement.  
 
• Your regular prescriber should check a medical reference or call your study doctor 
before prescribing any new medicine for you. Your study doctor’s name is: 
 
 
_____________________________________  
 
and he or she can be contacted at  
 
_____________________________________ 


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APPENDIX C 
 
PROHIBITED MEDICATIONS  
 
Generic Name 
Brand Name* 
aminophylline 
Aminocont; Aminomal; Diaphyllin; Filotempo; Neophyllin; Norphyl; Phyllocontin; 
Syntophyllin; Tefamin; Truphylline; Xing You Shan;  
aminophylline in 
combination 
Asmeton; Cha Xin Na Min; Emergent-Ez; Fufang Dan An Pian; Ke Zhi 
 
amitriptyline 
Amirol; Amitrip; Amixide; Deprelio; Diapatol; Elatrol; cElatrolet; Elavil; Endep; 
Enovil; Emitrip; Klotriptyl; Laroxyl; Levate; Limbitrol; Limbitryl; Mutabase; 
Mutabon; Nobritol; Novo-Triptyn; Pertriptyl; Redomex; Saroten; Sarotex; Sedans; 
Syneudon; Teperin; Triptizol; Triptyl; Tryptizol 
amitriptyline in 
combination 
PMS-Levazine 
 
bupropion 
 
Aplenzin; Buproban; Contrave; Elontril; Forfivo; Fortivo XL; Le Fu Ting; 
Prexaton; Quomem; Voxra; Wellbutrin; Wellbutrin XL; Wellbutrin SR; Yue Ting; 
Zyban 
chlorpromazine 
Aminazin; Chlorazin; Hibernal; Klorproman; Largactil; Megaphen; Ormazine; 
Plegomazin; Solidon; Taroctyl;Thorazine; Vegetamin; Wintermin; Zuledin 
Note: in Ireland also called “Clonazine” – very easy to confuse with clozapine. 
clozapine 
Azaleptin; Clopine; Closastene; Clozaril; CloZAPine; Denzapine; Elcrit; Fazacio 
ODT; Klozapol; Lanolept; Leponex; Lozapine; Nemea; Ozapim; Synthon, 
Versacloz; Zaponex 
desipramine  
Deprexan; Norpramin; Nortimil; Pertofrane 
doxepin 
Adapin; Anten; Aponal; Deptran; Gilex; Li Ke Ning; Quitaxon; Silenor; Sinepin; 
Sinequan; Zonalon 
imipramine 
Impril; Melipramin; Mipralin; Norfranil,; Novo-Pramine; Persamine; Pertofram; 
Pryleugan; Talendep; Tofranil; Tolerade 
lithium 
Arthriselect; Camcolit; Carbolith; Carbolithium; Eskolith; Hypnorex; Li-Liquid; 
Licarbium; Limas; Liskonum; Litarex; Lithane; Lithicarb; Lithioderm; Lithionit; 
Lithobid; Liticarb; Litiomal; Lito; Maniprex; Neurolepsin; Plenur; Priadel; 
Quilonorm; Quilonum; Saniquiet; Sedalit; Teralithe 
lithium in combination 
Boripharm No 23; Emser Salz; Girheulit HOM; Helidonium-Plus; Heweurat N; 
rheuma-loges; Rhus Toxicodendron Compose; Rhus-Plus; Ricinus Compose 
maprotiline 
Cronmolin; Deprilept; Ludiomil; Mapromil; Melodil; Neuomil; Psymion 
meperidine/pethidine 
Alodan ; Atropine and Demerol; Centralgine ; Demerol ; Dolantin ; Dolantina,; 
Dolantine ; Dolargan,; Dolcontral,; Dolestine ; Dolosal ; Dolsin; Fada; Hospira; 
Liba; Mepergan ; Meprozine,; Mialgin,; Opystan; Pethidine ; Petigan Miro ; 
Psyquil compositum 
meperidine/pethidine in 
combination 
Pamergan P100 
 
mesoridazine 
Serentil, Mesorin 
mirtazapine 
 
Arintapin; Avanza; Axit; Combar; Esprital; Mi Er Ning; Miro; Mirta TAD; 
Mirtabene; Mirtachem; Mirtadepi; Mirtagamma; Mirtalan; MirtaLich; Mirtamylan; 
Mirtaron; Mirtaz; Mirtazelon; Mirtazon; Mirtazonal; Mirtel; Mirtin; Mirtor; 
Mirzaten; Norset; Noxibel; Paidisheng; Psidep; Remergil; Remergon; Remeron; 
Remirta; Rexer; Yarocen; Zispin 
olanzapine 
Anzorin, Arenbil; Arkolamyl; Atyzyo; Bloonis; Clingozan; Egolanza; Lansyn; 
Lanzek; Lazapix; Nolian; Nykob; Olafid; Olanzaran; Olanzep; Olanzin; Olanzine; 
Olapin; Olasyn; Olazax; Olpinat; Olzapin; Olzin; Ou Lan Ning; Ozilormar; 
Parnassan; Ranofren; Sanza; Stygapon; Synza; Ximin; Zalasta; Zamil; Zappa; 
Zapris; Zerpi; Zolafren; Zolaxa; Zonapir; Zopridoxin; Zylap; Zypadhera; Zypine; 
Zyprexa; Zyprexa Relprew; Zydis 


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olanzapine in 
combination 
Symbyax 
 
risperidone 
Aleptan; Apo-Risperid; Arketin; Calmapride; Diaforin; Doresol; Hunperdal; Jing 
Ping; Ke Tong; Leptinorm; Lergitec; Orizon; Ozidal; Perdox; Ranperidon; 
Resdone; Ridal; Ridonex; Rileptid; Ripedon; Risepro; Rispa; Rispaksole; Rispefar; 
Rispemylan; Rispen; Rispera; Risperanne; Risperdal; Risperdalconsta; 
Risperdaloro; Risperigamma; Risperon; Rispolept; Rispolux; Rispond; Rispons; 
Risset; Rixadone; Rorendo; Ryspolit; Si Li Shu; Sizodon; Speridan; Suo Le; 
Torendo; Zhuo Fei; Zhuo Fu; Ziperid; Zoridal 
theophylline 
Aerolate; Afonilum; Aminomal; An Fei Lin; Apnecut; Apo-Theo; Asmalix; 
Asmalon; Bi Chuan; Bronchoparat; Bronchoretard; Cylmin; Diffumal; Elixifilin; 
Elixophyllin; Etipramid; Euphyllin; Euphyllina; Euphylline; Euphylong; Frivent; 
Gan Fei Lin; Nuelin; Protheo; Pulmophylline; Quelesu; ratio-Theo-Bronc; 
Respicur; Retafyllin; Shi Er Ping; Slo-Bid; Slo-Phyllin; Telbans; Teotard; Terdan; 
Teromol; Theo-24; Theo-Dur; Theo; Theochron; Theodur; Theofol; Theolair; 
Theoplus; Theospirex; Theostat ; Theotard; Theotrim; Theovent; Tromphyllin; 
Unicon; Unicontin; Unifyl; Uniphyl; Uniphyllin Continus; Uniphyllin; UniXan; 
Xanthium; Xi Fu Li; Yan Er 
theophylline in 
combination 
Antong; Baladex; Bi Chuan; Binfolipase; Broncho-Euphyllin; Broncomar; Do-Do 
ChestEze; Elixophyllin-GG; Elixophyllin-KI; Insanovin; Marax ; Neoasma; 
Theofol Comp; Theophedrinum-N; Xu Hong; Yi Xi Qing 
thioridazine 
Detril; Elperil; Melleril; Ridazin; Ridazine; Thiodazine; Thioril; Sonapa 
ziprasidone 
Geodon; Li Fu Jun An; Pramaxima; Si Bei Ge; Ypsila; Zeldox; Zipwell; Zypsila; 
Zypsilan 
 
** Note: this document is intended as an aid in identifying prohibited meds, but due to the 
global scope of the apalutamide studies may not be all inclusive.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX D 
PCWG2 CRITERIA 
 
The following eligibility and disease progression criteria were taken from the PCWG2 criteria 
established by Scher et al. 2008. 
Patients with Non-Measurable Disease 
A large percentage of men with metastatic prostate cancer have cancer involvement limited to 
bones, and therefore do not have measurable disease by RECIST v 1.1. These patients are 
eligible for this study, and will have response to treatment assessed by serial bone scans and 
serum PSA level.  
 
Eligibility Based on PSA Levels 
PSA level that has increased on 2 occasions obtained a minimum of 1 week apart and PSA level 
≥ 2 ng/ml (only the screening PSA needs to be ≥ 2 ng/ml; see Figure 2 below for an example).   
 
Figure 2           Eligibility based on PSA changes 
 
The baseline value is the last PSA measured before increases are documented and subsequent 
values are obtained a minimum of 1 week apart. If the PSA at time point 3 is greater than that at 
point 2 (2.0 ng/mL or higher), then eligibility has been met (Patient 1 in Figure 2). If the PSA at 
time point 3 is not greater than at time point 2, but the value at time point 4 is (2.0 ng/mL or 
higher), then the patient is eligible assuming that other criteria are met (Patient 2 in Figure 2), 
Bubley et al. 1999). 


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PCWG2 Criteria (continued) 
Details and dates of prior PSA measurements that can be used to estimate PSA doubling times 
(PSA-DTs) should be recorded. PCWG2 advises estimating a pretreatment PSA-DT if at least 
three values are available, but does not recommend delaying either treatment or enrollment onto 
a trial simply to estimate PSA-DT (Arlen et al. 2008). 
Eligibility Based on Bone Scan 
When the bone scan is the sole indicator of progression, PCWG2 defines progression in bone 
when at least 2 or more new lesions are seen on bone scan compared with a prior scan for trial 
entry. 
Disease Progression will be defined as follows: 
1) Bone Scan and Radiographic Progression 
Appearance of 2 or more new lesions on bone scan, and, for the first reassessment only, a 
confirmatory scan performed 6 or more weeks later that shows a minimum of 2 or more 
additional new lesions. The date of progression is the date of the first scan that shows the change.  
Or  
Soft tissue disease progression by modified RECIST v1.1 to report changes in lymph nodes that 
were ≥ 2 cm in diameter at baseline with additional requirement that progression at first 
assessment be confirmed by a second scan 6 or more weeks later. 
Note that for some treatments, a lesion may increase in size before it decreases. 
2) PSA Progression 
PSA progression is defined as ≥25% increase and ≥2 ng/mL increase above the nadir or baseline 
value for patients who had a PSA decrease on treatment which is confirmed by a second value 3 
or more weeks later.   
For patients without a decrease on treatment, PSA progression is defined as ≥25% and a ≥2 
ng/mL after 12 weeks.   
PSA progressions must be confirmed at the next study visit 4 weeks later. PSA will be collected 
at screening and on Day 1 of each treatment cycle.   
PSA progression alone will not be considered diagnostic of disease progression, and will not be 
used as a reason to discontinue study treatment. 
 
 
 
 
 
 
 
 


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 PCWG2 Criteria (continued) 
3) Symptomatic Progression 
Symptomatic progression is defined as evidence of unequivocal symptomatic or clinical 
progression defined by at least 1 of the following:  
• A marked escalation in cancer-related pain that is assessed by the Investigator to indicate 
the need for other systemic therapy or palliative radiotherapy. Ignore early changes (≤ 12 
weeks) in pain or health-related quality of life in absence of compelling evidence of 
disease progression. Confirm progression of pain or health-related quality of life ≥ 3 
weeks later,  
• An immediate need for initiation of new anticancer treatment, surgical or radiological 
intervention for complications due to tumor progression,  
• A marked deterioration in ECOG performance status to Grade 3 or higher, or  
• It is felt to be in the best interest of the patient to come off study due to clinical 
progression 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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