Conditions: Small Cell Neuroendocrine Carcinoma Prostate Cancer Small Cell Carcinoma
Keywords: Immunotherapy Androgen receptor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
Despite the low androgen receptor (AR) transcriptional activity of treatment-emergent small cell neuroendocrine prostate cancer, there is persistent AR expression observed in the majority of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) biopsies. This indicates that epigenetic dysregulation leads to reprogramming away from an AR-driven transcriptional program. Therefore, continuation of AR blockade in the form of apalutamide may provide additive benefit compared to immune checkpoint blockade alone. The investigators hypothesize that the combination of apalutamide plus cetrelimab will achieve a clinically significant composite response rate with sufficient durability of response in mCRPC patients with evidence of treatment-emergent small cell neuroendocrine prostate cancer

Detailed description:
This is a phase 2, single arm, Simon's two-stage evaluation of the combination of apalutamide plus cetrelimab in patients with mCRPC and histologic and/or genomic evidence of treatment-emergent small cell neuroendocrine prostate cancer who have previously progressed on at least one prior androgen signaling inhibitor.

Participants may continue study treatment from the time of treatment initiation until confirmed radiographic progressive disease (PD) per PCWG3 and RECIST 1.1 criteria, unequivocal clinical progression, unacceptable toxicity, or patient withdrawal, whichever occurs first, for a maximum of 24 months.

PRIMARY OBJECTIVE:

I. To determine the composite response rate as defined by achieving one or more of the following at any time point during study treatment:

1. Decline from baseline in serum PSA of \>= 50% (PSA50), confirmed by repeat measurement \>= 4 weeks later and/or
2. Objective response by RECIST 1.1 criteria

SECONDARY OBJECTIVES:

I. To determine safety of the combination as determined by CTCAE version 5.0.

II. To determine the median radiographic progression-free survival by PCWG3 criteria.

III. To determine the PSA50 and decline from baseline in serum PSA of \>= 90% (PSA90) response proportion achieved.

IV. To determine the median PSA progression-free survival.

V. To determine the median overall survival.

VI. To determine the objective response rate and median duration of response by RECIST 1.1 criteria.

Patients will be followed up for safety evaluations 30 days and 100 days after treatment completion. Patients will be followed for overall survival every 90 days (+/- 30 days) from last dose of study treatment, until death, withdrawal of consent, or the end of the study, whichever occurs first.

Arms:
arm 1: Participants will be given Apalutamide tablets combined with infusions of Cetrelimab in 28-day cycles, for up maximum of two years.

Interventions: intervention 1: Apalutamide intervention 2: Cetrelimab
Intervention descriptions: intervention 1: 240 mg once daily, for a 28 day cycle intervention 2: 480 mg given through intravenous infusion (IV) on day 1 of every 28-day treatment cycle and administered over a 60-minute infusion

Protocol document:
Prot_SAP_000.pdf: 
Proprietary and Confidential
The information in this document is considered privileged and confidential and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by federal 
and state laws.  Persons to whom this information is disclosed should be informed that this information is privileged 
and confidential and that it should not be further disclosed.
A Phase 2 Study of Apalutamide Plus Cetrelimab in 
Patients with Treatment-Emergent Small Cell 
Neuroendocrine Prostate Cancer
Protocol Number:  CC# 21553
Investigational Product(s):  Apalutamide, cetrelimab
Version Number:  1.8
Version Date:  07/24/2023
IND Number:  155372
NCT Number: NCT04926181
Principal Investigator (Sponsor-Investigator)
Rahul Aggarwal, MD
University of California San Francisco
Funding Support and Investigational Products Provided by Janssen Scientific Affairs
Statistician
Li Zhang, PhD
Revision History
Version 1.0
10/21/2020
Version 1.1
12/28/2020
Version 1.2
02/11/2021
Version 1.3
03/17/2021
Version 1.4
05/27/2021
Version 1.5
06/28/2022
Version 1.6
03/16/2023
Version 1.7
06/20/2023
Version 1.8
07/24/2023


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 07/24/2023
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Phase II – Apalutamide + Cetrelimab
Page 2 of 71
Protocol Signature Page
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review and 
Monitoring Committee (PRMC), Institutional Review Board (IRB), and Data and Safety 
Monitoring Committee (DSMC). 
2.
I will conduct the study in accordance with the International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices 
(GCP) and the applicable IRB, ethical, federal, state, and local regulatory requirements. 
3.
I certify that I, and the study staff, have received the required training to conduct this 
research protocol. 
4.
I agree to maintain adequate and accurate records in accordance with IRB policies, federal, 
state and local laws and regulations.
UCSF Principal Investigator 
Printed Name
Signature
Date


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 07/24/2023
Protocol CC#: 21553
Phase II – Apalutamide + Cetrelimab
Page 3 of 71
Abstract
Title
A Phase 2 Study of Apalutamide Plus Cetrelimab in Patients with 
Treatment-Emergent Small Cell Neuroendocrine Prostate Cancer
Study 
Description
Phase 2 single arm, Simon two stage evaluation of the combination of 
apalutamide plus cetrelimab in patients with mCRPC and histologic 
and/or genomic evidence of treatment-emergent small cell 
neuroendocrine prostate cancer who have previously progressed on at 
least one prior androgen signaling inhibitor. The primary study endpoint 
is composite response rate as defined by PSA50 response and/or 
objective response by RECIST 1.1 criteria.  
Phase of Study
Phase 2
Investigational 
Products
Apalutamide, Cetrelimab 
Study 
population
Male, adult (18 years of age and older) patients with metastatic castration 
resistant prostate cancer (mCRPC) with disease progression (PD) on at 
least one second generation androgen signaling inhibitor, including 
abiraterone acetate, apalutamide, darolutamide, and/or enzalutamide 
and evidence of treatment-emergent small cell neuroendocrine cancer (t-
SCNC). All races/ethnicity are included.
Primary 
Objective
To determine the composite response rate as defined by achieving one 
or more of the following at any time point during study treatment:

PSA50, decline from baseline in serum PSA of ≥ 50%, confirmed 
by repeat measurement ≥ 4 weeks later 

Objective response by RECIST 1.1 criteria
Secondary 
Objectives
1.
To determine safety of the combination as determined by CTCAE 
version 5.0
2.
To determine the median radiographic progression-free survival by 
PCWG3 criteria
3.
To determine the PSA50 and PSA90 response proportion achieved
4.
To determine the median PSA progression-free survival 
5.
To determine the median overall survival
6.
To determine the objective response rate and median duration of 
response by RECIST 1.1 criteria
Sample Size
N = 24 patients. 


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 07/24/2023
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Phase II – Apalutamide + Cetrelimab
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Duration of 
Study 
Treatment
Participants may continue study treatment from the time of treatment 
initiation until confirmed radiographic PD per PCWG3/RECIST 1.1 
criteria, unequivocal clinical progression, unacceptable toxicity, or patient 
withdrawal, whichever occurs first – for a maximum of 24 months.
Duration of 
Follow Up
Safety Follow up: 30 days
Safety Follow-up: 100 days
Long Term / Survival Follow up: Patients will be followed for overall 
survival every 90 days (+/- 30 days) from last dose of study treatment, 
until death, withdrawal of consent, or the end of the study, whichever 
occurs first.


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 07/24/2023
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Phase II – Apalutamide + Cetrelimab
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List of Abbreviations
ADT
androgen deprivation therapy
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AR
androgen receptor
ARPI
androgen receptor pathway inhibitors
AST
aspartate aminotransferase
BET
Bromodomain extraterminal protein 
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CNS
central nervous system
CR
complete response
CRF
case report form
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTMS
Clinical Trial Management System
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECG/EKG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBV
hepatitis B virus
HCV
hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
IAC
intermediate atypical carcinoma
ICF
informed consent form
ICH
International Conference on Harmonization
IDS
Investigational Drug Services (UCSF)
IND
investigational new drug application
IP
investigational product
IRB
Institutional Review Board
IV
Intravenous


UCSF Helen Diller Family Comprehensive Cancer Center
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Phase II – Apalutamide + Cetrelimab
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List of Abbreviations
mCPRC
metastatic castration resistant prostate cancer
MRI
magnetic resonance imaging
NCI
National Cancer Institute
PD
disease progression
PD-1
programmed cell death 1
PO
Per os (by mouth, orally)
PR
partial response
PRC
Protocol Review Committee (UCSF)
PSA
Prostate Serum Antigen
rPD
Radiographic progressive disease
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SLD
Sum of longest diameters
t-SCNC
treatment-emergent small cell neuroendocrine carcinoma


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Table of Contents
Protocol Signature Page ............................................................................................................2
Abstract
3
List of Abbreviations...................................................................................................................5
Table of Contents.......................................................................................................................7
1
Introduction...................................................................................................................10
1.1
Background..............................................................................................10
1.2
Transdifferentiation is an Adaptive Response to Long-term ADT..........10
1.3
Activity of Immune Checkpoint Inhibition in Unselected mCRPC Alone 
and in Combination with AR Pathway Inhibition ...................................11
1.4
Immunogenicity of t-SCNC compared to adenocarcinoma without 
neuroendocrine features and clinical activity of immune checkpoint 
blockade in high grade neuroendocrine cancers......................................12
1.5
Cetrelimab in Prostate and Other Solid Tumor Malignancies.................12
1.6
Combination of Apalutamide Plus Cetrelimab........................................14
1.7
Rationale for the Continuation of Androgen Receptor Blockade in 
Transdifferentiated Prostate Cancer.........................................................14
2
Study Objectives ..........................................................................................................14
2.1
Hypothesis ...............................................................................................14
2.2
Primary Objective and Endpoints............................................................15
2.3
Secondary Objectives and Endpoints ......................................................16
2.4
Exploratory (Correlative) Objectives.......................................................17
3
Study Design................................................................................................................17
3.1
Characteristics..........................................................................................17
3.2
Sample Size..............................................................................................18
3.3
Eligibility Criteria....................................................................................18
3.3.1
Inclusion Criteria ..........................................................................................18
3.3.2
Exclusion Criteria .........................................................................................20
3.4
Inclusion of Women and Minorities........................................................22
3.4.1
Eligibility of Women and Minorities............................................................22
3.4.2
Recruitment of Minority Groups ..................................................................22
3.5
Criteria for Treatment Discontinuation....................................................22
3.6
Criteria for Study Discontinuation...........................................................23
3.7
Primary Completion.................................................................................23
3.8
Study Completion ....................................................................................23
4
Investigational Products ...............................................................................................23
4.1
Description, Supply and Storage of Investigational Products .................23
4.1.1
Apalutamide..................................................................................................23
4.1.2
Cetrelimab.....................................................................................................24
4.2
Accountability Records for Investigational Products..............................26
5
Treatment Plan.............................................................................................................26
5.1
Dosage and Administration .....................................................................26
5.2
Dose Modifications and Management of Toxicity ..................................27


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Table of Contents
5.2.1
Retreatment Criteria for Cetrelimab and Apalutamide.................................27
5.2.2
Dose Delay for Cetrelimab ...........................................................................28
5.2.3
Dose Modification for Apalutamide .............................................................29
5.3
Management of Infusion-related Reactions.............................................29
5.4
Management of Rash ...............................................................................30
6
Study Procedures and Schedule of Events..................................................................31
6.1
Study Calendar.........................................................................................33
6.2
Participant Registration............................................................................36
6.3
Schedule of Procedures and Observations...............................................36
6.3.1
Pretreatment Period.......................................................................................36
6.3.2
Treatment Period...........................................................................................37
6.3.3
End-of-Treatment Study Procedures.............................................................38
6.3.4
30-day Safety Follow Up (+/- 7 days) ..........................................................39
6.3.5
100-day Safety Follow-Up (+/- 14 days)......................................................39
6.3.6
Long Term/Survival Follow-up ....................................................................39
6.4
Correlative Studies...................................................................................39
6.4.1
Metastatic Tumor Biopsy..............................................................................39
6.4.2
Peripheral blood immune profiling...............................................................39
6.4.3
Circulating tumor cells..................................................................................40
6.4.4
Circulating tumor DNA ................................................................................40
6.4.1
Skin Biopsy...................................................................................................40
6.5
Use of Concurrent/Concomitant Medications .........................................40
6.5.1
Prohibited Concomitant Medications ...........................................................40
6.5.2
Acceptable Concomitant Medications/Supportive Care...............................41
6.6
Lifestyle/Dietary Restrictions..................................................................42
6.6.1
Contraception and Pregnancy .......................................................................42
7
Reporting and Documentation of Results ....................................................................42
7.1
Evaluation of Efficacy: Antitumor Effect – Solid Tumors......................42
7.1.1
Definitions.....................................................................................................42
7.1.2
Disease Parameters .......................................................................................42
7.1.3
Methods for Evaluation of Measurable Disease ...........................................44
7.1.4
Response Criteria..........................................................................................45
7.2
Evaluation of Safety.................................................................................48
7.3
Definitions of Adverse Events.................................................................48
7.3.1
Adverse Event...............................................................................................48
7.3.2
Adverse Reaction..........................................................................................48
7.3.3
Suspected Adverse Reaction.........................................................................48
7.3.4
Recording of Adverse Events .......................................................................51
7.3.5
Follow-up of Adverse Events .......................................................................51
7.3.6
Adverse Events Monitoring ..........................................................................51
7.3.7
Expedited Reporting .....................................................................................51
8
Statistical Considerations and Evaluation of Results ...................................................53
8.1
Sample Size Considerations.....................................................................53


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Phase II – Apalutamide + Cetrelimab
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Table of Contents
8.1.1
Sample Size and Power Estimate..................................................................53
8.1.2
Accrual Estimates .........................................................................................54
8.2
Interim Analyses and Stopping Rules......................................................54
8.3
Analyses Plans.........................................................................................54
8.3.1
Analysis Population ......................................................................................54
8.3.2
Primary Analysis (or Analysis of Primary Endpoints) .................................54
8.3.3
Secondary Analysis (or Analysis of Secondary Endpoints) .........................54
8.3.4
Exploratory/Correlative Analysis/Assessments............................................55
9
Study Management ......................................................................................................57
9.1
Pre-study Documentation ........................................................................57
9.2
Institutional Review Board Approval......................................................57
9.3
Informed Consent ....................................................................................57
9.4
Changes in the Protocol...........................................................................57
9.5
Handling and Documentation of Clinical Supplies .................................58
9.6
Case Report Forms (CRFs)......................................................................58
9.7
Oversight and Monitoring Plan................................................................58
9.8
Record Keeping and Record Retention ...................................................58
9.9
Publications..............................................................................................59
10
References...................................................................................................................60
Appendix 1
Performance Status Criteria............................................................................66
Appendix 2
(Single Site): Phase II or III Institutional Trial..................................................67
Appendix 3
Approved Methods of Contraception...............................................................70
Appendix 4
Prohibited Medications List .............................................................................71


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1
Introduction
1.1Background 
Prostate cancer is the second leading cause of cancer death in men in the Western World, 
largely driven by patients harboring recurrent or newly diagnosed metastatic disease. These 
patients have a rapid and favorable response to androgen deprivation therapy (ADT). However, 
most patients inevitably develop hormone refractory disease, termed metastatic castration 
resistant prostate cancer (mCRPC). Over the last decade, there has been an expansion of 
therapies for patients with mCRPC beyond traditional cytotoxic chemotherapies, including novel 
androgen receptor (AR) pathway inhibitors (ARPI) that more completely ablate androgen 
signaling such as abiraterone acetate, enzalutamide, and apalutamide (Beer et al., 2014; de 
Bono et al., 2011; Fizazi et al., 2012; Ryan et al., 2015, 2013; Scher et al., 2012; Smith et al., 
2018), sipuleucel-T, an autologous cellular immunotherapy targeting prostatic acid phosphatase 
(PAP) (Kantoff et al., 2010), and radium-223, a bone-targeting alpha emitter (Parker et al., 
2013). Despite these therapeutic advances, many patients on mCRPC eventually succumb to 
their disease, often due to acquired tumor resistance to these novel agents. In particular, there 
remain few treatment options for men with mCRPC refractory to the ARPI. Therefore, there is a 
great need to develop clinically efficacious, well-tolerated, novel therapies for this patient 
population. 
1.2Transdifferentiation is an Adaptive Response to Long-term ADT
There is marked heterogeneity across mCRPC patients with widely varying clinical outcomes 
and therapeutic responses driven largely from diverse mechanisms of resistance to overcome 
androgen-signaling inhibition. Transdifferentiation to a neuroendocrine phenotype, termed 
treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC), represents a highly 
aggressive and lethal subset of prostate cancer that is becoming increasingly common in 
previously treated mCRPC. While de novo SCNC represent 1-2% of new cases, in our 
prospective, multi-institutional study of over 200 unselected mCRPC patients previously treated 
with ARPI, treatment-emergent SCNC (t-SCNC) was identified in 17% of mCRPC biopsies 
(Aggarwal et al., 2018). Compared to mCRPC with adenocarcinoma features, t-SCNC is 
characterized by decreased AR signaling, enrichment for loss of RB1 and TP53, and 
enrichment of activation of transcriptional factors including EZH2, POU3F2, ASCL1, among 
others. 
It is hypothesized that t-SCNC arise clonally from adenocarcinoma, though through which 
molecular mechanisms, i.e. de-differentiation to a primitive progenitor or transdifferentiation from 
epithelial to neuronal phenotypes, remains under active investigation (Aggarwal et al., 2019; 
Beltran et al., 2016; Guo et al., 2011; Zou et al., 2017). Importantly, patients with t-SCNC exhibit 
poor prognoses compared to mCRPC with adenocarcinoma (Aggarwal et al., 2018; Small et al., 
2016). Furthermore, patients with t-SCNC have limited effective treatment options outside of 
traditional platinum-based chemotherapies, which itself have limited durability of response and 
carry significant risk of undesired side effects (Aparicio et al., 2013). In the Aparicio et al. study, 
97% of patients treated with platinum therapy experienced progression of disease with a median 
time of 3.0 months. Therefore, there is an unmet clinical need to develop new, durable therapies 
for these two high-risk mCRPC subtypes. 
Identification of t-SCNC currently relies on histologic evaluation of a metastatic tumor biopsy, 
which can be difficult to obtain in patients owing to the sclerotic nature of this bone-tropic 
disease entity. Contrary to the classic clinical characteristics of de novo t-SCNC, the presence 
of visceral metastases or elevation of serum neuroendocrine markers does not reliably identify t-
SCNC on paired tumor biopsies. Several clinical and/or genomic hallmarks enrich for the 
identification of t-SCNC, including the presence of RB1 genomic loss on somatic tumor profiling, 
as well as the presence of low PSA secretion in relation to metastatic disease burden. 


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Phase II – Apalutamide + Cetrelimab
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Among 183 evaluable patients, low PSA secretion (PSA < 5 ng/mL) with concomitant high 
metastatic disease burden (> 5 metastases on conventional imaging) was found in 15 patients 
(8%) and was associated with enrichment for t-SCNC transcriptional signature, low AR 
transcriptional activity.  RB1 genomic loss is enriched in t-SCNC vs. adenocarcinoma biopsies 
(Aggarwal et al. JCO 2018) and is likewise associated with significant shortened survival (Chen 
et al. Eur Urol 2019). 
Figure 1.2 AR Transcriptional Signature Score and T-SCNC Signature Score
1.3Activity of Immune Checkpoint Inhibition in Unselected mCRPC Alone and in 
Combination with AR Pathway Inhibition
In patients with unselected mCRPC, pembrolizumab has modest anti-tumor activity, but durable 
responses can be achieved in a minority of patients. In the recently reported updated analysis of 
the KEYNOTE-199 study of mCRPC patients who had previously received docetaxel, the 
objective response rate in patients with measurable disease was 5% and 3% in those with PD-
L1 positive and negative tumors, respectively (Antonarakis et al. 2019). Duration of responses 
lasting ≥ 12 months was 71% and 50%, respectively, in the two cohorts. The PSA50 response 
rate was 11% overall, and there did not appear to be an enrichment of response in PD-L1 
positive vs. negative tumors. 
Figure 1.3 Change from Baseline in PSA, Cohorts 1+2+3
Pembrolizumab combined with AR targeted therapy may lead to increased response rate 
however this has not been definitively demonstrated in a randomized trial setting. In a single 
arm study (KEYNOTE-365, Cohort C) of pembrolizumab plus enzalutamide in abiraterone 


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acetate-resistant, chemotherapy-naïve mCRPC, the PSA50 response rate was 27% (18/67 
patients), and the objective response rate was 20% (5/25 patients with measurable disease) 
(Fong P, et al. 2019). 
1.4Immunogenicity of t-SCNC compared to adenocarcinoma without 
neuroendocrine features and clinical activity of immune checkpoint blockade 
in high grade neuroendocrine cancers
The immunogenicity of mCRPC tumors, including the mutation burden, tumor infiltrating 
lymphocytes, and expression of T-cell regulatory checkpoint molecules like PD-1 and PD-L1 are 
low in an unselected population of prostate tumors compared to other tumor types that show a 
higher response rate to checkpoint blockade, like melanoma (Haffner et al., 2018). PD-L1 
expression strongly correlates with objective response to anti-PD-1 therapy (Taube et al., 2014). 
However, only 14% of mCRPC patients in the KEYNOTE-028 study examining pembrolizumab 
in this patient population screened positive for PD-L1 expression. Recent work has 
demonstrated that PD-L1 expression was higher in patients with t-SCNC compared to mCRPC 
without evidence of neuroendocrine features (Ferguson et al., 2019; Nappi et al., 2019). This 
suggests that de-differentiated t-SCNC have increased immunogenicity and may have a better 
response rate to anti-PD-1 therapy compared to mCRPC cases without neuroendocrine 
features. 
The efficacy of immune checkpoint inhibition in high grade neuroendocrine cancers is supported 
by recent clinical efficacy and accelerated FDA approval for nivolumab in small cell lung cancer 
(Antonia et al. Lancet Oncology 2016). An objective response was achieved in ten (10%) of 98 
patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg 
plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 
and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. 
In extrapulmonary high grade neuroendocrine cancers, immune checkpoint inhibition has shown 
preliminary evidence of activity. In the neuroendocrine tumor cohort of the basket DART study, 
the objective response rate with combination of ipilimumab + nivolumab was 44% in the subset 
of patients with high-grade disease.  
1.5Cetrelimab in Prostate and Other Solid Tumor Malignancies
Cetrelimab (JNJ-63723283) is a fully human immunoglobulin G4 (IgG4) kappa mAb containing 
the hinge-stabilizing S228P mutation. This mutation prevents the fragment antigen binding (Fab) 
arm exchange that normally occurs with IgG4 antibodies. Cetrelimab binds to PD-1 with high 
affinity and specificity, blocks binding to both PD-L1 and PD-L2 ligands, enhances pro-
inflammatory cytokine production from ex vivo stimulated T cells, and reduces tumor volume in 
a number of preclinical models in vivo.
Study 63723283LUC1001 is an ongoing, multicenter, Phase 1/2 FIH study of cetrelimab in 
subjects with advanced solid tumor malignancies. Part 1 of the study, initiated on 21 November 
2016 (date of consent of the first eligible subject), consists of dose escalation cohorts and 
PK/PD cohorts. Part 1 established the recommended Phase 2 dose (RP2D), which may be 
administered at either 240 mg once every 2 weeks (q2w) or 480 mg once every 4 weeks (q4w). 
In Part 2, initiated on 03 May 2017 (date of consent of the first eligible subject), this RP2D is 
being evaluated in selected solid tumor types, including non-small cell lung cancer (NSCLC), 
melanoma and high-level microsatellite instability (MSI-H) or mismatch-repair deficiency 
(dMMR) colorectal cancer (CRC). The purposes of dose expansion in Part 2 are to further 
characterize the safety and to assess the antitumor activity of the RP2D.
As of the clinical safety and efficacy data cutoff date of 02 September 2019, a total of 204 
subjects have received at least 1 dose of cetrelimab. The age of enrolled subjects ranged from 


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23 to 86 years. The majority of subjects treated with cetrelimab had Stage III or IV malignancy 
at the time of initial diagnosis and metastatic disease at study entry, consistent with the 
protocol-specified requirements of metastatic or unresectable advanced cancers. The number of 
prior regimens of anticancer therapy ranged from 1 to 12, with a median number of 2 prior 
therapies. As of the clinical safety data cutoff date, the duration of cetrelimab treatment ranged 
from 1 to 28.5 months, with a median treatment duration of 3.25 months. The number of doses 
administered ranged from 1 to 63.
The RP2D of 240 mg q2w was determined based on interim safety, PK, and PD data as of 27 
April 2017. The additional interim safety, PK and PD data as of September 2017 support an 
alternate regimen, namely 480 mg q4w, with the same total dose as RP2D of 240 mg q2w but 
given with a longer dosing interval which enables flexibility of drug administration in various 
clinical settings. Selection of the RP2D of 240 mg q2w and 480 mg q4w was based on the 
following:

No maximum tolerated dose has been identified with administration of doses up to 460 
mg q2w and 480 mg q4w and doses were well tolerated (Section 4.4).

Cetrelimab demonstrated comparable preclinical in vivo TGI and comparable in vitro 
activity across various assays as the approved PD-1 inhibitors nivolumab and 
pembrolizumab (Section 3.1.1). Therefore, similar clinical efficacious target 
concentrations would be expected for cetrelimab.

Based on preliminary PK data, the median observed near-steady state Cmin for 
cetrelimab at 240 mg q2w is 44.8 μg/mL (N=5, trough concentration before the fifth 
dose). This is comparable to the Cmin,ss reported for nivolumab (57 μg/mL7,9) and 
pembrolizumab (23 μg/mL6,10) at their approved doses (240 mg q2w for nivolumab and 
2 mg/kg or 200 mg q3w for pembrolizumab).

The median steady state Cmin,ss for cetrelimab at 480 mg q4w is expected to be

approximately 42 μg/mL, based on an observed median Cmin after first dose at 30 
μg/mL and predicted accumulation ratio of ~1.4 based on preliminary PK modeling. The 
Cmin,ss from 240 mg q2w and 480 q2w is therefore expected to be comparable, and in 
range with other anti-PD-1 agents nivolumab and pembrolizumab at their approved 
clinical dose.

Administration of cetrelimab resulted in saturation of PD-1 RO on circulating CD3+ T 
cells at all administered doses (80 to 480 mg) and dosing frequencies (q2w and q4w).
In subjects receiving the RP2D of 240 mg IV every 2 weeks in the cetrelimab monotherapy 
study (Study 63723283LUC1001; NCT02908906), the observed ORR (CR+PR) was 21.9% 
(32/146) in all subjects evaluable for response. Five of the 146 (3.4%) subjects (all with 
melanoma) demonstrated a complete response (CR) and 27 (18.5%) had a partial response 
(PR) as assessed by the investigator. Overall, 29 (19.9%) subjects receiving cetrelimab had 
stable disease (SD). 
Overall, 207 (97.2%) of the 213 subjects who received treatment experienced at least 1 TEAE. 
One hundred forty-two (142, 66.7%) subjects experienced TEAEs considered to be possibly, 
probably, or very likely related to cetrelimab administration by the investigator. Across all dose 
cohorts, the most frequently reported TEAEs (≥10% of subjects) were as follows: asthenia 
(24.4%), fatigue (20.7%), dyspnea (20.2%), pyrexia (19.7%), diarrhea (18.8%), anemia, 
decreased appetite, and nausea (17.8% each), cough (17.4%), back pain (15.5%), aspartate 
aminotransferase (AST) increased and vomiting (13.1% each), alanine aminotransferase (ALT) 
increased (12.7%), abdominal pain (11.7%), constipation (11.3%), and arthralgia and rash 


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(10.3% each). In the 161 subjects receiving 240 mg q2w, the most frequent TEAEs (≥10% of 
subjects) were as follows: asthenia (27.9%), dyspnea, diarrhea, and pyrexia (21.8% each), 
cough (20.0%), fatigue and decreased appetite (18.2% each), anemia (17.6%), nausea (17.0%), 
ALT increased (15.2%), AST increased (14.5%), and back pain (15.8%).
Overall, Grade 3 or higher TEAEs were experienced by 113 (53.1%) of the 213 subjects in the 
monotherapy studies (Table 26). The most frequently reported Grade 3 or higher TEAEs (≥2% 
of subjects) were as follows: anemia (7.0%), dyspnea (5.6%), GGT increased (4.7%), 
hyponatremia (4.2%), AST increased and hyperamylasemia (3.3% each), ALT increased, 
hypertension, fatigue and lipase increased (2.8% each), pleural effusion, abdominal pain and 
general physical health deterioration (2.3% each), and urinary tract infection, neutropenia, blood 
alkaline phosphatase (ALP) increased, asthenia, and hyperbilirubineamia (1.9%).
Overall, 71 (33.3%) of the 213 subjects treated in the monotherapy studies experienced 
treatment-emergent irAEs as assessed by the investigator. The most commonly reported irAEs 
(>2% of subjects) included hypothyroidism (6.1%), rash (4.7%), asthenia (4.2%), 
hyperthyroidism and dyspnea (3.3% each), pruritus and diarrhea (2.8% each), and pneumonitis 
(2.3%). Nine (9, 4.2%) subjects experienced irAEs that led to treatment discontinuation: 
pneumonitis in 3 subjects, and myocarditis, hyperthyroidism, autoimmune colitis, hepatotoxicity, 
ALT increased, GGT increased, myopathy, and myasthenia gravis in 1 subject each.
PK/PD and immunogenicity data are presented in the Investigational Brochure. 
1.6Combination of Apalutamide Plus Cetrelimab
Study 56021927PCR2032 (NCT03551782) is an ongoing, multicenter, apalutamide Phase 1b 
study of subjects who currently have mCRPC and who have progressed on therapy with 
abiraterone acetate plus prednisone/prednisolone (AA-P), apalutamide, or enzalutamide. The 
study was initiated on 2 July 2018 (date of first subject consent). As of the clinical data cutoff 
date of 02 September 2019, a total of 27 subjects have received at least 1 dose of apalutamide 
in combination with cetrelimab. The combination was overall deemed tolerable with no dose-
limiting toxicities noted. Grade 3 or higher treatment-emergent adverse events (AEs) included: 
rash (37.0%), and fatigue/asthenia (14.8%). Overall, AEs leading to treatment discontinuation 
occurred in 6/27 patients (22.2%), including three patients with rash, one patient with 
hypersensitivity reaction, one patient with serum sickness, and one patient with asthenia. 
1.7Rationale for the Continuation of Androgen Receptor Blockade in 
Transdifferentiated Prostate Cancer
Despite the low AR transcriptional activity of treatment-emergent small cell neuroendocrine 
prostate cancer, there is persistent AR expression observed in the majority of t-SCNC biopsies 
(Aggarwal et al. JCO 2018). This indicates that epigenetic dysregulation leads to 
reprogramming away from an AR-driven transcriptional program. Therefore, continuation of AR 
blockade in the form of apalutamide may provide additive benefit compared to immune 
checkpoint blockade alone. 
2
Study Objectives 
2.1Hypothesis
We hypothesize that the combination of apalutamide plus cetrelimab will achieve a clinically 
significant composite response rate with sufficient durability of response in mCRPC patients 
with evidence of treatment-emergent small cell neuroendocrine prostate cancer. 


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2.2Primary Objective and Endpoints
Primary Objective
Endpoints
Time Frame
To determine the composite 
response rate (achieving 
one or more of the 
endpoints) of apalutamide 
plus cetrelimab. 

PSA50 (decline from baseline in 
serum PSA of ≥ 50%, confirmed by 
repeat measurement ≥ 4 weeks later)*
AND/OR

Objective response by RECIST 1.1 
criteria** 
From initiation of 
study treatment 
until 
discontinuation of 
treatment 
(maximum of 2 
years).
* to be considered evaluable for PSA50 response, patients must have baseline PSA level > 2 ng/mL
** to be considered evaluable for objective response, patients must have measurable soft tissue disease by RECIST 
1.1 criteria on baseline scan assessment


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2.3Secondary Objectives and Endpoints
Secondary Objective
Endpoints
Time Frame
1.
To determine safety of 
the combination of 
apalutamide and 
cetrelimab

Proportion of participants with 
treatment-related AEs, as 
graded by National Cancer 
Institute Common Terminology 
Criteria for Adverse Events (NCI 
CTCAE version 5.0)
From initiation of study 
treatment until 
treatment 
discontinuation. 
2.
To determine the 
median radiographic 
progression-free 
survival by PCWG3 
criteria

Median progression free survival 
by PCWG3 criteria. 
From initiation of study 
treatment until 
radiographic 
progression by PCWG3 
criteria or death, 
whichever occurs first. 
3.
To determine the PSA50 
and PSA90 response 
proportion. 

≥ 50% and ≥ 90% decline from 
baseline in PSA, respectively, 
confirmed by repeat 
measurement ≥ 4 weeks after 
first time point*
From initiation of study 
treatment until maximal 
decline in serum PSA 
during study treatment. 
4.
To determine the 
median PSA 
progression-free 
survival. 

Median PSA progression-free 
survival by PCWG3 criteria. 
From initiation of study 
treatment until PSA 
progression by PCWG3 
criteria or death, 
whichever occurs first. 
5.
To determine the 
median overall survival. 

Median overall survival from 
date of start of protocol 
treatment until death from any 
cause. 
From initiation of study 
treatment until death 
from any cause. (3 
years)
6.
To determine the 
objective response rate 
by RECIST 1.1 criteria

Objective response rate by 
RECIST 1.1 criteria. 

Median duration of response
From initiation of study 
treatment until maximal 
percent decline from 
baseline in SLD of 
target lesions. 
* To be considered evaluable for this endpoint, patients must have baseline PSA level > 2 ng/mL.


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2.4Exploratory (Correlative) Objectives
Exploratory Objectives
Endpoints
1.
To explore the association between 
baseline metastatic tumor characteristics 
including t-SCNC, AR, RB1 loss, and 
immune response transcriptional signatures 
with clinical outcomes. 
Association of specific gene and 
transcriptional gene signatures using RNA-
seq and targeted next-gen DNA 
sequencing with composite response rate 
and PFS.  
2.
To evaluate objective response rate and 
median progression-free survival by 
irRECIST criteria. 
Objective response rate and median PFS 
by irRECIST. 
3.
To evaluate the association between 
immune related adverse events (irAEs) and 
clinical efficacy outcomes. 
Association between irAEs with efficacy 
endpoints including composite response 
rate, PSA50 response, and progression-
free survival.  
4.
To evaluate the association between 
baseline and change from baseline in 
circulating T cell and myeloid cell subsets 
with clinical outcomes. 
Association between baseline and fold 
change in circulating T cell and myeloid 
subsets by CyTOF with efficacy endpoints 
including composite response, PSA50 
response, and progression-free survival.  
5.
To explore the mechanism of skin rash in 
patients receiving combination of 
apalutamide plus cetrelimab. 
Infiltration of immune cells in skin biopsies 
performed in patients experiencing rash on 
study. 
6.
To explore the association between 
genomic and epigenomic features of 
circulating tumor DNA with clinical 
outcomes. 
Association between genomic and 
epigenomic alterations in ctDNA with 
clinical outcomes. 
7.
To explore the association between 
circulating tumor cell (CTC) characteristics 
including heterogeneity, overall CTC count, 
and expression of markers of interest (AR, 
CD56, cytokeratin) with clinical outcomes. 
Association between CTC characteristics 
with clinical outcomes. 
3
Study Design
3.1Characteristics
This is a phase 2, single arm, Simon’s two-stage evaluation of the combination of apalutamide 
plus cetrelimab in patients with mCRPC and histologic and/or genomic evidence of treatment-
emergent small cell neuroendocrine prostate cancer who have previously progressed on at least 
one prior androgen signaling inhibitor. The primary study endpoint is composite response rate 
as defined by PSA50 response and/or objective response by RECIST 1.1 criteria. 
A planned interim safety and efficacy analysis is planned after 14 patients are treated (see 
Section 8). 


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Figure 3.1 Study Schema
3.2Sample Size
A total of 24 patients will be enrolled over an accrual period of approximately 18 months. 
3.3Eligibility Criteria
Patients must have screening procedures performed prior to Cycle 1, Day 1 of treatment and 
must meet all inclusion and exclusion criteria. In addition, the patient must be thoroughly 
informed about all aspects of the study, including study visit schedule, required evaluations, and 
all regulatory requirements for informed consent.  The written informed consent must be 
obtained from the patient prior to enrollment. The following criteria apply to all patients enrolled 
onto the study unless otherwise specified. 
3.3.1
Inclusion Criteria
1.
Participants must have histologically confirmed prostate adenocarcinoma at the time of 
diagnosis, with subsequent development of metastatic castration-resistant prostate 
cancer. Prostate adenocarcinoma with neuroendocrine features (e.g. positive 
chromogranin and/or synaptophysin expression by IHC) is allowed.   
2.
Evidence of disease progression (PD) by PSA and/or radiographic progression by 
PCWG3 criteria at the time of study entry. 
3.
Prior progression on at least one androgen signaling inhibitor (e.g. abiraterone acetate, 
apalutamide, enzalutamide, darolutamide). Treatment with prior androgen signaling 
inhibitor may have been initiated in either the CSPC and/or CRPC setting. 
4.
Patients must be evaluable for the primary endpoint of composite response and must 
have either serum PSA > 2 ng/mL during Screening and/or measurable disease by 
RECIST 1.1 criteria. 


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5.
Participants must have clinicogenomic evidence of treatment emergent small cell 
neuroendocrine prostate cancer as defined by one or more of the following:
i.
Histologic evidence of small cell neuroendocrine prostate cancer on evaluation of 
CRPC tissue by centralized pathology review
and/or
ii.
Presence of loss-of-function mutation or deletion of RB1 on a CLIA-approved 
genomic-sequencing platform. Either monoallelic or biallelic mutations in RB1 are 
allowed. 
6.
No more than one prior line of taxane-based chemotherapy administered in the mCRPC 
setting. Chemotherapy administered in the castration-sensitive setting does not count 
towards this limit. Prior carboplatin is allowed and does not count as an additional line of 
therapy when given in conjunction with taxane.
7.
Castrate level of serum testosterone at study entry (<50 ng/dL). Patients without prior 
bilateral orchiectomy are required to remain on LHRH analogue treatment for duration of 
study.  
8.
No other systemic anti-cancer therapies administered other than LHRH analogue within 
14 days or, 5 half-lives, whichever is shorter, prior to initiation of study treatment. AEs 
related to prior anti-cancer treatment must have recovered to Grade ≤ 1 with the 
exception of any grade alopecia and Grade ≤ 2 neuropathy. 
b.
Patients receiving apalutamide prior to study entry may continue treatment at 
their current apalutamide dose level without requirement for wash-out period. 
9.
Age ≥ 18 years
10. ECOG performance status ≤ 1 (Karnofsky performance status ≥ 70%, see Appendix 1)
11. Demonstrates adequate organ function as defined below:
Adequate bone marrow function:
Absolute neutrophil count
≥ 1,500/mcL
Platelets
Hemoglobin
≥ 100,000/mcL
≥ 9.0 g/dL
Adequate hepatic function:
Total bilirubin
≤ 1.5 x institutional upper limit of normal, 
unless elevated due to Gilbert’s syndrome and 
direct bilirubin is within normal limits
AST (SGOT)
≤3 X institutional upper limit of normal (≤ 5 x 
ULN in presence of liver metastases)
ALT (SGPT)
≤3 X institutional upper limit of normal (≤ 5 x 
ULN in presence of liver metastases)
Adequate renal function:
Serum creatinine
≤ 1.5 x institutional upper limit of normal


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OR
Calculated creatinine 
clearance
GFR ≥ 30 mL/min/1.73 m2, calculated using 
the CKD-EPI equation 
12. Ability to understand a written informed consent document, and the willingness to sign it. 
13. Patients must agree to use adequate contraception and to not donate sperm prior to the 
study, for the duration of study participation, and 5 months after last administration of 
study treatment. Adequate contraception includes (see Appendix 3 for more detail):
c.
Patients who are sexually active should consider their female partner to be of 
childbearing potential if she has experienced menarche and is not 
postmenopausal (defined as amenorrhea > 24 consecutive months) or has not 
undergone successful surgical sterilization. 
d.
Even participants who have undergone vasectomy should still use acceptable 
method of contraception.  
e.
Acceptable methods of contraception include hormonal combined (estrogen + 
progesterone) or progesterone only given orally, injected or implanted; IUD, IUS, 
tubal ligation, vasectomy and complete sexual abstinence.
14. Patients must be willing to undergo metastatic tumor biopsy during Screening if no 
biopsy has previously been done. If no metastatic lesion is safely accessible to tumor 
biopsy, this requirement will be waived. Bone or soft tissue lesion is allowed, but soft 
tissue will be prioritized. If a patient has archival tissue obtained within 90 days of C1D1 
the requirement for fresh tumor biopsy will be waived. 
3.3.2
Exclusion Criteria 
1.
De novo small cell carcinoma of the prostate.  
2.
Has participated in a study of an investigational product and received study treatment or 
used an investigational device other than those specified in the protocol within 2 weeks 
of C1D1. 
3.
Hypersensitivity to cetrelimab, apalutamide, or any of its excipients. 
4.
Has received prior radiotherapy within 2 weeks of C1D1.  Participants must have 
recovered from all radiation-related toxicities, not require corticosteroids, and not have 
had radiation pneumonitis.  A 1-week washout is permitted for palliative radiation (≤2 
weeks of radiotherapy) to non-central nervous system (CNS) disease.
5.
Receipt of prior cetrelimab or another immune checkpoint inhibitor targeting PD-1/PD-L1 
and/or CTLA-4 (e.g. pembrolizumab, nivolumab, ipilimumab). Prior treatment with 
sipuleucel-T is allowed. 
6.
Has an active autoimmune disease that has required systemic treatment in the past 2 
years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Patients on low dose oral weekly methotrexate are allowed. Replacement 
therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for 
adrenal or pituitary insufficiency) or treatment with drugs (e.g. methimazole, 
neomercazol, carbamazole, etc.) that function to decrease the generation of thyroid 
hormone by a hyper-functioning thyroid gland (e.g., in Graves’ disease) is not 
considered a form of systemic treatment of an autoimmune disease.


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7.
Has received a live vaccine within 30 days prior to the first dose of study drug.  
Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–
Guérin (BCG), and typhoid vaccine.  Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza vaccines 
(e.g., FluMist®) are live attenuated vaccines and are not allowed. COVID-19 vaccine is 
allowed. 
8.
Individuals with concurrent second malignancy requiring active treatment at study entry 
that could affect safety or efficacy endpoints. Non-melanoma skin cancer, non-muscle 
invasive bladder cancer, and other carcinomas-in-situ are allowable exceptions.
9.
Cardiac condition as defined as one or more of the following:
a.
Uncontrolled supraventricular arrhythmia or ventricular arrhythmia requiring 
treatment
b.
NYHA congestive heart failure class III or IV
c.
History of unstable angina, myocardial infarction, or cerebrovascular accident 
within 6 months prior to C1D1
d.
Uncontrolled hypertension defined as SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm 
Hg. Treatment and re-screening are permitted. 
10. History of seizure or pre-disposing condition (e.g. brain metastases). Medications known 
to lower seizure threshold must be discontinued at least 4 weeks prior to C1D1. 
11. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a 
prednisone equivalent dose of > 10 mg daily or other form of immunosuppressive 
therapy within 7 days prior to first dose of study drug. 
12. Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviral 
therapy with undetectable viral load within 6 months are eligible for this trial (screening 
not required in the absence of risk factors).
13. For participants with evidence of chronic hepatitis B virus (HBV) infection (positive 
HBsAg and/or HBcAb), the HBV viral load must be undetectable at the time of study 
enrollment (screening not required in the absence of risk factors). 
14. Chronic active HCV infection defined as positive viral load (screening not required in the 
absence of risk factors). 
15. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
16. Gastrointestinal disorder affecting absorption. 
17. Has an active infection requiring intravenous (IV) antibiotics within 7 days prior to C1D1. 
18. Use of a prohibited concomitant medication (see Appendix 4 and Section 6.5.1) within 7 
days of C1D1. Medications known to lower seizure threshold must be discontinued at 
least 4 weeks prior to C1D1. 
19. Major surgery within 28 days prior to C1D1. Minor procedures including biopsies, dental 
surgery, cataract surgery, or outpatient procedure are allowed. 


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20. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation for 
the full duration of the study, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.  
21. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
3.4Inclusion of Women and Minorities
3.4.1
Eligibility of Women and Minorities
Individuals of any race or ethnicity are eligible for this study. The inclusion of women is not 
appropriate for the trial design given this is a study of prostate cancer.
3.4.2
Recruitment of Minority Groups
The study recruitment strategy aims to achieve representation of minority groups that reflects 
the demographics of the affected population in the catchment area. In particular, this will include 
utilization of collaboration with Lazarex Foundation to help defray travel costs associated with 
clinical trial participation for patients with limited financial resources, utilization of a Redcap 
clinical trial tracker (ucsftrials.com), with outreach to community oncologists serving minority 
groups within the UCSF catchment region, engagement with the Office of Community Outreach 
and Engagement (COE) with the UCSF Cancer Center. 
3.5Criteria for Treatment Discontinuation
In the absence of treatment delays due to AEs, treatment (both study drugs) may continue until 
first occurrence of one or more of the following:

Radiographic PD by PCWG3/RECIST 1.1 criteria. If patients are clinically stable in the 
judgment of treating investigator, continuation of protocol therapy is allowed until 
progression is confirmed by repeat tumor assessment performed ≥ 4 weeks following 
first scan demonstrating progression. 

Unequivocal clinical progression

Inter-current illness that prevents further administration of treatment;

Unacceptable AE(s);

Participant decides to withdraw from the study;

Significant participant non-compliance with protocol;

Receipt of non-protocol therapy

General or specific changes in the participant’s condition render the participant 
unacceptable for further treatment in the judgment of the investigator

Study closure

Completion of 2 years of protocol therapy. 
Patients with PSA-only progression in the absence of radiographic or unequivocal progression 
should remain on study treatment per PCWG3 guidelines. 


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3.6Criteria for Study Discontinuation
Participants will have safety follow up assessment 30 (+/- 7 days) and 100 days (+/- 14 days) 
following End of Treatment. 
Following completion of safety follow up visits, patients will subsequently be followed for overall 
survival every 90 days (+/- 30 days) until death, withdrawal of consent, or the end of the study, 
whichever occurs first. 
3.7Primary Completion 
The estimated primary completion is approximately 24 months after the study opens to accrual.
3.8Study Completion
The expected study completion date is approximately 78 months after the study opens to 
accrual.
4
Investigational Products
4.1Description, Supply and Storage of Investigational Products
4.1.1
Apalutamide
Classification
Apalutamide is in a class of medications called androgen receptor inhibitors. 
Mechanism of Action
The mechanism of action of apalutamide is through inhibition of the androgen receptor. 
Apalutamide prevents AR nuclear translocation and DNA binding to AREs.
Unlike bicalutamide, apalutamide shows no significant agonist properties in a model of CRPC 
(e.g., AR-over-expressing prostate cancer cells; LNCaP/AR cells). Gene transcription of PSA 
and TMPRSS2 is inhibited by apalutamide and results in concentration-dependent reduction of 
these protein levels in vitro. Apalutamide was also shown to reduce proliferation of CRPC cells 
as well as increase apoptosis in mouse models of prostate cancer. In addition, apalutamide has 
significant anti-tumor activity in murine tumor CRPC models, where apalutamide showed dose-
dependent tumor growth inhibition and tumor regression over a dose range of 0.1 to 10 
mg/kg/day, with effects that were superior to bicalutamide.
Metabolism
Apalutamide is primarily metabolized by CYP2C8 and CYP3A4 to form active metabolite, N-
desmethyl apalutamide. The contribution of CYP2C8 and CYP3A4 in the metabolism of 
apalutamide is estimated to be 58% and 13% following single dose but changes to 40% and 
37%, respectively at steady state. Apalutamide represented 45% and N-desmethyl apalutamide 
represented 44% of the total AUC following a single oral administration of radiolabeled 
apalutamide 240 mg.
Contraindications
Apalutamide can cause fetal harm and potential loss of pregnancy.


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Apalutamide is contraindicated for use in pregnant women because the drug can cause fetal 
harm and potential loss of pregnancy. Apalutamide is not indicated for use in females, so animal 
embryo-fetal developmental toxicology studies were not conducted with apalutamide. There are 
no human data on the use of apalutamide in pregnant women. Based on its mechanism of 
action, apalutamide may cause fetal harm when administered during pregnancy.
Formulation, Appearance, Packaging, and Labeling
Apalutamide is supplied as 60 mg tablets for oral administration. The 60-mg tablets consist of 
apalutamide drug substance, which is a white to slightly yellow powder. Apalutamide tablets (60 
mg) are packaged in 120-count, 160 cc HDPE bottles with CRC and include desiccant, and 
should at all times be kept in the original packaging.
Availability
Apalutamide is being obtained as study supply provided by Janssen.
Storage and Handling
Detailed information on handling and storage conditions will accompany the clinical drug 
supplies to the clinical study site(s). The storage conditions and expiry will be indicated on the 
label of the drug product.
Side Effects
Complete and updated adverse event information is available in the Investigational Drug 
Brochure (IB) and/or product package insert.
Dosage and Administration
Apalutamide is administered orally on a continuous once daily dosing schedule. Each cycle of 
drug administration consists of 28 days. Doses from 30 to 480 mg daily were tested in the 
Phase 1 portion of the first clinical study (Study ARN-509-001). The therapeutic dose is 240 mg 
(4 x 60 mg tablets) once daily. Apalutamide can be taken with or without food. 
For patients who have difficulty swallowing tablets whole, the recommended dose of 
apalutamide tablets may be mixed with 4 ounces (120 mL) of applesauce. Do not crush the 
tablets. Stir applesauce upon introduction of whole tablets as well as at 15 minutes and 30 
minutes afterwards until tablets are dispersed (well mixed with no chunks remaining). Using a 
spoon, swallow the mixture right away. Rinse the mixture container with 2 ounces of water and 
immediately drink the contents. Repeat the rinse with 2 ounces of water one more time to 
ensure the whole dose is taken. The mixture should be consumed within one hour of 
preparation.
4.1.2
Cetrelimab
Classification
Antineoplastics; immunotherapies; monoclonal antibodies
Cetrelimab is a fully human IgG4 kappa mAb against PD-1 with an S228P stabilizing mutation in 
the hinge region.2 Cetrelimab is produced in a Chinese hamster ovary cell line.
Mechanism of Action


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Antibody-dependent cell cytotoxicity; programmed cell death-1 receptor antagonists; T 
lymphocyte stimulants
Formulation, Appearance, Packaging, and Labeling
The drug product (DP) is supplied as a lyophilized DP that, upon reconstitution, results in a 
liquid for IV infusion. 
Availability
Cetrelimab is being obtained as study supply provided by Janssen.
Storage and Handling
Drug product should be stored at 2°C to 8°C and protected from light. 
Side Effects
Complete and updated adverse event information is available in the Investigational Drug 
Brochure (IB) and/or product package insert.
Physical and Chemical Characteristics
Cetrelimab has a molecular weight of approximately 148,000 Daltons and an isoelectric point of 
7.2 for the major peak. The absorptivity constant for cetrelimab at 280 nm was determined to be 
1.36 (mg/mL)-1cm-1.
Formulation Information
The DP has an approximate pH of 6.5 and does not contain a preservative. The fill volume is 
8.6 mL prior to lyophilization. Post lyophilization and prior to use, the lyophilized DP is 
reconstituted with 8 mL of sterile water for injection (sWFI). The dissolution of the lyophilized 
cake with the sWFI yields a final concentration of 30 mg/mL. The lyophilized DP includes 7.5% 
overfill to allow withdrawal of up to 360 mg/vial.
The DP is filled aseptically in a glass vial. The composition of the DP is provided in Table 2.


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Table 2
Composition and Concentration of Lyophilized Drug Product
Ingredient
Targeted Fill
Amount per Viala (mg)
Targeted Amount per mL 
(mg/mL)b
Cetrelimab
258
30
L-Histidine
9.89
1.15
L-Histidine monohydrochloride 
monohydrate
4.64
0.54
Sucrose
688
80
Polysorbate 20c
1.32
0.4c
EDTA, disodium salt, dihydrate 
crystal
0.17
0.02
Water for injection
Reconstitute with 8.0 mL
NA
a The target fill volume is 8.6 mL. This includes a 0.6 mL overfill to allow withdrawal of at least 240 
mg/vial (8.0 mL volume).
b Target amount per mL post reconstitution.
c Vegetable based; low peroxide.
NA = Not applicable
EDTA = ethylenediaminetetraacetic acid
4.2Accountability Records for Investigational Products
UCSF Investigational Drug Services (IDS) will manage drug accountability records for UCSF.
5
Treatment Plan
5.1Dosage and Administration
Treatment will be administered on an outpatient basis.
The starting dose of apalutamide will be 240 mg daily for patients not on apalutamide prior to 
study enrollment. For patients on apalutamide during Screening will be permitted to continue 
dose prior to enrollment.  
Cetrelimab will be given at the recommended phase 2 dose of 480 mg via IV on day 1 of every 
28-day treatment cycle. C1D1 dose will be administered over a 60-minute infusion. In the 
absence of infusion-related reactions, subsequent infusions may be administered IV over 30 
minutes, depending on the volume administered. Subjects should be carefully observed during 
cetrelimab infusions. Trained study staff at the clinic should be prepared to intervene in case of 
an IRR. Resources necessary for resuscitation (e.g., agents such as epinephrine and 
aerosolized bronchodilator, medical equipment such as oxygen tanks, tracheostomy equipment, 
and a defibrillator) must be available at the bedside. Attention to staffing should be considered if 
multiple subjects will be dosed at the same time. If an IRR develops, then the infusion should be 
temporarily interrupted or slowed down and the guidelines in Section 6 should be followed to 
manage the IRR.
For the first infusion, vital signs should be assessed before the start of the infusion, every 15 to 
20 minutes during the infusion, at the end of infusion, and approximately 2 hours after the end of 


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infusion. After the completion of the first infusion the subject may be discharged if considered 
clinically stable and all other study procedures have been completed. During subsequent 
infusions of cetrelimab, vital signs should be assessed pre-dose, once during infusion, and at 
the end of infusion. Cetrelimab infusions will be prepared and administered as described in the 
Investigational Product Preparation Instructions (IPPI).
Table 5.1
Regimen Description
Investigational 
Product
Premedication; 
precautions
Starting 
Dose
Route
Schedule
Cycle 
Length
Cetrelimab
See below*
480 mg
IV
Day 1
Apalutamide
See below*
240 mg
Oral
Daily
28 days
* During the first 2 cycles of study treatment, all subjects will receive prophylactic 
treatment with an oral H1 receptor antagonist (e.g., cetirizine, fexofenadine, loratadine) 
plus an H2 receptor antagonist (e.g., famotidine) plus montelukast at 10 mg daily on a 
continuous basis, starting at Cycle 1 Day 1. That treatment may be discontinued after 
Cycle 3 Day 1 at the discretion of the investigator and so long as the subject does not 
experience rash, pruritus, or other hypersensitivity manifestations during the first 2 
cycles of treatment (see below for management of drug-related rash).
5.2Dose Modifications and Management of Toxicity
Dose interruptions for up to 28 days are allowed. For treatment interruptions lasting > 28 days, 
resumption of treatment is only allowed if patients are experiencing clinical benefit and only 
upon approval of Principal Investigator. 
If one or more agent(s) is permanently discontinued due to AE, the patient may continue to 
receive the other medication(s) within regimen. 
5.2.1
Retreatment Criteria for Cetrelimab and Apalutamide
Table 5.2
Retreatment Criteria
Adverse Event
Requirements before each study agent 
administration
Absolute neutrophil count
≥ 1.0 x 109/L
Platelet count
≥ 50 x 109/L with or without platelet transfusions 
and/or growth factors
Hemoglobin
≥ 8.0 g/dL with or without transfusion, growth 
factors, or both
Fasting glucose, if 
prompted by HbA1c
≤ 250 mg/dL
Hyperthyroidism
Grade ≤ 2
AST and ALT
≤ 3 x ULN (≤ 5 x ULN for patients with liver 
metastases)
Total bilirubin
≤ 1.5 x ULN
Rash
Grade ≤ 2
Other clinically significant 
toxicity`
Recovery to Grade ≤ 1 or baseline


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5.2.2
Dose Delay for Cetrelimab  
Dose reduction of cetrelimab is not permitted. Treatment delay of cetrelimab is required until re-
treatment criteria are met (Table 5.2) and for any of the following AEs:

Grade 2 pneumonitis (recurrent Grade 2 or Grade ≥ 3 pneumonitis, cetrelimab must be 
permanently discontinued

Grade 2 or 3 diarrhea or colitis

Grade 2 nephritis with creatinine > 1.5 – 3 x ULN

Grade 2 or 3 creatinine elevation

Grade 2 elevation in AST or ALT except for patients with liver metastases at baseline, or 
total bilirubin 1.5 – 3 x ULN

Grade 2 toxicity related to treatment with cetrelimab that is intolerable or persistent (lasts 
> 28 days)

Symptomatic endocrinopathies (hypothyroidism, hyperthyroidism, hypophysitis, adrenal 
insufficiency diabetes)

Grade 3 rash

Other Grade 3 treatment related toxicity assessed as related to cetrelimab
If a cetrelimab dose must be delayed by more than 2 weeks, administration should continue at 
the next planned dosing date and the dose will be considered a missed dose.
Study treatment with cetrelimab should be permanently discontinued for any of the following: 

The investigator believes that for treatment-emergent toxicity it is in the best interest of 
the subject to discontinue study treatment

Grade 4 toxicities except for:
o
endocrinopathies that are controlled with replacement hormones
o
Grade 4 hematologic toxicities that resolve in less than 7 days may not result in 
study treatment discontinuation at the discretion of the treating physician.

Grade 2 or 3 irAEs that persist despite treatment modifications or corticosteroid dosing 
cannot be reduced to 10 mg prednisone or equivalent per day within 12 weeks

A treatment-related AE does not resolve to Grade ≤1 within 12 weeks of the last dose of 
study drug unless otherwise agreed to by the sponsor medical monitor and the 
investigator based on evidence of clinical benefit

Any non-hematological treatment-related event occurs a second time at Grade 3 
severity

Grade 3 (or recurrent Grade 2) pneumonitis

Grade 3 nephritis with creatinine ≥3xULN

Grade 3 elevation of AST or ALT >5xULN or total bilirubin >3xULN
o
For subjects with baseline Grade 2 elevation of AST or ALT due to liver 
metastasis, only Grade ≥3 elevations that are ≥50% of baseline for ≥7 days will 
require discontinuation of study treatment

Grade 3 infusion-related reactions (IRRs)

Immune-mediated encephalitis
Once a subject discontinues treatment, the subject may not be retreated with the study drug.


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5.2.3
Dose Modification for Apalutamide
Apalutamide dose reductions due to toxicities other than rash are described in the table 
immediately below. Management of rash, including dose reductions, is described in Section 5.4. 
Apalutamide dose may be reduced as follows: first dose-level reduction to 180 mg/day, second 
dose-level reduction to 120 mg/day. If further dose reduction is required, apalutamide should be 
discontinued.
Event
Clinically Significant Hematologic and Non-Hematologic AEs 
Deemed Related to Apalutamide
Grade 1 or 2
Dose delay up to 4 weeks or dose reduction at the discretion of the 
investigator.  
Grade 3
Hold apalutamide until AE has improved to Grade ≤1 or baseline 
and resume with a dose reduction. If apalutamide cannot be 
restarted within 4 weeks, it should be discontinued.
Discontinue for Grade 3 toxicity that recurs after 2 dose reductions.
Grade 4
Permanently discontinue apalutamide. 
Doses re-escalation back to the previous dose level may be permitted upon discretion of the 
Principal Investigator. 
5.3Management of Infusion-related Reactions
Guidelines for the management of IRRs are described in Table below. A reaction may manifest 
with fever, chills, rigors, headache, rash, pruritus, arthralgias, hypo- or hypertension, 
bronchospasm, or other symptoms. IRRs should be graded per NCI-CTCAE criteria.
Management of Infusion Related Reactions
Grade 1
No intervention indicated; remain at bedside and monitor subject 
until recovery from symptoms, Consider diphenhydramine 50 mg (or 
equivalent) or paracetamol 325 to 1000 mg (acetaminophen) or both 
at least 30 minutes before additional study drug administration.
Grade 2
Stop infusion; start IV saline infusion; give diphenhydramine 50 mg 
(or equivalent) IV or paracetamol 325 to 1000 mg (acetaminophen) 
or both; consider corticosteroids and bronchodilator therapy.
Restart infusion at 50% of initial rate: if no further complications 
ensue after 30 minutes, the rate may be increased to 100% of the 
original infusion rate; monitor subject closely.
Symptoms recur: discontinue treatment at that visit; administer 
diphenhydramine 50 mg IV. 


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Grade 3-4
Stop infusion; start IV saline infusion, bronchodilators, epinephrine 
0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 
0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV 
administration, or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), or all 4, as needed.
Subject should be monitored until the investigator is comfortable 
that the symptoms will not recur. Study drug will be permanently 
discontinued. Investigators should follow their institutional guidelines 
for the treatment of anaphylaxis. 
In the case of late-occurring hypersensitivity symptoms (e.g., 
appearance of a localized or generalized pruritus within 1 week after 
treatment), symptomatic treatment may be given (e.g., oral 
antihistamine, or corticosteroids).
Secondary 
Prophylaxis
Prophylactic medications (after initial event): diphenhydramine 50 
mg (or equivalent) or paracetamol 325 to 1000 mg (acetaminophen) 
or both at least 30 minutes before additional study drug 
administrations; if necessary, corticosteroids (recommended dose: 
up to 80 mg of IV methylprednisolone or equivalent) may be used. 
5.4Management of Rash
Interventions for the management of skin rash are listed in Table below. Document skin rash of 
any type or grade by de-identified photographs. 
For skin rash with any component of desquamation, mucosal involvement, or pustules:

Stop dosing with apalutamide and cetrelimab

Refer to dermatologist for evaluation

Consider skin biopsy in patients experiencing Grade ≥ 2 rash, if clinically indicated per 
conventional (standard of care) management. 
OPTIONAL: In the event that one or more standard of care skin biopsies are conducted, 
extra tissue may be collected for research (immune correlate assay to explore the 
mechanism of skin rah) only for patients who give optional consent for the extra tissue 
collection. Refer to the Lab Manual and Section 6.4.5 for additional information.


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Management of Drug Related Rash
Grade 1

Reduce apalutamide dose by one dose level

Continue cetrelimab at current dose

Initiate oral corticosteroids. Taper corticosteroid doses as clinically 
indicated while monitoring clinically for worsening symptoms

Consider topical steroid cream

Reinitiate oral H1 receptor blockers, if previously discontinued

Consider re-starting H2 receptor blockers and/or montelukast, if 
previously discontinued

Monitor for change in severity
Grade 2 (or 
symptomatic 
grade 1a)

At principal investigator discretion, hold cetrelimab and apalutamide for 
up to 28 days and reinitiate when rash Grade is ≤1

Reduce apalutamide dose by one dose level

Initiate oral corticosteroids or consider escalating corticosteroid dose if 
already prescribed. Taper corticosteroid doses as clinically indicated 
while monitoring clinically for worsening symptoms

Consider topical steroid cream

Reinitiate oral H1 receptor blockers, if previously discontinued

Consider re-starting H2 receptor blockers and/or montelukast, if 
previously discontinued

Monitor for change in severity
Grade ≥ 3b

Hold cetrelimab and apalutamide for up to 28 days and reinitiate when 
rash

Grade is ≤1; if after 28 days, the rash has not resolved to Grade ≤1, 
contact the sponsor to discuss further management and possible 
discontinuation of study drug

Reduce apalutamide dose by one dose level at time of re-initiation

Initiate oral corticosteroids or consider escalating corticosteroid dose if 
already prescribed. Taper corticosteroid doses as clinically indicated 
while monitoring clinically for worsening symptoms

Consider topical steroid cream

Initiate oral H1 and H2 receptor blockers and montelukast, if previously 
discontinued

Monitor for change in severity

Consider early referral to dermatologist
a. Patient presents with other rash-related symptoms such as pruritus, stinging, or burning
b. If there is blistering or mucosal involvement, stop cetrelimab and apalutamide dosing immediately.
6
Study Procedures and Schedule of Events
The study-specific procedures and assessments are detailed in this section and outlined in the 
Study Calendar – Section 6.1.  
Screening assessments must be performed within 28 days prior to the first dose of 
investigational product, unless otherwise noted.  Any results falling outside of the reference 
ranges may be repeated at the discretion of the investigator. 


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All on-study visit procedures are allowed a window of ± 3 days unless otherwise noted.  
Treatment or visit delays for public holidays or weather conditions do not constitute a protocol 
violation.


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6.1Study Calendar
Period/
Procedure
Screening
Cycle 1
Cycle 2+
End of 
Treatment 
Safety Follow-
up
Safety 
Follow-up
Long Term 
Follow-Up
Study Day/Visit Day
Day -28 to -1
unless 
otherwise noted 
D1
(± 3d)
D15
(± 3d)
D1
(± 3 days)
30 days
(± 7 days)
post-last dose
100 days
(± 14 days)
post-last 
dose
Every 90 
days1 
(± 30 days)
Study Treatment/Drug Administration
Apalutamide
X
Cetrelimab infusion
X
X
Administrative Procedures
Informed Consent
X
Clinical Assessments
Medical History
X
Concurrent Medications
X
X
X
X
Physical Exam14
X13
X13
X13
X13
X13
Vital Signs (blood 
pressure and heart rate)
X
X
X
X
X
AE assessment
X
X
X
X
X
X
X15
ECOG/Karnofsky 
Performance Status
X
X
X
X
X
Survival/Long-term 
Follow-up1
X
Laboratory Assessments
Hematology 2
X
X
X
X
X
X
Chemistry 3
X
X
X
X
X
X
Thyroid Function Tests 4
X
X
X
X
Serum PSA
X
X
X
X
Serum Total Testosterone
X
Whole blood peripheral 
immune markers5
X
X5
X


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Period/
Procedure
Screening
Cycle 1
Cycle 2+
End of 
Treatment 
Safety Follow-
up
Safety 
Follow-up
Long Term 
Follow-Up
Study Day/Visit Day
Day -28 to -1
unless 
otherwise noted 
D1
(± 3d)
D15
(± 3d)
D1
(± 3 days)
30 days
(± 7 days)
post-last dose
100 days
(± 14 days)
post-last 
dose
Every 90 
days1 
(± 30 days)
Isolation of peripheral 
blood mononuclear cells 
(PBMC)
X10
X10
Circulating tumor cells11
X11
X11
X11
Circulating tumor DNA12
X12
X12
X12
Imaging Procedures
CT Chest, Abdomen, and 
Pelvis6
X
X
Bone scan6
X
X
CT/MR brain7
Tissue Collection/ Biopsy
Tumor Tissue Collection8
X
X
Skin biopsy for Grade ≥2 
rash, if clinically indicated9
X9
1 Patients will be followed for overall survival every 90 days (+/- 30 days) from last dose of study treatment. Follow up will be conducted via chart review and/or telephone 
call. 
2 Including complete blood cell (CBC) with differential and platelet count. All laboratory assessments have a window of +/- 3 days.
3 Chemistry panel includes: sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN)/creatinine, calcium, alkaline phosphatase (ALP), ALT/AST, total bilirubin. 
All laboratory assessments have a window of +/- 3 days. 
4 Thyroid function tests - including thyroid-stimulating hormone (TSH), with reflex free T4, total/free T3. Thyroid function tests will be performed on Day 1 of each Treatment 
Cycle. 
5 Whole Blood for peripheral immune marker assessment will be collected on C1D1 (pre-dose), C2D1 (pre-dose), C3D1 (pre-dose), and End of Treatment.  
6 Tumor assessment will be performed with CT Chest/Abdomen/Pelvis and whole-body bone scan during screening, C4D1 (-14d), C7D1 (-14d) and on D1 (-14d) of every 4 
cycles thereafter (e.g. C11D1, C15D1). If PD by RECIST1.1/PCWG3, confirmatory scans are required ≥ 4 weeks following first scan showing progression. Lesions on 
chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung.  However, CT is preferable.
7 CT with contrast or MR brain is required during Screening only if history of brain metastases or clinical suspicion. 
8 Optional Tumor biopsy will be performed during Screening. Biopsy only required if no biopsy has previously been done. If no metastatic lesion is safely accessible to 
tumor biopsy, this requirement will be waived. Bone or soft tissue lesion is allowed, but soft tissue will be prioritized. If a patient has archival tissue obtained within 90 
days of C1D1, and no intervening therapy between tissue acquisition and C1D1, the requirement for fresh tumor biopsy will be waived. Tumor biopsy at progression is 


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Page 35 of 71
optional and should be the same lesion as Screening biopsy whenever feasible. Biopsy at PD also optional. Refer to Lab Manual for detail regarding tissue 
collection/biopsy.
9  If a subject experiences a treatment-emergent rash of Grade ≥ 2, consider referral to Dermatology for skin biopsy if clinically indicated per conventional (standard of care) 
rash management. See Section 5.4 for rash management.
OPTIONAL: In the event that one or more standard of care skin biopsies are conducted, extra tissue may be collected for research (immune correlate assay to explore 
the mechanism of skin rash) only for patients who give optional consent for the extra tissue collection. Refer to the Lab Manual and Section 6.4.5 for additional 
information.
10 PBMCs will be isolated from blood of patients experiencing Grade ≥ 2 rash (within 14 days of symptom onset when feasible) and from patients which have not 
experienced any Grade rash at end of treatment.
11 Whole blood will be collected on C1D1 (pre-dose), C2D1 (pre-dose), C3D1 (pre-dose), and End of Treatment. Samples were stored at Epic Sciences for circulating tumor 
cell analysis, however, as of Amendment 1.8 dated 07-24-2023, Epic Sciences is no longer analyzing these samples. All remaining samples stored at Epic Sciences will 
be returned to UCSF and stored at the UCSF CTSI lab. Whole blood will continue to be collected and stored at the CTSI for future research..
12 Plasma for circulating tumor DNA analysis including 5-hydroxymethyl cytosine (5-hmC) sequencing will be collected on C1D1 (pre-dose), C2D1 (pre-dose), C3D1 (pre-
dose), and End of Treatment. Plasma will be sent to the Feng laboratory at UCSF. 
13 Height at screening only. Weight at each physical exam visit (patient will self-report if PE is during a telemedicine visit).
14 On Cycle 1 Day 15 and the End of Treatment (EOT) visit, the physical exam may be done via a telemedicine visit.  Other physical exams must be performed in-person. 
Vital signs (BP and heart rate) will be self-reported by the patient when the physical exam is a telemedicine visit.
15 If AE assessment done at EOT visit, just needs to be done at 30-day Safety Follow-Up
 


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6.2Participant Registration
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record.  The original will be kept on file with the study records.  
All participants consented to the study will be registered in OnCore®, the UCSF Helen Diller 
Family Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The system 
is password protected and meets HIPAA requirements.
6.3Schedule of Procedures and Observations
6.3.1
Pretreatment Period
6.3.1.1 Screening Assessments 
The Screening procedures and assessments must be completed within 28 days of initiating 
study treatment. 

Clinical Assessments
o
Complete medical history
o
Concomitant medication review
o
Physical examination (including height and weight) and vital signs (BP and heart 
rate)
o
AE assessment
o
Performance status

Laboratory Assessments
o
Hematology labs - CBC with differential and platelet count 
o
Blood chemistry assessment, including: ALP, ALT/AST, total bilirubin, calcium, 
BUN, creatinine, potassium, sodium, chloride, bicarbonate
o
Thyroid function tests - including thyroid-stimulating hormone (TSH), with reflex 
free T4 and total/free T3
o
Serum Prostate Serum Antigen (PSA)
o
Testosterone level 

Imaging Procedures
o
CT of Chest, Abdomen and Pelvis (with IV contrast unless contra-indicated)
o
Bone scan
o
CT or MR brain with contrast (only if history of brain metastases or clinical 
suspicion) 

Tumor Tissue Collection (optional): A pre-treatment core biopsy is only required of 
patients who have not had a previous biopsy. In these cases, a biopsy must be obtained 
prior to study enrollment for all patients with safely accessible lesion, unless metastatic 
biopsy has been previously obtained within 90 days of C1D1 without intervening 
systemic therapy. For all other patients, the biopsy is optional.


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6.3.2
Treatment Period
6.3.2.1 Study Procedures, Cycle 1, Day 1

Study Treatment/Drug Administration
o
Initiation or continuation of apalutamide
o
Cetrelimab infusion

Clinical Assessments
o
Concomitant medication review
o
Physical examination (including weight) and vital signs
o
AE assessment
o
Performance status

Laboratory Assessments
o
Hematology labs - CBC with differential and platelet count 
o
Blood chemistry assessment, including: ALP, ALT/AST, total bilirubin, calcium, 
BUN, creatinine, potassium, sodium, chloride, bicarbonate, 
o
Thyroid function tests - including thyroid-stimulating hormone (TSH), free T4, 
total/free T3
o
Serum PSA
o
Whole blood peripheral immune markers (pre-dose)
o
Circulating tumor cells (pre-dose)
o
Circulating tumor DNA (pre-dose)
6.3.2.2 Study Procedures, Cycle 1, Day 15

Study Treatment/Drug Administration
o
Continuation of apalutamide

Clinical Assessments
o
Concomitant medication review
o
Physical examination (including weight), may be done via a telemedicine visit 
o
Vital signs (BP and heart rate)
o
AE assessment
o
Performance status

Laboratory Assessments
o
Hematology labs - CBC with differential and platelet count 
o
Blood chemistry assessment, including: ALP, ALT/AST, total bilirubin, calcium, 
BUN, creatinine, potassium, sodium, chloride, bicarbonate 
6.3.2.3 Study Procedures Cycle 2+, Day 1

Study Treatment/Drug Administration
o
Continuation of apalutamide
o
Cetrelimab infusion


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
Clinical Assessments
o
Concomitant medication review
o
Physical examination (including weight) 
o
Vital signs (BP and heart rate)
o
AE assessment
o
Performance status

Laboratory Assessments
o
Hematology labs - CBC with differential and platelet count 
o
Blood chemistry assessment, including: ALP, ALT/AST, total bilirubin, calcium, 
BUN, creatinine, potassium, sodium, chloride, bicarbonate 
o
Thyroid function tests - including thyroid-stimulating hormone (TSH), reflex free 
T4, reflex total/free T3 (D1 of every cycle)
o
Serum PSA
o
Whole blood peripheral immune markers (C2D1, C3D1, pre-dose)
o
Isolation of peripheral blood mononuclear cells (PBMC)
o
Circulating tumor cells (C2D1, C3D1, pre-dose)
o
Circulating tumor DNA (C2D1, C3D1, pre-dose)

Imaging Procedures
o
CT of Chest, Abdomen and Pelvis (with IV contrast unless contra-indicated) and 
whole-body bone scan (C4D1, C7D1, and D1 of every 4 cycles thereafter). 
Scans have window of -14 days and may be performed earlier than pre-specified 
as clinically indicated. 
6.3.2.4 Other On-Treatment Procedures

Dermatology referral and tissue collection/skin biopsy:
If a subject experiences a treatment-emergent rash of Grade ≥ 2, consider referral to 
Dermatology for skin biopsy if clinically indicated per conventional (standard of care) 
rash management. See Section 5.4 for rash management.
OPTIONAL: In the event that one or more standard of care skin biopsies are 
conducted, extra tissue may be collected for research (immune correlate assay to 
explore the mechanism of skin rash) only for patients who give optional consent for 
the extra tissue collection. Refer to the Lab Manual and Section 6.4.5 for additional 
information.
6.3.3
End-of-Treatment Study Procedures

Clinical Assessments
o
Physical examination (including weight), may be done via a telemedicine visit 
o
Vital Signs (BP and heart rate)
o
AE assessment
o
Performance status

Laboratory Assessments
o
Hematology labs - CBC with differential and platelet count 


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o
Blood chemistry assessment, including: ALP, ALT/AST, total bilirubin, calcium, 
BUN, creatinine, potassium, sodium, chloride, bicarbonate 
o
Thyroid function tests - including thyroid-stimulating hormone (TSH), reflex free 
T4, reflex total/free T3
o
Serum PSA
o
Whole blood peripheral immune markers 
o
Isolation of peripheral blood mononuclear cells (PBMC)
o
Circulating tumor cells
o
Circulating tumor DNA

Tissue Collection/Biopsy (optional)
o
Tumor Tissue Collection: A CT-guided core biopsy is optional at End of 
Treatment. The same lesion that was biopsied during Screening should be 
biopsied whenever feasible. 
6.3.4
30-day Safety Follow Up (+/- 7 days)

Clinical Assessments
o
AE assessment (may be performed via telephone)

Laboratory Assessments
o
Hematology labs - CBC with differential and platelet count 
o
Blood chemistry assessment, including: ALP, ALT/AST, total bilirubin, calcium, 
BUN, creatinine, potassium, sodium, chloride, bicarbonate 
6.3.5
100-day Safety Follow-Up (+/- 14 days)

Clinical Assessments
o
AE assessment (may be performed via telephone; if AE assessment was done at 
EOT visit, 100-day Safety Follow-Up AE assessment not required)
6.3.6
Long Term/Survival Follow-up 
Patients will be followed for overall survival every 90 days (+/- 30 days) from last dose of study 
treatment, until death, withdrawal of consent, or the end of the study, whichever occurs first.
Follow up will be conducted via chart review and/or telephone call. 
End of study is defined as three years after last dose of study drug. 
6.4Correlative Studies
6.4.1
Metastatic Tumor Biopsy
Metastatic tumor biopsies are only required if the patient has no previous metastatic biopsy 
(within 90 days of C1D1 without intervening systemic therapy). 
Metastatic tumor biopsy is at Screening is optional. 
Assays to be performed include RNA-seq, targeted genomic sequencing, histological 
assessment, and tumor content permitting, additional IHC and/or DNA-seq. 
Metastatic tumor biopsy is optional at PD. 


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6.4.2
Peripheral blood immune profiling
The Fong laboratory at UCSF will perform whole blood immune profiling for this study. Research 
blood (6 heparin green top tubes) will be collected C1D1 (pre-dose), C2D1, C3D1 (pre-dose), 
and EOT and transported to the Fong laboratory as per instructions in the Lab Manual. 
6.4.3
Circulating tumor cells
Circulating tumor cells were analyzed using the Epic Sciences’ platform. Morphology and 
heterogeneity, quantification of total number of CTCs, and expression of cell surface markers 
including AR, CD46, and CK, were analyzed. As of Protocol Amendment 1.8 dated 07-24-2023, 
Epic Sciences is no longer providing analysis of the samples.  Blood will continue to be 
collected on C1D1, C2D1, C3D1, and EOT, and will be stored at the UCSF CTSI Lab. All 
samples stored at Epic Sciences will be returned to UCSF, and will be stored in the CTSI Lab.
6.4.4
Circulating tumor DNA
The Feng laboratory at UCSF will analyze circulating tumor DNA for genomic alterations 
including alterations of RB1, TP53, and PTEN. In addition, 5-hydroxy methyl cytosine (5-hmC) 
sequencing of ctDNA will be performed to infer gene expression of key genes of interest 
including AR, ASCL1, EZH2, RB1, PTEN, TP53, and CTNNB1. Plasma for ctDNA analyses will 
be collected on C1D1, C2D1, C3D1, and EOT. 
6.4.5
Immune correlate assay to explore the mechanism of skin rash
If a subject experiences a treatment-emergent rash of Grade ≥ 2, consider referral to 
Dermatology for skin biopsy if clinically indicated per conventional (standard of care) rash 
management. See Section 5.4 for rash management.
OPTIONAL: In the event that one or more standard of care skin biopsies are conducted, extra 
tissue may be collected for research (immune correlate assay to explore the mechanism of skin 
rash) only for patients who give optional consent for the extra tissue collection (Refer to the Lab 
Manual). The risk of obtaining additional skin biopsy specimens at the time of a standard of care 
skin biopsy procedure will be minimized. The biopsy site and number of punches/samples 
obtained will be determined in consultation with the professional performing the procedure 
based on safe accessibility and size of lesion.
6.5Use of Concurrent/Concomitant Medications
6.5.1
Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial (see 
Appendix 4):

Antineoplastic systemic chemotherapy or biological therapy other than LHRH analogue 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents not specified in this protocol

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic solitary metastatic lesion or to the 
brain may be allowed at the investigator’s discretion.  


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Live vaccines within 30 days prior to the first dose of study treatment and while participating in 
the study.  Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed; however, 
intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. 
COVID-19 vaccine is allowed. 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination may 
be required.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue the 
participant on study treatment requires the mutual agreement of the Principal Investigator and 
subject. 
Prohibited Therapies

Aminophylline/theophylline

Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone)

Bupropion

Lithium

Meperidine and pethidine

Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine)

Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, 
imipramine, maprotiline, mirtazapine)

Systemic immunotherapy or immunosuppressants (e.g., ipilimumab, cyclosporine, 
infliximab). However, the use of immunosuppressive medications for the management of 
irAEs, IRRs, or in subjects with contrast allergies is acceptable.

Live or live attenuated vaccines; annual inactivated influenza vaccine is permitted

Other anticancer therapies, excluding GnRH analog
6.5.2
Acceptable Concomitant Medications/Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines. Where 
appropriate, these guidelines include the use of oral or IV treatment with corticosteroids, as well 
as additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.  Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased.  For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care.  The treatment guidelines are intended to be applied when 
the Investigator determines the events to be related to cetrelimab.  
Note: If after the evaluation of the event, it is determined not to be related to cetrelimab, the 
Investigator does not need to follow the treatment guidance.  Refer to guidelines regarding dose 
modification and supportive care. 
Patients are recommended to use bone-modifying agents (e.g. denosumab, zoledronic acid) 
during Screening and Treatment phases of the study to decrease risk of fracture. 


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LHRH analogues are required during Study Treatment except for patients with history of 
bilateral orchiectomy. 
Patients are recommended to taper off prednisone prior to study enrollment but are allowed to 
take doses up to ≤ 10 mg daily prednisone or prednisone equivalent. Doses of steroids higher 
than prednisone 10 mg daily (or prednisone equivalent) are permitted only for the treatment of 
immune related AEs. 
Treatment with antiemetic therapy will be permitted, if clinically indicated. 
Treatment with filgrastim or other colony stimulating factors will be permitted for Grade 3 or 
higher hematologic toxicity as per Package Insert but may not be used prophylactically. 
Treatment required for care of complications/AEs arising from the cancer and/or treatment will 
be permitted. 
6.6Lifestyle/Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Apalutamide may be taken with or without food. 
6.6.1
Contraception and Pregnancy
Study medications may have adverse effects on a fetus in utero.  Refer to Appendix 3 for 
approved methods of contraception.
7
Reporting and Documentation of Results
7.1Evaluation of Efficacy: Antitumor Effect – Solid Tumors
Response and progression in this study will be evaluated using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009] with use of PCWG3 criteria for assessment of 
new/pre-existing bone lesions.  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 v1.1 criteria. 
7.1.1
Definitions
Evaluable for toxicity
All participants will be evaluable for toxicity from the time of their first protocol-defined treatment 
on C1D1. 
Evaluable for objective response
Only those participants who have measurable disease present at baseline, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable 
for response.  These participants will have their response classified according to the definitions 
stated below.  (Note:  Participants who exhibit objective disease progression prior to the end of 
Cycle 1 will also be considered evaluable.)
Evaluable Non-Target Disease Response 


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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. 
7.1.2
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 (≥2 cm) by chest x-ray or as ≥10 mm 
(≥1 cm) 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 considered measurable 
only if radiographic evidence of progression following completion of prior radiation treatment. 
Malignant lymph nodes
To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm (≥1.5 
cm) in short axis when assessed by CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm [0.5 cm]).  At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable disease (Tumor Markers)
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm [<1 cm] 
or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as 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 patient, 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


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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.  It is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g. “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”).  Bone lesions may be measurable if ≥ 1 cm on MRI.    Measurements of 
these lesions are not required, but the presence or absence of each will be noted throughout 
follow-up.
Non-measurable disease (Tumor Markers)
Non-measurable disease is all other lesions (or sites of disease), including small lesions 
(longest diameter < 20 mm with conventional techniques or < 10 mm using spiral CT scan).  
Leptomeningeal disease, ascites, pleural or pericardial effusion, lymphangitic involvement of 
skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques are all non-measurable. 
7.1.3
Methods for Evaluation of Measurable Disease
All measurements will be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations will 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 will be used to characterize each 
identified and reported lesion at baseline and during follow-up whenever feasible.  Imaging-
based evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the antitumor effect of a treatment.
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) 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 slice thickness is 5 mm (0.5 cm) or less.  If CT scans have 
slice thickness greater than 5 mm (0.5 cm), the minimum size for 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.
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 


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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.  
Tumor markers:  Serum PSA will be used as part of the composite response definition as 
outlined in Section 2 and Section 8 of the protocol. 
7.1.4
Response Criteria
Evaluation of Target Lesions
Complete Response (CR)
Disappearance of all target lesions, determined by two separate observations conducted not 
less than 4 weeks apart.  Any pathological lymph nodes (whether target or non-target) must 
have reduction in short axis to <10 mm (the sum may not be “0” if there are target nodes).  
There can be no appearance of new lesions.
Partial Response (PR)
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as 
reference the baseline sum LD.  There can be no appearance of new lesions.
Progressive Disease (PD)
At least a 20% increase in the sum of the diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of 
at least 5 mm (0.5 cm).  (Note:  the appearance of one or more new lesions is also considered 
progressions).
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum LD since the treatment started.
Evaluation of 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.
Incomplete Response/Stable Disease (SD)
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.


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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 participant’s best response 
assignment will depend on the achievement of both measurement and confirmation criteria.
Table 7.1 Response Criteria 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
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not evaluated
No
PR
≥4 wks. Confirmation**
SD
Non-CR/Non-
PD/not evaluated
No
SD
Documented at least once ≥4 wks. 
from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

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.
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
PD.
Note:  Participants with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD at that time should be reported as “symptomatic deterioration.”  
Every effort should be made to document the objective progression even after discontinuation of 
treatment.
Table 7.2 Response Criteria 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
Duration of Response
Duration of overall response
The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).


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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented.
Duration of stable disease
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started. 
Progression-Free Survival
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression or death, whichever occurs first.
Evaluation of non-measurable bone disease per PCWG3 criteria
Bone scans obtained after the baseline evaluation will be used to evaluate post-treatment 
changes. Bone scans obtained will be evaluated as either “no new lesions” or “new lesions” on 
the tumor measurement forms.

For the first scheduled reassessment: If 2 or more new bone lesions are detected at the 
first scheduled evaluation (9 weeks), confirmatory bone scan is required 6 or more 
weeks later. If < 2 additional new lesions are observed on the confirmatory bone scan, 
study therapy is continued. If ≥ 2 additional new lesions are observed, then the patient 
has experienced radiographic progression by PCWG criteria. Progression in this 
situation is dated as the time of the first reassessment scan.

For subsequent scheduled reassessments: If no new lesions are observed, study 
therapy will continue. If ≥ 2 new bone lesions are observed, this is evidence of 
radiographic PD. Date of progression is the date at which the first scan demonstrating 
radiographic progression was obtained.
Evaluation of Post-treatment PSA changes
All patients will be evaluated for PSA decline. Patients with disease that is not measurable will 
be eligible for this study and will be assessed for response based on changes in PSA and serial 
bone scans (if appropriate). The baseline serum PSA must be at least 2 ng/mL to be evaluable 
for PSA response. 

50% and 90% PSA Decline: PSA decline of at least 50% and 90%, respectively, from 
baseline confirmed by a second measurement at least 3 weeks later. The reference for 
these declines should be a PSA measured within 2 weeks prior to starting therapy.

PSA Progression: Prostate Cancer Working Group 3 (PCWG3) Criteria will be reported. 
PSA progression occurs when the PSA has increased 25% or greater above nadir and 
an absolute increase of 2 ng/mL or more from the nadir is documented. Where no 
decline is observed, PSA progression similarly occurs when a 25% increase from 
baseline value along with an increase in absolute value of 2 ng/mL or more. PSA 
progression (without evidence of progression on scans) will not be criteria for 
discontinuation of study therapy.

PSA Response Duration: The PSA response duration commences on the date of the 
first 50% decline in PSA. The response duration ends when the PSA value increases by 
25% above the nadir, provided that the increase in the absolute-value PSA level is at 
least 5 ng/mL or back to baseline, whichever is lower

Progressive disease by PSA is defined by PSA progression, noted above. 


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
Time to PSA Progression: The start of the time to PSA progression is the day treatment 
is initiated. The end date is the date of the first PSA rise over the determined PSA PD 
value. 
Definition of Progressive Disease
A composite definition of PD will be defined by first occurrence of any one of the following:

Appearance of new metastatic lesions outside the bone

New metastatic lesions on bone scan confirmed as described above

Development of an indication for radiotherapy while on treatment

Unequivocal progression of non-target lesions

Global deterioration of health status requiring discontinuation of treatment without 
objective evidence of PD

Development of an indication for non-protocol systemic therapy
Patients experiencing radiographic progression in the absence of clinical progression are 
allowed to remain on treatment until follow up scan confirms progression. 
Note that PSA progression (as defined above) alone does not meet the criteria for progressive 
disease. 
7.2Evaluation of Safety
The safety parameters for this study include all clinically significant laboratory abnormalities, 
clinically significant physical findings, clinically significant findings on scans and/or ECG, and 
spontaneous reports of AEs reported to the investigator by participants.
Toxicity will be assessed according to the NCI CTCAE version 5.0. Safety analyses will be 
performed for all participants from the time of first study drug administration on C1D1.
7.3Definitions of Adverse Events 
7.3.1
Adverse Event
An AE (also known as an adverse experience) is defined as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related.  More 
specifically, an AE (can be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality.  An AE can arise from any use of the drug (e.g., off-label use, use in 
combination with another drug) and from any route of administration, formulation, or dose, 
including an overdose. 
7.3.2
Adverse Reaction
An adverse reaction is defined as any AE caused by the use of a drug.  Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event.
7.3.3
Suspected Adverse Reaction
A suspected adverse reaction is defined as any AE for which there is a reasonable possibility 
that the drug caused the AE. For the purposes of IND safety reporting, “reasonable possibility” 
indicates that there is evidence to suggest a causal relationship between the drug and the AE.  


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A suspected adverse reaction implies a lesser degree of certainty about causality than an 
adverse reaction.
7.3.3.1 Unexpected 
An AE or suspected adverse reaction is considered unexpected if it is not listed in the 
investigator brochure or package insert(s), or is not listed at the specificity or severity that has 
been observed, or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in the current 
application. 
“Unexpected,” as used in this definition, also refers to AEs or suspected adverse reactions that 
are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation.
AEs that would be anticipated to occur as part of the disease process are considered 
unexpected for the purposes of reporting because they would not be listed in the investigator 
brochure.  For example, a certain number of non-acute deaths in a cancer trial would be 
anticipated as an outcome of the underlying disease, but such deaths would generally not be 
listed as a suspected adverse reaction in the investigator brochure.
Some AEs are listed in the Investigator Brochure as occurring with the same class of drugs, or 
as anticipated from the pharmacological properties of the drug, even though they have not been 
observed with the drug under investigation.  Such events would be considered unexpected until 
they have been observed with the drug under investigation. For example, although angioedema 
is anticipated to occur in some participants exposed to drugs in the angiotensin-converting 
enzyme inhibitor class and angioedema would be described in the investigator brochure as a 
class effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes.
For apalutamide, the link to the package insert is:
http://www.janssenlabels.com/package-insert/product-monograph/prescribing-
information/ERLEADA-pi.pdf
For cetrelimab, the expectedness of an AE will be determined by whether or not it is listed in the 
Investigator's Brochure.
7.3.3.2 Serious
An AE or suspected adverse reaction is considered serious if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 

Death

Life-threatening AE

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function

Congenital anomaly/birth defect
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent 


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one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.
7.3.3.3 Life-threatening
An AE or suspected adverse reaction is considered life-threatening if, in the view of either the 
investigator or sponsor, its occurrence places the participant at immediate risk of death. It does 
not include an AE or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death.
7.3.3.4 Adverse Events of Special Interest 
AEs of special interest are events that the drug manufacturer is actively monitoring as a result of 
a previously identified signal (even if non-serious).  
For cetrelimab, the AEs of special interest are:

Immune-related reactions
There are no non-serious AEs of special interest for apalutamide. 
Any AE of special interest that is to be reported to the drug manufacturer should be recorded on 
a Serious Adverse Event Report Form and be reported to the drug manufacturer within 24 
hours of becoming aware of the event.
7.3.3.5 Product Quality Complaint (PQC)
A product quality compliant is defined as any suspicion of a product defect related to a potential 
quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product, or delivery system.  Not all PQCs involve a 
subject.  Lot and batch numbers are of high significance and need to be collected whenever 
available.
Examples of PQC include but not limited to:

Functional Problem: e.g., altered delivery rate in a controlled release product

Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules

Potential Dosing Device Malfunction: e.g., autoinjector button not working, needle 
detaching from syringe

Suspected Contamination

Suspected Counterfeit
7.3.3.6 Special Reporting Situations
Safety events of interest for a J&J medicinal product that require expediting reporting and/or 
safety evaluation include, but are not limited to:

Drug exposure during pregnancy (maternal and paternal)

Overdose of a J&J medicinal product 

Exposure to a J&J medicinal product from breastfeeding 

Suspected abuse/misuse of a J&J medicinal product


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
Inadvertent or accidental exposure to a J&J medicinal product 

Medication error involving a J&J medicinal product (with or without patient exposure to 
the J&J medicinal product, e.g., name confusion)

Suspected transmission of any infectious agent via administration of a medicinal product
Special situations should be recorded on the Adverse Event page of the CRF.
Any special situation that meets the criteria of a serious adverse event should be recorded on a 
MedWatch form and be reported to the J&J within 24 hours of becoming aware of the event.
7.3.3.7 Pregnancy
Because the J&J medicinal product may have an effect on sperm, pregnancies in partners of 
male subjects exposed to a J&J medicinal product will be reported by the PRINCIPAL 
INVESTIGATOR within 24 hours of their knowledge of the event using the Serious Adverse 
Event Form.  Depending on local legislation this may require prior consent of the partner.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in 
the infant will be required.
7.3.4
Recording of Adverse Events
Refer to the Data Safety Monitoring Plan, located in Appendix 2.  
7.3.5
Follow-up of Adverse Events
All participants who experience AEs will be followed with appropriate medical management until 
resolved or stabilized, as determined by the investigator, or until the initiation of new anti-cancer 
therapy, whichever occurs first.  For selected AEs for which administration of the investigational 
product was stopped, a re-challenge of the subject with the investigational drug may be 
conducted if considered both safe and ethical by the investigator.
7.3.6
Adverse Events Monitoring
Refer to the Data Safety Monitoring Plan, located in Appendix 2. 
7.3.7
Expedited Reporting 
Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 100 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event.  The contact may be by 
phone or e-mail.
Reporting to Institutional Review Board
The UCSF PI must report events to the UCSF IRB according to institutional guidelines.
UCSF IRB website for guidance in reporting AEs: https://irb.ucsf.edu/adverse-event
The PI at each participating site is responsible for reporting events to the IRB of record 
according to IRB guidelines. 
Expedited Reporting to the FDA


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If the study is being conducted under an IND, the Sponsor (or the Sponsor-Investigator) is 
responsible for determining whether or not the suspected adverse reaction meets the criteria for 
expedited reporting in accordance with federal regulations (21 CFR §312.32). 
The Sponsor (or Sponsor-Investigator) must report in an IND safety report any suspected 
adverse reaction that is both serious and unexpected. The Sponsor needs to ensure that the 
event meets all three definitions: 

Suspected adverse reaction 

Unexpected 

Serious 
If the AE does not meet all three of the definitions, it should not be submitted as an expedited 
IND safety report.
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
Reporting to Industry Partners
All AEs and special situations, whether serious or non-serious, related or not related, following 
exposure to 
 medicinal product are to be documented by the investigator and recorded in 
the CRF and in the subject’s source records. Investigators must record in the CRF (if consistent 
with Sponsor policies) or MedWatch form their opinion concerning the relationship of the AE to a 
medicinal product. 
All (serious and non-serious) AEs reported for a 
medicinal product should be followed-up in 
accordance with clinical practice.
SAEs, Adverse Events of Special Interest and Special Reporting Situations
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
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The Sponsor and the Investigator) will transmit all SAEs, AEs of Special Interest and special 
situations following exposure to a 
product under study using MedWatch Form 3500A in 
accordance with Section 9 of this Exhibit B, Transmission Methods, in English within twenty-
four (24) hours of becoming aware of the event(s).
All follow-up information for serious adverse events that are not resolved at the end of the study 
or by the time of patient withdrawal must be reported directly by the PRINCIPAL 
INVESTIGATOR, within 24 hours becoming aware, 
 using the Serious Adverse 
Event Report 
All available clinical information relevant to the evaluation of a related SAE, AEs of Special 
Interest, serious ADR or special situation is required.

The INSTITUTION and/or PRINCIPAL INVESTIGATOR is responsible for ensuring that 
these cases are complete and if not are promptly followed-up. A safety report is not 
considered complete until all clinical details needed to interpret the case are received. 
Reporting of follow-up information should follow the same timeline as initial reports.

Copies of any and all relevant extraordinary (not including routine initial or follow-up 
ICSR submission) correspondences with regulatory authorities and ethics committees 
regarding any and all serious adverse irrespective of association with the J&J Product 
under study, are to be provided to the COMPANY using a transmission method in 
Section 9 within 24 hours of such report or correspondence being sent to 
applicable health authorities.
Non-Serious AEs
All non-serious AEs should be reported to COMPANY according to the timeframe outlined in the 
Agreement section entitled Reporting of Data.
PQC Reporting
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and 
complete reporting and analysis of PQC information from studies are crucial for the protection of 
patients, investigators, and the COMPANY, and are mandated by regulatory agencies 
worldwide. The COMPANY has established procedures in conformity with regulatory 
requirements worldwide to ensure appropriate reporting of PQC information. Lot and/or Batch 
#s shall be collected or any reports failure of expected pharmacological action (i.e., lack of 
effect). The product should be quarantined immediately and if possible, take a picture.
All initial PQCs involving a J&J medicinal product under study must be reported to the 
COMPANY by the PRINCIPAL INVESTIGATOR within 24 hours after being made aware of 
the event. The J&J contact will provide additional information/form to be completed.
If the defect for a 
medicinal product under study is combined with either a serious adverse 
event or non-serious AE, the PRINCIPAL INVESTIGATOR must report the PQC to the 
COMPANY according to the serious adverse event reporting timelines.  A sample of the 
suspected product should be maintained for further investigation if requested by the COMPANY.


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8
Statistical Considerations and Evaluation of Results
8.1Sample Size Considerations
8.1.1
Sample Size and Power Estimate
The sample size determination is based on the primary endpoint of the study, the composite 
response rate. Composite response rate is defined in Section 3 and below in Section 8.3.2. 
Based on historical control data, the null hypothesis is a 15% composite response rate. Simon's 
two-stage minimax design will be used. The null hypothesis that the true response rate is 15% 
will be tested against a one-sided alternative. In the first stage, 14 patients will be accrued. If 
there are 2 or fewer composite responses in these 14 patients, the study will be stopped. 
Otherwise, 10 additional patients will be accrued for a total of 24 patients. The null hypothesis 
will be rejected if 8 or more responses are observed in 24 patients. This design yields a type I 
error rate of 0.025 and power of 80.2% when the true composite response rate is 40%. 
8.1.2
Accrual Estimates
Based on our historical data, we estimate that approximately 15% of all mCRPC patients will 
meet the definition of treatment-emergent small cell NEPC (t-SCNC) as outlined in the Eligibility 
criteria in Section 3 of the protocol. We estimate an accrual rate of approximately 1.5 patients 
per month, and estimated accrual duration of approximately 18 months. 
8.2Interim Analyses and Stopping Rules
An interim analysis for safety and efficacy will be conducted after 14 patients are enrolled and 
have completed treatment. Criteria for efficacy stopping rule are outlined above in Section 8.1.1. 
With respect to interim safety analysis, if more than 33% (5 or more patients) experiences a 
Grade ≥ 3 treatment-related AE in cycle 1, excluding anemia or clinically insignificant laboratory 
abnormality, study accrual will be halted and alternative dose level and/or schedule may be 
investigated following safety analysis and protocol amendment. 
8.3Analyses Plans
8.3.1
Analysis Population
The safety population is defined as any patients who received at least one dose of protocol 
therapy on study. 
The analysis population for the primary composite response endpoint includes all patients 
evaluable for composite response, defined as possessing either a Screening PSA > 2 ng/mL 
and/or measurable disease by RECIST 1.1 criteria. 
The analysis population for the time-to-event efficacy endpoints including progression-free 
survival, PSA progression-free survival, and overall survival are all patients who receive at least 
one dose of protocol therapy. Criteria for censoring for each of the study endpoints is listed 
below in Section 8.3.3.
The analysis population for correlative endpoints include all patients who receive at least one 
dose of protocol therapy who have evaluable correlative sample/data. 
8.3.2
Primary Analysis (or Analysis of Primary Endpoints)
The composite response rate is the primary endpoint of the study, defined as:


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
≥ 50% decline from baseline PSA (defined by C1D1 value), confirmed by repeat 
measurement ≥ 3 weeks later AND/OR

Objective tumor response by RECIST 1.1 criteria AND/OR
The composite response rate along with 95% confidence interval will be reported. 
8.3.3
Secondary Analysis (or Analysis of Secondary Endpoints)
Secondary Objective 1 Analysis: AEs will be recorded and severity-graded using CTCAE 
version 5.0. Clinically significant laboratory, physical exam, scan, and ECG abnormalities will be 
captured as AEs. The frequency and severity of AEs will be descriptively reported on a per-
patient analysis.
Secondary Objective 2 Analysis: The median radiographic progression-free survival determined 
by PCWG3 criteria 
Secondary Objective 3 Analysis: PSA50 and PSA90 response are defined as above, a ≥ 50% 
and > 90% decline from baseline in serum PSA, respectively, confirmed by repeat 
measurement ≥ 4 weeks later. The PSA50 and PSA 90 response proportions will be reported 
along with 95% confidence interval for each study cohort, for the subset of PSA-evaluable 
patients (serum PSA ≥ 2 ng/mL at baseline).
Secondary Objective 4 Analysis: Median progression-free survival will be determined for each 
cohort as from the date of first dose of protocol-defined therapy, using Kaplan-Meier product 
limit method. Progression is defined as per Section 7.1.4. The first scan time point 
demonstrating radiographic progression requires confirmatory scans performed ≥ 4 weeks after 
first scan time point to confirm progression. Patients who discontinue treatment for reasons 
other than those listed above (e.g. AE, patient withdrawal) will be censored by the date of last 
treatment. 
Secondary Objective 5 Analysis: The median overall survival along with 95% confidence interval 
will be determined from the date of first dose of protocol-defined therapy until death from any 
cause, using the Kaplan-Meier product limit method. Patients will be followed for long-term 
survival as outlined in the Study Procedures. Patients who withdraw from study will be censored 
for analysis of overall survival using the date of study withdrawal. 
Secondary Objective 6 Analysis: The objective response rate and median duration of response 
will be reported along with 95% confidence interval, for the subset of patients with measurable 
soft tissue disease by RECIST 1.1 criteria. 
8.3.4
Exploratory/Correlative Analysis/Assessments
Exploratory Objective 1 Analysis: To explore the association between baseline metastatic tumor 
characteristics including t-SCNC, AR, RB1 loss, and immune response transcriptional 
signatures with clinical outcomes
Exploratory Objective 2 Analysis: To evaluate objective response rate and median progression-
free survival by irRECIST criteria
Exploratory Objective 3 Analysis: To evaluate the association between immune related AEs 
(irAEs) and clinical efficacy outcomes
Exploratory Objective 4 Analysis: To evaluate the association between baseline and change 
from baseline in circulating T cell and myeloid cell subsets with clinical outcomes


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Exploratory Objective 5 Analysis: To explore the mechanism of skin rash in patients receiving 
combination of apalutamide plus cetrelimab
Exploratory Objective 6 Analysis: To explore the association between genomic and epigenomic 
features of circulating tumor DNA with clinical outcomes
Exploratory Objective 7 Analysis: To explore the association between circulating tumor cell 
(CTC) characteristics including heterogeneity, overall CTC count, and expression of markers of 
interest (AR, CD56, cytokeratin) with clinical outcomes
Quantification of circulating T cell subsets will be performed using mass cytometry analysis of 
whole blood. The percent change from baseline in the circulating T cell subsets will be reported 
using descriptive statistics (e.g. median, range, standard deviation). In an exploratory fashion, 
the study cohort will be dichotomized by those with percent change from baseline above and 
below median and efficacy outcomes will be compared between dichotomized subgroups using 
log-rank test for time-to-event endpoints (e.g. PFS, duration of response) and Fisher’s exact test 
for categorical variables (e.g. composite response rate, objective response rate, PSA50 
response rate). 
Baseline metastatic tumor biopsies will be evaluated for following biomarkers of interest:

Genomic alterations by targeted next-generation sequencing including presence of RB1 
loss

Transcriptional profiling and application of previously validated signatures and specific 
genes implicated with immune response, t-SCNC, RB1 loss, and AR activity 

Histologic assessment for t-SCNC morphology

When feasible, immunohistochemical analysis to identify PD-L1 expression level and 
tumor infiltrating lymphocytes
As of Protocol Amendment 1.8 dated 07-24-2023, the italicized analyses below will no longer be 
performed. Epic Sciences is no longer involved in sample analysis and will return UCSF 
samples back to UCSF.
Circulating tumor cells be analyzed using the Epic Sciences’ platform for the following 
biomarkers of interest:

Heterogeneity score 

NEPC probability using previously published prediction tool (Beltran et al. CCR 2015)

Enumeration

Expression of AR, CD56, cytokeratin, and RB1 using IF assays
Circulating tumor DNA will be analyzed by the Feng laboratory at UCSF for the following 
biomarkers of interest:

Genomic alterations by targeted next-generation sequencing including presence of RB1 
loss

Inference of gene expression of target genes of interest, including AR, EZH1, ASCL1, 
using 5-hydroxymethyl cytosine (5-hmC) sequencing of ctDNA
The association between the above tissue-based biomarkers (baseline and change from 
baseline) with clinical efficacy endpoints including PFS, ORR, PSA50, and overall survival will 
be analyzed using log-rank test for time-to-event endpoints (e.g. PFS, duration of response) and 
Fisher’s exact test for categorical variables (e.g. composite response rate, objective response 
rate, PSA50 response rate). 


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The Lymphocyte Proliferation Assay to study mechanism of apalutamide induced rash
The lymphocyte proliferation assay (LPA) allows an assessment of the role of immunological 
reactions in drug-induced adverse reactions. The assay allows a measurement of the ability of 
lymphocytes placed in short-term tissue culture to undergo a clonal proliferation when 
stimulated in vitro by a foreign molecule, antigen or mitogen. Several studies have shown that 
CD4+lymphocytes proliferate in response to antigenic peptides in association with Class II MHC 
molecules on antigen-presenting cells. This proliferative response of lymphocytes to antigen in
vitro occurs only if the patient has been immunized to that antigen, either by having recovered 
from an infection with the microorganism containing that antigen, or by having been vaccinated. 
Therefore, some normal individuals may not respond to a given antigen, but most people will 
respond to at least one of several common microbial antigens.
This study will determine whether subjects who have experienced skin rash while on
apalutamide have an apalutamide (metabolite) specific LPA response. Besides lymphocyte 
proliferation various other endpoints will be assessed on PBMCs like Elispot. If lymphocyte 
proliferation is observed, additional studies will be conducted to isolate the individual T-cell 
clones. 
9
Study Management
9.1Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements.
Before initiating this trial, the PI will have written and dated approval from the Institutional 
Review Board for the protocol, written informed consent form, subject recruitment materials, and 
any other written information to be provided to participants before any protocol related 
procedures are performed on any participants.  
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the FDA has determined that the 
study is exempt from IND requirements. 
The PI must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements.
9.2Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant-facing materials 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF IRB.  Prior to obtaining IRB approval, the protocol must be approved by 
the Helen Diller Family Comprehensive Cancer Center Site Committee and by the Protocol 
Review Committee (PRC).  The initial protocol and all protocol amendments must be approved 
by the IRB prior to implementation.  


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9.3Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the IRB -approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  
The original signed copy of the consent document must be retained in the medical record or 
research file. 
9.4Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the PI and 
approved by PRC and the IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to participants, an 
amendment may be implemented prior to IRB approval.  In this circumstance, however, the PI 
must then notify the IRB according to institutional requirements. 
9.5Handling and Documentation of Clinical Supplies
The Principal Investigator will maintain complete records showing the receipt, dispensation, 
return, or other disposition of all investigational drugs at the site.  The date, quantity and batch 
or code number of the drug, and the identification of participants to whom the investigational 
product has been dispensed by participant number and initials will be included.  
The PI at each study site shall not make the investigational drug available to any individuals 
other than to qualified study participants.  Furthermore, the PI at each study site will not allow 
the investigational product to be used in any manner other than that specified in this protocol.
9.6Case Report Forms (CRFs)
The PI and/or designee at each study site will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study specific Case 
Report Forms (CRFs) will document safety and treatment outcomes for safety monitoring and 
data analysis.  All study data will be entered into OnCore® via standardized CRFs in accordance 
with the CTMS study calendar, using single data entry with a secure access account.  Study 
personnel for each study site will complete the CRFs; the PI for the study site will review and 
approve the completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the participant’s medical records maintained by 
study personnel at each study site.  All source documentation should be kept in separate 
research files for each participant. 
In accordance with federal regulations, the PI at each study site is responsible for the accuracy 
and authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
The PI at each study site will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked.  Any changes to the data entered into the CRFs after that time can only 
be made by joint written agreement among the Study Chair and the trial statistician.
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies. 


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9.7Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-
approved Data and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all AEs 
and suspected adverse reactions considered “serious”.  The DSMC will audit study-related 
activities to ensure that the study is conducted in accordance with the protocol, local standard 
operating procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant results of 
the DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at 
the time of continuing review, or in an expedited fashion, as applicable.  See Appendix 2 - Data 
and Safety Monitoring Plan.
9.8Record Keeping and Record Retention
The PI at each study site is required to maintain adequate records of the disposition of the drug, 
including dates, quantity, and use by subjects, as well as written records of the disposition of the 
drug when the study ends.  
The PI at each study site is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the CRFs and supporting data including, for example, signed and dated 
consent forms and medical records including, for example, progress notes of the physician, the 
individual's hospital chart(s), and the nurses' notes. The case history for each individual shall 
document that informed consent was obtained prior to participation in the study.
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed participant consent 
forms).
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study.
In accordance with FDA regulations, the PI at each study site shall retain records for a period of 
2 years following the date a marketing application is approved for the drug for the indication for 
which it is being investigated; or, if no application is to be filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and FDA is 
notified.
9.9Publications
The preparation and submittal for publication of manuscripts containing the study results shall 
be in accordance with a process determined by mutual written agreement among the Sponsor-
Investigator and collaborators.  


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Epstein, J.I., Netto, G.J., Liu, W., Isaacs, W.B., Marzo, A.M.D., Lotan, T.L., 2014. Rb 
Loss Is Characteristic of Prostatic Small Cell Neuroendocrine Carcinoma. Clin. Cancer 
Res. 20, 890–903. https://doi.org/10.1158/1078-0432.CCR-13-1982
Tang, Y., Gholamin, S., Schubert, S., Willardson, M.I., Lee, A., Bandopadhayay, P., Bergthold, 
G., Masoud, S., Nguyen, B., Vue, N., Balansay, B., Yu, F., Oh, S., Woo, P., Chen, S., 
Ponnuswami, A., Monje, M., Atwood, S.X., Whitson, R.J., Mitra, S., Cheshier, S.H., Qi, 
J., Beroukhim, R., Tang, J.Y., Wechsler-Reya, R., Oro, A.E., Link, B.A., Bradner, J.E., 
Cho, Y.-J., 2014. Epigenetic targeting of Hedgehog pathway transcriptional output 
through BET bromodomain inhibition. Nat. Med. 20, 732–740. 
https://doi.org/10.1038/nm.3613
Taube, J.M., Klein, A., Brahmer, J.R., Xu, H., Pan, X., Kim, J.H., Chen, L., Pardoll, D.M., 
Topalian, S.L., Anders, R.A., 2014. Association of PD-1, PD-1 ligands, and other 
features of the tumor immune microenvironment with response to anti-PD-1 therapy. 
Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 20, 5064–5074. 
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Wyce, A., Degenhardt, Y., Bai, Y., Le, B., Korenchuk, S., Crouthamel, M.-C., McHugh, C., 
Vessella, R., Creasy, C., Tummino, P., Barbash, O., 2013. Inhibition of BET 
bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget 4, 
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Zhu, H., Bengsch, F., Svoronos, N., Rutkowski, M.R., Bitler, B.G., Allegrezza, M.J., Yokoyama, 
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Appendix 1 Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease
0
Normal activity
Fully active, able to carry on all 
pre-disease performance 
without restriction
90
Able to carry on normal activity; 
minor signs or symptoms of disease
80
Normal activity with effort; some 
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)
70
Cares for self, unable to carry on 
normal activity or to do active work
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs
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
50
Requires considerable assistance 
and frequent medical care
40
Disabled, requires special care and 
assistance
3
In bed > 50% of the time
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking hours
30
Severely disabled, hospitalization 
indicated
Death not imminent
20
Very sick, hospitalization indicated
Death not imminent
4
100% bedridden
Completely disabled
Cannot carry on any self-care
Totally confined to bed or chair
10
Moribund, fatal processes 
progressing rapidly
5
Dead
0
Dead


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 07/24/2023
Protocol CC#: 21553
Phase II – Apalutamide + Cetrelimab
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Appendix 2 (Single Site): Phase II or III Institutional Trial
1.
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for auditing data quality and participant safety for 
all HDFCCC institutional clinical trials.  A summary of DSMC activities for this trial includes: 

Semiannual auditing (depending on trial accrual)

Review of serious adverse events

Minimum of biennial regulatory auditing
2.
Monitoring and Reporting Guidelines
Investigators will conduct a continuous review of data and participant safety at monthly site 
committee meetings where the results of each participant’s treatment are discussed and 
documented in the site committee minutes.  
All institutional Phase II and III therapeutic trials are audited on a semiannual basis, with all data 
from twenty percent of the enrolled participants audited by the DSMC Monitor/Auditor.  The 
assigned DSMC Monitor/Auditor will review no more than a total of 10 participant charts during 
the course of auditing this trial. DSMC Monitor/Auditors will send a follow-up report to the study 
team within 20 business days after the auditing visit is complete for the PI and the study team to 
resolve all action items from this report within 20 business days.  An abbreviated regulatory 
review (i.e., reviewing protocol and consent versions, SAEs, PVs, DOA logs, 1572 forms, etc.) 
will occur at each participant monitoring review; however, a full regulatory review will occur on a 
biennially basis by the DSMC for regulatory compliance.
Auditing of all enrolled participants in these trials will be complete after 20% of enrolled 
participants have been audited through five cycles of treatment.  However, regulatory reviews of 
the trial, safety reviews (i.e., Serious Adverse Event (SAE) reviews and Protocol Violation (PV) 
reviews), and audit/inspection preparation (as applicable) will continue until the trial is closed by 
the IRB.  
3.
Review and Oversight Requirements
3.1 Adverse Event Monitoring 
All Grade 3-5 adverse events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the use of the 
investigational agent(s) or study procedure, will be entered into OnCore®, UCSF’s 
Clinical Trial Management System.  
Adverse events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) as developed and revised by the Common Therapy Evaluation 
Program (CTEP) of the National Cancer Institute.  Adverse events are further given an 
assignment of attribution or relationship to investigational agent or study procedure.  
Attribution categories are:

Definite – The adverse event is clearly related to the investigational agent(s) or 
study procedure.

Probable – The adverse event is likely related to the investigational agent(s) or 
study procedure.


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
Possible – The adverse event may be related to the investigational agent(s) or study 
procedure.

Unrelated – the adverse event is clearly not related to the investigational agent(s) or 
study procedure.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the Site Committee meetings.  The Site Committee will review and discuss the 
selected toxicity, the toxicity grade, and attribution assignment.
3.2 Serious Adverse Event Reporting 
By definition, an adverse event is defined as a serious adverse event (SAE) according to 
the following criteria:

Death.

Life-threatening (i.e., results in an immediate risk of death).

Requires inpatient hospitalization or prolongation of existing hospitalization,

Permanent or significant disability/incapacity

Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may 
require medical or surgical intervention to prevent one of the outcomes listed above. 

Event occurring in a gene therapy study.

Event that changes the risk/benefit ratio of a study.

Any other event the Principal Investigator judges to be serious or which would 
suggest a significant hazard, contraindication, side effect, or precaution.
Serious adverse event reporting will be in accordance with all IRB regulations. For trials 
conducted under an investigational new drug (IND) application, the SAE will be reported 
in accordance with Code of Federal Regulation Title 21 Part 312.32 and will be reported 
on a Med Watch form.  
UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event 
Med Watch forms and information:
www.fda.gov/medwatch/getforms.htm
All serious adverse events are entered into OnCore®, as well as submitted to the IRB 
(per IRB guidelines).  The SAEs are reviewed and monitored by the Data and Safety 
Monitoring Committee on an ongoing basis and discussed at DSMC meetings, which 
take place every six weeks.  The date the SAE is sent to all required reporting agencies 
will be documented in OnCore®. 
If the SAE involves a subject death, and is determined to be possibly, probably or 
definitely related to the investigational drug or any research related procedure, the event 
must be reported to the DSMC Chair (or Vice Chair) and DSMC Director within one 
business day.  
3.3 Review of Adverse Event Rates


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Version date: 07/24/2023
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If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported 
in the Investigator Brochure or package insert) is noted in the study, the Principal 
Investigator will notify the DSMC via report at the time the increased rate is identified.  
The report will indicate if the incidence of adverse events observed in the study is above 
the range stated in the Investigator Brochure or package insert.
If at any time the Investigator voluntarily holds enrollment or stops the study due to 
safety issues, the DSMC Chair (or Vice Chair) and the DSMC Director must be notified 
within one business day and the IRB must be notified as per IRB reporting regulations.
Data and Safety Monitoring Committee Contacts:
Katie Kelley, MD (DSMC Chair)
UCSF HDFCCC
San Francisco, CA 94158
John McAdams (DSMC Director)
UCSF HDFCCC
San Francisco, CA 94143


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 07/24/2023
Protocol CC#: 21553
Phase II – Apalutamide + Cetrelimab
Page 70 of 71
Appendix 3 Approved Methods of Contraception
To avoid risk of drug exposure through the ejaculate (even men with vasectomies), patients 
must use a condom during sexual activity while on study drug and for 5 months following the 
last dose of study drug. Donation of sperm is not allowed during the study and for 5 months 
following the last dose of study drug.
Maternal use of an anti-androgen is expected to produce changes in hormone levels that may 
affect fetal development. 
If the patient is engaged in sexual activity with a woman of childbearing potential, a condom is 
required along with another effective contraceptive method consistent with local regulations 
regarding the use of birth control methods for patients participating in clinical studies and their 
partners. Highly effective forms of contraception include:

Established use of oral, injected or implanted hormonal methods of contraception; 
placement of an intrauterine device (IUD) or intrauterine (IUS) system;

Barrier methods: condom with spermicidal foam/gel/film/cream/suppository or occlusive 
cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository;

Vasectomy;

True abstinence (an option when this is in line with the preferred and usual lifestyle of 
the patient).
Two highly effective forms of contraception are required during the study and for 5 months after 
the last dose of study drug.


UCSF Helen Diller Family Comprehensive Cancer Center
Version date: 07/24/2023
Protocol CC#: 21553
Phase II – Apalutamide + Cetrelimab
Page 71 of 71
Appendix 4 Prohibited Medications List 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy other than LHRH analogue 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents not specified in this protocol

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic solitary metastatic lesion or to the 
brain may be allowed at the investigator’s discretion.  
Live vaccines within 30 days prior to the first dose of study treatment and while participating in 
the study.  Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed; however, 
intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. 
COVID-19 vaccine is allowed.
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination may 
be required.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue the 
participant on study treatment requires the mutual agreement of the Principal Investigator and 
subject. 
Prohibited Therapies

Aminophylline/theophylline

Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone)

Bupropion

Lithium

Meperidine and pethidine

Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine)

Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, 
imipramine, maprotiline, mirtazapine)

Systemic immunotherapy or immunosuppressants (e.g., ipilimumab, cyclosporine, 
infliximab). However, the use of immunosuppressive medications for the management of 
irAEs, IRRs, or in subjects with contrast allergies is acceptable.

Live or live attenuated vaccines; annual inactivated influenza vaccine is permitted

Other anticancer therapies, excluding GnRH analog