IMPACT: Immunotherapy in Patients With Metastatic Cancers and CDK12 Mutations
Phase: PHASE2
Conditions: Metastatic Castration Resistant Prostate Cancer, Metastatic Cancer, Solid Tumor
Sponsor: University of Michigan Rogel Cancer Center

 
UMCC 2018.050 
 
 
Immunotherapy in PaƟents with MetastaƟc Cancers and CDK12 MutaƟons 
 
 
NCT03570619 

 
 
  PROTOCOL UMCC 2018.050 [CA209-8JJ] 
IMPACT: Immunotherapy in Patients with Metastatic Cancers and CDK12 Mutations 
 
 
 
Sponsor-Investigator/  
Ajjai Alva, MD 
Principal Investigator:  
Internal Medicine/Hematology-Oncology 
 
 
 
 
University of Michigan  
 
 
 
 
7316 Cancer Center 
 
 
 
 
1500 E. Medical Center Drive 
 
 
 
 
Ann Arbor, MI 48109 
 
 
 
 
Phone: (734) 936-0091 
 
 
 
 
Fax: (734) 615-2719 
 
 
 
 
Email: ajjai@umich.edu 
 
 
 
 
 
 
 
 
Biostatistician: 
 
Veerabhadran Baladandayuthapani  
 
 
 
 
Phone (832)-729-7653  
 
 
 
 
Email: veerab@med.umich.edu  
 
Coordinating Center:  
University of Michigan 
 
Study Drug: 
 
 
Nivolumab, Ipilimumab  
 
 
 
 
 
IND #:  
 
 
139,599 
 
Initial version:  
 
April 26, 2018 
Amended: 
 
 
December 4, 2018 
Amended: 
 
 
October 4, 2019 
Amended: 
 
 
November 25, 2019 
Amended: 
 
 
March 25, 2020 
Amended: 
 
 
August 10, 2020 
Amended: 
 
 
February 01, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol UMCC 2018.050 
________________________________________________________________________ 
 
 
TABLE OF CONTENTS 
ABBREVIATIONS ............................................................................................................................ 1 
STUDY SYNOPSIS .......................................................................................................................... 4 
1.0 
BACKGROUND AND RATIONALE ....................................................................................... 9 
1.1 
Disease Background ........................................................................................................... 9 
1.2 
Study Agent(s) Background and Associated Known Toxicities ......................................... 11 
1.3 
Rationale ............................................................................................................................ 12 
1.4 
Exploratory Studies ........................................................................................................... 12 
2.0 
STUDY OBJECTIVES/ENDPOINTS .................................................................................... 12 
2.1 
Primary Objective .............................................................................................................. 12 
2.2 
Secondary Objectives ........................................................................................................ 12 
2.3 
Exploratory Objectives ....................................................................................................... 13 
2.4 
Primary Endpoint ............................................................................................................... 13 
2.5 
Secondary Endpoints ........................................................................................................ 13 
3.0 
PATIENT ELIGIBILITY ......................................................................................................... 14 
3.1 
Inclusion Criteria ................................................................................................................ 14 
3.2 
Exclusion Criteria ............................................................................................................... 15 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES ....................................... 16 
5.0 
TREATMENT PLAN ............................................................................................................. 16 
5.1 
Treatment Dosage and Administration .............................................................................. 16 
5.2 
Toxicities and Dosing Delays/Dose Modifications ............................................................. 17 
5.3 
Concomitant Medications/Treatments ............................................................................... 26 
5.4 
Duration of Therapy ........................................................................................................... 27 
5.5 
Off Treatment Criteria ........................................................................................................ 27 
5.6 
Duration of Follow-Up ........................................................................................................ 27 
5.7 
Off Study Criteria ............................................................................................................... 27 

Protocol UMCC 2018.050 
________________________________________________________________________ 
 
 
5.8 
Patient Replacement ......................................................................................................... 28 
6.0 
STUDY PROCEDURES ....................................................................................................... 28 
7.0 
MEASUREMENT OF EFFECT ............................................................................................. 30 
7.1 
Antitumor Effect- Prostate Cancer ..................................................................................... 30 
7.2 
Antitumor Effect- Non-Prostate Malignancies ................................................................... 32 
7.3 
Guidelines for Evaluation of Measurable Disease............................................................. 35 
7.4 
Response Criteria .............................................................................................................. 36 
7.5 
Duration of Response - Non prostate malignancies .......................................................... 38 
7.6 
Progression-Free Survival - Non prostate malignancies ................................................... 38 
7.7 
 Safety/Tolerability ............................................................................................................. 38 
8.0 
ADVERSE EVENTS ............................................................................................................. 38 
8.1 
Experimental Therapy ....................................................................................................... 38 
8.2 
Adverse Event Reporting Requirements ........................................................................... 39 
8.3 
Definitions .......................................................................................................................... 39 
8.4 
Adverse Event Characteristics .......................................................................................... 41 
8.5 
Serious Adverse Event Reporting Guidelines ................................................................... 41 
8.6 
Routine Reporting .............................................................................................................. 42 
8.7 
Reporting of Unanticipated Problems ................................................................................ 42 
8.8 
Safety Report Reconciliation ............................................................................................. 42 
9.0 
DRUG INFORMATION ......................................................................................................... 43 
10.0 CORRELATIVES/SPECIAL STUDIES ................................................................................ 46 
10.1 Sample Collection Guidelines ............................................................................................ 46 
10.2 Specimen Banking ............................................................................................................. 46 
11.0 STATISTICAL CONSIDERATIONS ..................................................................................... 47 
11.1 Study Design/Study Endpoints .......................................................................................... 47 
11.2 Sample Size and Accrual .................................................................................................. 47 

Protocol UMCC 2018.050 
________________________________________________________________________ 
 
 
11.3 Data Analyses Plans ......................................................................................................... 47 
12.0 DATA AND SAFETY MONITORING ................................................................................... 48 
13.0 DATA MANAGEMENT ......................................................................................................... 49 
14.0 QUALITY ASSURANCE AND AUDITS ............................................................................... 49 
15.0 CLINICAL TRIAL MONITORING ......................................................................................... 50 
16.0 REFERENCES ..................................................................................................................... 51 
17.0 APPENDICES ....................................................................................................................... 53 
 
 
 
 
 
 
 
 
 

 
Page 1 of 52 
ABBREVIATIONS 
 
AE 
Adverse Event 
 
ALT 
Alanine Aminotransferase 
 
ALC 
Absolute Lymphocyte Count 
 
AST 
Aspartate Aminotransferase 
 
BUN 
Blood Urea Nitrogen 
 
CBC 
Complete Blood Count 
 
CDK 
Cyclin-Dependent Kinase 
 
CMP 
Comprehensive Metabolic Panel 
 
CR 
Complete Response 
 
CT 
Computed Tomography 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
CTLA-4 
Cytotoxic T-lymphocyte Antigen-4 
 
CTSU 
Clinical Trials Support Unit 
 
DLT 
Dose Limiting Toxicity 
 
DSMC 
Data and Safety Monitoring Committee 
 
H&P 
History & Physical Exam 
 
HR 
Homologous Recombination 
 
HRPP 
Human Research Protections Program 
 
IND 
Investigational New Drug 
 
IRB 
Institutional Review Board 
 
IV (or iv) 
Intravenously 
 
mCRPC 
Metastatic Castrate Resistant Prostate Cancer 
 
MMR 
Mismatch Repair 
 
MTD 
Maximum Tolerated Dose 
 
NCI 
National Cancer Institute 
 
ORR 
Overall Response Rate 
 
OS 
Overall Survival 
 
PARP 
Poly (ADP-ribose) Polymerase 
 
PBMCs 
Peripheral Blood Mononuclear Cells 
 
PD 
Progressive Disease 
 
PDL1 
Programmed Death Ligand 1 
 
PFS 
Progression Free Survival 
 
PI 
Principal Investigator 
 
PO 
per os/by mouth/orally 
 
PR 
Partial Response 
 
PRC 
Protocol Review Committee 
 
RPFS 
Radiographic Progression Free Survival 
 
SAE 
Serious Adverse Event 
 
SD 
Stable Disease 
 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
 

 
Page 2 of 52 
SPGT 
Serum Glutamic Pyruvic Transaminase 
 
UaP 
Unanticipated Problem 
 
WBC 
White Blood Cells 
 
WXS 
Whole Genome Sequencing 
 

 
Page 3 of 52 
STUDY SCHEMA 
 
This is a multi-center, open label, 3 cohort study of patients with metastatic cancer, either metastatic 
castration resistant prostate cancer, or metastatic non-prostate cancer whose tumor harbors CDK12 loss 
of function. Patients with metastatic castration resistant prostate cancer (mCRPC) will be enrolled in 
cohort A or C, and patients with all other metastatic subtypes will be enrolled in cohort B. Cohorts A and B 
patients will begin receiving combination therapy with nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV 
every 3 weeks for up to 4 cycles if tolerated, followed by nivolumab maintenance therapy at flat dose 480 
mg IV every 4 weeks through the end of the planned study duration, for up to 104 weeks of total therapy. 
Cohort C patients will receive nivolumab at flat dose 480 mg IV every 4 weeks for up to 104 weeks of total 
therapy. Cohort C will open after enrollment is complete to Cohort A. 
 
 
 
 
Metastatic cancer with 
CDK12 loss of function 
by NGS 
Nivolumab 480 mg IV q4 wks 
for up to 92 additional wks 
(total up to 104 weeks) 
with restaging every 12 wks 
Nivolumab 3 mg/kg IV  
+ 
 ipilimumab 1 mg/kg IV 
(up to 4 doses) 
every 3 wks 
Cohort A: 
Metastatic CRPC 
Cohort B: 
Solid tumors (non-
prostate) 
Cohort C: 
Metastatic Prostate 
Cancer 

 
Page 4 of 52 
STUDY SYNOPSIS 
 
Title 
IMPACT: Immunotherapy in Patients with Metastatic Cancers 
and CDK12 Mutations 
Phase 
Phase II 
Methodology 
Open label,  3 non-randomized cohorts 
Study Duration 
72 months  
Study Center(s) 
Multi-site; this is a multicenter trial including the lead site 
University of Michigan   
Objectives and Endpoints 
Primary Objective: 
To determine the efficacy of checkpoint inhibitor 
immunotherapy, nivolumab and ipilimumab combination therapy 
followed by nivolumab monotherapy, or nivolumab monotherapy 
only, in patients with metastatic prostate cancer harboring loss 
of CDK12 function. 
 
Secondary Objectives: 
1. To determine the efficacy of checkpoint inhibitor 
immunotherapy,nivolumab and ipilimumab combination 
therapy followed by nivolumab monotherapy, or nivolumab 
monotherapy only, in patients with metastatic non-prostate 
cancer harboring loss of CDK12 function. 
 
2. To determine the safety and tolerability of, nivolumab and 
ipilimumab combination therapy followed by nivolumab 
monotherapy, or nivolumab monotherapy only, in patients 
with metastatic cancers with loss of CDK12 function. 
 
3. To evaluate other measures of clinical efficacy of checkpoint 
inhibitor immunotherapy in metastatic tumors with loss of 
CDK12 function. 
 
4. To assess the Quality of Life (QoL) in subjects treated on 
protocol therapy. 
 
Exploratory Objectives: 
1. To assess changes in the tumor genome with therapy.  
 
2. To profile immune infiltration in tumor biopsies. 
 
Endpoints 
Primary Endpoint:  
The overall response rate (ORR) in subjects with metastatic 
castration resistant prostate cancer whose tumors harbor a 
genomic change resulting in CDK12 loss of function and who 
are treated with, nivolumab and ipilimumab combination therapy 
followed by nivolumab monotherapy, or nivolumab monotherapy 
only, as measured by PSA 50% decline from baseline as 
determined by PCWG3 criteria.  
 
Secondary Endpoints: 
1. The overall response rate (ORR) in patients with metastatic 
non-prostate cancer harboring loss of CDK12 function, who 
are treated with nivolumab and ipilimumab combination 

 
Page 5 of 52 
therapy followed by nivolumab monotherapy, as measured 
by RECIST 1.1 criteria. 
 
2.  The frequency and severity of adverse events, as assessed 
by CTCAE version 4.03 criteria, in patients with metastatic 
cancer harboring loss of CDK12 function treated with, 
nivolumab and ipilimumab combination therapy followed by 
nivolumab monotherapy, or nivolumab monotherapy only. 
 
3. Assess the radiographic progression-free survival (rPFS), 
progression-free survival (PFS), duration of response (DOR) 
among responders, duration of therapy (DOT), time to 
progression (TTP), overall survival (OS) and objective tumor 
response in patients with measurable disease by RECIST 
1.1 criteria. For subjects with metastatic CRPC, determine 
the PSA progression-free survival and time to PSA 
progression by PCWG3 criteria. 
 
4. Measure the Quality of Life (QoL) in subjects treated on 
protocol therapy using EORTC-QLQ-C30 and BPI-SF. 
 
Exploratory Endpoints 
1. Tumor genome profiling by integrated DNA and RNA 
sequencing (including molecular tumor burden assessment) 
at baseline and optionally at progression. 
 
2. Profiling of Immune infiltration in tumor biopsies. 
 
Number of Subjects 
25 mCRPC each in Cohorts A and C; and15 of non-prostate in 
Cohort B, 65 total subjects 
 
Key Inclusion Criteria 
1. Age ≥ 18 years and ability to understand and the willingness 
to sign a written informed consent. 
 
2. ECOG performance status of 0, 1 or 2. 
 
3. Subjects must have histologic or cytologic or radiographic 
evidence of metastatic adenocarcinoma of the prostate 
without small cell histology OR another type of metastatic 
carcinoma. Radiologic or pathologic evidence of metastases 
is allowed. 
4. All subjects, regardless of cancer type, must have 
documented CDK12 loss on a CLIA approved, CAP certified 
next generation sequencing assay (tissue, cell-free DNA or 
other is allowed). (Further details section 3.1.4.) 
 
5. Subjects with prostate cancer must have documented 
prostate cancer progression within six months prior to 
screening with PSA progression defined as a minimum of two 
rising PSA levels at least ≥ 1; one week between each 
assessment with at least one of those baseline PSA values ≥ 
2 ng/mL, including after first generation anti-androgen 
withdrawal.  
 

 
Page 6 of 52 
6. Subjects with prostate cancer must have ongoing androgen 
deprivation with total serum testosterone < 50 ng/dL (or < 
0.50 ng/mL or 1.73 nmol/L). If the subject is currently being 
treated with LHRH agonists (subjects who have not 
undergone an orchiectomy), this therapy must have been 
initiated at least 4 weeks prior to first dose of trial treatment. 
This treatment must be continued throughout the study. 
 
7. Subjects with non-prostate histologies must have RECIST 
1.1-measurable cancer on computed tomography (CT) or 
magnetic resonance imaging (MRI) scans. 
 
8. 
Subjects must have recovered to baseline or ≤ grade 1 
CTCAE v 4.03 from toxicities related to any prior treatments 
unless AE(s) are clinically non-significant and/or stable. 
 
9. 
Patients must be ≥ 2 weeks from most recent systemic 
therapy or most recent radiation therapy.  
 
10. Women of childbearing potential must have a negative 
serum or urine pregnancy test within 28 days prior to 
registration. Women of non-childbearing potential are 
defined as those who have no uterus, ligation of the 
fallopian tubes, are naturally postmenopausal for at least 12 
consecutive months or have undergone surgical removal of 
the ovaries. 
 
11. Female and male subjects of reproductive potential must 
agree to use an adequate method of contraception starting 
with the first dose of study therapy through 5 months (for 
women) and 7 months (for men) after the last dose of study 
therapy.     
 
12. Adequate organ function with absolute neutrophil count 
(ANC) ≥ 1,000/mm3, hemoglobin ≥ 8.0 g/dL with or without 
pRBC transfusion; bilirubin/ALT/AST < 2.5 x upper limit of 
normal (patients with known Gilbert disease who have 
serum bilirubin ≤3x ULN may be enrolled); serum creatinine 
<3.0 mg/dL or if elevated, a calculated estimated 
glomerular filtration rate (eGFR) of ≥30 mL/min/1.73 m2. 
 
Key Exclusion Criteria 
1. 
Prior treatment with anti-PD-1/PD-L1 and anti-CTLA-
4 is NOT allowed.  
 
2. 
Treatment with any investigational agent within 28 
days prior to registration on this protocol. 
 
3. 
Prior or concurrent malignancy that has needed 
active interventional systemic therapy in the last 2 
years. Adequately treated basal cell or squamous 
cell skin cancer, non muscle-invasive urothelial 
cancer, or in situ cervical cancer are permitted. For 
subjects in the non-prostate cancer cohort, localized 
or locally advanced prostate cancer definitively 
treated without recurrence or with biochemical 
recurrence only are permitted. 

 
Page 7 of 52 
 
4. 
History or risk of any significant  autoimmune 
diseases are excluded, including but not limited to 
systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis 
associated with antiphospholipid syndrome, 
Wegener’s granulomatosis, Sjӧgren’s syndrome, 
Bells’ palsy, Guillain-Barre syndrome, multiple 
sclerosis, autoimmune thyroid disease, vasculitis, or 
glomerulonephritis. Vitiligo, mild psoriasis (topical 
therapy only) or hypothyroidism are allowed. No prior 
history of autoimmune pneumonitis allowed. Patients 
with previous drug-related or radiation therapy-
associated pneumonitis that has since resolved are 
allowed.  
 
5. 
Need for systemic corticosteroids > 10 mg 
prednisone daily or equivalent alternative steroid or 
other systemic immunosuppressive agents (such as 
cyclosporine or methotrexate). Physiologic doses of 
steroid for adrenal replacement therapy; topical and 
inhaled corticosteroids are permitted. 
 
6. 
Any history of organ allografts. 
 
7. 
Must not have known active hepatitis B, hepatitis C, 
or HIV seropositivity. Negative PCR suggests 
infection is not active or latent; however testing is not 
required in the absence of clinical suspicion. 
 
Study Product(s), Dose, 
Route, Regimen 
 
Nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV every 3 
weeks for up to 4 doses (12 weeks)-Cohort A and B 
 
Nivolumab (480 mg/dose IV every 4 weeks) for up to 92 
weeks or until progression in follow-up-Cohort A and B 
 
Nivolumab (480 mg/dose IV every 4 weeks) for up to 104 
weeks or until progression in follow-up-Cohort C 
 
Total of up to 104 weeks therapy- Cohort A, B, and C 
 
 
Duration of Administration 
Up to a total of 104 weeks of study treatment and 24 months of 
follow up in all Cohorts. 
Statistical Methodology 
A Mini-Max Simon Two-Stage design will be used to 
assess ORR defined as a 50% decline in PSA from 
baseline in CDK12 loss of function metastatic CRPC 
patients. It is assumed that an ORR of 30% or more 
would be interesting for further study compared to a 
reference ORR of 10% based on the KEYNOTE-199 
trial [35] [1]. Accrual of 25 patients will provide 80% 
power to detect this difference in ORR with a type I 
error of 5%. Interim analysis will be completed after 15 
patients (Cohort A only). If 2 or more patients have a 
PSA response, then the 2nd stage will open and 
accrue 10 more patients. If 6 or more patients out of 25 
have a PSA response, then the treatment will be 

 
Page 8 of 52 
 
 
 
recommended for further study in this population. No 
interim analysis is planned for Cohort C. 
 
Cohort B will accrue 15 patients with non-prostate 
histology. A reference ORR of 5% is assumed in 
patients with non-prostate histology. With 15 patients, 
we have 76% power to detect an ORR of 25% with a 
one-sided type I error of 5%. If 3 or more responses 
are seen in cohort B, then we will conclude that there is 
preliminary evidence of activity. A total trial population 
of 65 subjects is planned. 
 

 
Page 9 of 52 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Metastatic castrate-resistant prostate cancer (mCRPC) remains a challenging disease, 
with incremental resistance to multiple lines of therapy over time. However, greater 
understanding of the mutational landscape of mCRPC is providing more treatment 
options for advanced prostate cancer. Whole exome and transcriptome sequencing of a 
large multi-site cohort of patients with mCRPC performed by our group has identified 
several aberrations in DNA repair defect genes, including BRCA2, BRCA1, and ATM [1], 
and has provided the rationale for the clinical use of PARP inhibitors. However, one of 
the novel genomic aberrations in mCRPC demonstrated in our tumor genome 
sequencing initiative is the loss of CDK12 function [1] [2].  
 
CDK12: 
 
 
Cyclin-dependent kinases (CDKs) have an important role in cell cycle regulation in 
conjunction with cyclin. Some cyclin-specific kinases function in gene transcription 
control, including CDK12 and CDK13, which are associated with cyclin K and have a role 
in regulating transcription elongation and RNA splicing. In an evaluation of CDK12 gene 
modification prevalence across various tumor types, there was a 1.08% mutation rate 
across 1203 prostate cancer samples, compared with 2.3% in 915 ovarian cancer 
samples [3]. In another recent analysis, the prevalence of CDK12 mutation in metastatic 
prostate cancer was found to be as high as 5-6%, as shown in Figure 1 [4]. Impairing 
CDK12 function in ovarian cancer cells decreases BCRA1 levels and disrupt homologous 
recombination repair, leading to reported increased sensitivity to cisplatin and PARP 
inhibition [5]. In addition to an association with non-functional homologous recombination 
(HR) repair, tumors with inactivated CDK12 have also demonstrated increased genomic 
instability. In a series of 556 ovarian carcinomas, 17 tumors were found to have markedly 
increased genomic copy number. 15 of these 17 cases also harbored CDK12 mutations, 
Figure 1 Tepley et al. Treatment strategies for DNA repair-deficient prostate cancer. 
Expert Rev Clin Pharmacol. 2017 Aug; 10(8):889-898. 

 
Page 10 of 52 
the majority of which were deleterious [6]. Mutations in CDK12 are shown to cause 
downregulation of genes in the HR pathway, disabling repair of double-strand DNA 
breaks and leading to tumor genomic instability [7]. The work in the Michigan Center for 
Translational Pathology (MCTP) has recently identified a novel genetically unstable 
subset of prostate cancer typified by biallelic inactivation of CDK12. CDK12-mutants are 
genomically, transcriptionally, and phenotypically distinct from other DNA repair deficient 
subtypes such as mismatch repair (MMR) deficient tumors. CDK12 deficient CRPC 
tumors display a large number of gene fusions (Figure 1A, unpublished). Further, 
CDK12-mutant tumors exhibit a higher neoantigen burden than mCRPC in general 
(Figure 1B, unpublished). These attributes of the CDK12-mutant tumors could potentially 
be exploited clinically as tumor mutational burden and higher neoantigen load generally 
correlate with response to checkpoint inhibitor immunotherapy [8, 9]. 
 
 
 
 
 
 
MiOncoSeq-Directed Patient Selection: 
To effectively conduct clinical studies targeting patients with CDK12 aberrations, rapid 
and accurate tumor sequencing to identify patients harboring this defect is needed. Dr. 
Chinnaiyan’s lab has unparalleled expertise and experience for accomplishing this task, 
including on the Stand Up 2 Cancer (SU2C) East Coast Dream Team. The MCTP, which 
Dr. Chinnaiyan directs, also has extensive experience with correlative studies associated 
with tumor specimens and in the context of clinical trials. The Oncoseq1700 assay is a 
hybrid capture approach that currently interrogates 1733 genes in tumor DNA and 
germline DNA as well as RNA capture transcriptome of the tumor. Over 500X cover of 
the tumor and matched normal is achieved, and is compatible with formalin fixed or 
frozen samples obtained by soft tissue or bone biopsy. The Oncoseq assay is run in the 
MCTP’s CLIA/CAP laboratory, with results provided as a report within 2-3 weeks. The 
Oncoseq approach can successfully identify sub-clones that comprise 2% or less of 
tumor cells as well as clinical biopsies with as little as 5% tumor content. By including 
whole RNA transcriptome analysis, we complement DNA-based mutational and copy 
number analyses with a functional read-out that highlights outlier expression and gene 
fusions. The composition of the 1733 gene panel begins with the 300-350 genes known 
to be recurrently mutated in a variety of cancers which form components of targeted 
cancer gene panels currently in use (e.g., FoundationOne). Our emphasis on sequencing 
matched normal allows the Oncoseq assay to make clear-cut germline calls which can 
often be useful to the family or have therapeutic implications (e.g., DNA repair gene 
defects and hypermutation/mismatch repair).  
 
Immunotherapy in Prostate Cancer: 
It has now been established that tumor mutational load and increased pathologic 
mutation rate correlate with a higher clinical benefit rate with cytotoxic T-lymphocyte 
antigen 4 (CTLA-4) blockade [8], and also correlate with prolonged overall survival with 
Fig. 1 A. Types of Genomic Aberrations in 
CDK12 mutant CRPC 
Fig. 1 B. Neoantigen load among 
various DNA defective CRPC tumors 

 
Page 11 of 52 
immunotherapy [9]. In prostate cancer, however, prior studies evaluating the use of 
immunotherapy have been largely disappointing. In a phase I study of 39 patients treated 
with nivolumab anti-PD monotherapy, none of the 9 CRPC patients responded [10]. A 
recently published phase III study randomizing over 400 metastatic prostate cancer 
patients without visceral metastases to ipilimumab 10 mg/kg every 3 weeks versus 
placebo followed by maintenance therapy did not result in an overall survival benefit [11]. 
However, a recent phase II study showed early response to PDL-1 therapy in 
enzalutamide-resistant prostate cancer, with three of the first ten patients enrolled 
demonstrating rapid and deep PSA declines to ≤ 0.2 ng/ml. In one patient, this 
impressive response was associated with tumor microsatellite instability [12], and a 
similar response was reported in a patient with loss of function in MSH2 and MSH6 [13]. 
Aside from rare patients harboring mismatch repair mutations, there are some prostate 
cancer patients who have demonstrated response to immunotherapy where an 
underlying driver of response has not yet been identified. This inconsistent clinical 
response to immunotherapy suggests that the underlying tumor characteristics in 
prostate cancer that portend response to immunotherapy have not yet been identified. 
Clinically validated biomarkers for predicting response to immunotherapy have not yet 
been established, and greater understanding of additional drivers of response to these 
therapies in prostate cancer is urgently needed. 
Combination therapy with ipilimumab and nivolumab has been used with success in the 
treatment of metastatic melanoma [14] and is now also being evaluated in small cell lung 
cancer [15]. Despite the potential for increased toxicities with a two-drug regimen, a 
recent meta-analysis evaluating immunotherapy in melanoma and lung cancer 
demonstrated improved PFS, OS, and ORR rates with combination therapy compared 
with monotherapy [16]. 
1.2 
Study Agent(s) Background and Associated Known Toxicities 
Nivolumab: 
The clinical use of nivolumab, a fully human IgG4 monoclonal antibody that binds to the 
programmed cell death-1 (PD-1) receptor and selectively inhibits PD-1 has been well-
established across multiple cancer types. Through inhibition of the PD-1/PDL-1 
interaction, immune pathway inhibition is therefore released, allowing increased T-cell 
activity against cancer cells. This drug has now been FDA approved in multiple disease 
types, including in unresectable or metastatic melanoma, metastatic non-small cell lung 
cancer, urothelial carcinoma, renal cell carcinoma. 
 
Potential toxicities associated with the use of nivolumab immunotherapy have been well-
established. The most common adverse reactions (in ≥20% of patients) with nivolumab 
as a single agent include fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, 
asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper 
respiratory tract infection, and pyrexia.  Most commonly documented adverse reactions of 
nivolumab in combination with ipilimumab include fatigue, rash, diarrhea, nausea, 
pyrexia, vomiting, and dyspnea.    
 
Ipilimumab: 
Clinical use of ipilimumab, a human CTLA-4-blocking antibody is approved for treatment 
of unresectable or metastatic melanoma and for adjuvant treatment of patients with 
cutaneous melanoma with pathologic involvement of regional lymph nodes. Ipilimumab is 
approved at a dose of 3 mg/kg for unresectable or metastatic melanoma and at 10 mg/kg 
for adjuvant therapy in melanoma. The most common adverse reactions (in ≥5% of 
patients) are fatigue, diarrhea, pruritus, rash, and colitis. Additional common adverse 
reactions at the 10 mg/kg dose (≥5%) include nausea, vomiting, headache, weight loss, 
pyrexia, decreased appetite, and insomnia. 

 
Page 12 of 52 
1.3 
Rationale 
In this study, we seek to assess the efficacy of immunotherapy in patients with CDK12 
mutations in metastatic prostate cancer patients, and in other tumor histologies with 
CDK12 alterations. Increasing data has shown a correlation between response to 
immunotherapy and loss of normal DNA repair mechanisms [17] [18]. However, as 
previously discussed, CDK12 aberrations appear to be concordant with increased tumor 
genomic instability, suggesting a potentially robust response to immunotherapy not 
directly related to changes in DNA repair pathways. Combination immunotherapy has 
been shown to be associated with an improved response rate compared with single-
agent therapy, and given the absence of identifiable benefit with ipilimumab monotherapy 
to date in prostate cancer, combination therapy with ipilimumab and nivolumab in a 
susceptible patient population may be associated with higher response rates. However, 
we hypothesize that CDK12 alterations would also result a baseline increased likelihood 
of response to immunotherapy. A robust treatment response with single-agent therapy 
may be seen in this highly selected population, while a therapeutic response was not 
previously captured in an unselected metastatic prostate cancer population.  
 
We therefore propose a phase II study of nivolumab and ipilimumab combination therapy 
followed by nivolumab monotherapy in patients with metastatic prostate cancer who have 
evidence of disease progression after at least one standard therapy (cohort A). Other 
advanced metastatic cancers with CDK12 changes, including ovarian cancer, would also 
be included (cohort B). Maintenance nivolumab at a flat dose of 480 mg IV given every 4 
weeks will be continued until total protocol therapy of up to 104 weeks of therapy. 
Nivolumab at a flat dose of 480 mg IV given every 4 weeks will be continued until total 
protocol therapy of up to 104 weeks of therapy in Cohort C for prostate cancer patients. 
1.4 
Exploratory Studies 
1.4.1 
Mi-ONCOSEQ 
We will sequence patients under our established Mi-ONCOSEQ [19] study, which 
is an effort to use integrative clinical sequencing towards personalized medicine 
for cancer patients. The matched tumor-normal library from WXS (whole exome 
sequencing) along with strand specific all-exon captured library from total RNA 
(captured transcriptome) will be sequenced at our CLIA certified sequencing 
laboratory. 
1.4.2 
Immune infiltration 
To date, a definite correlation between response to immunotherapy and tumor 
cell or immune-infiltrating PD-L1 expression has not been established. We seek 
to profile immune infiltration in tumor biopsies in both patient cohorts. 
 
2.0 
STUDY OBJECTIVES/ENDPOINTS 
2.1 
Primary Objective 
To determine the efficacy of checkpoint inhibitor immunotherapy, nivolumab and 
ipilimumab combination therapy followed by nivolumab monotherapy, or nivolumab 
monotherapy only, in patients with metastatic prostate cancer harboring loss of CDK12 
function. 
2.2 Secondary Objectives 
2.2.1 To determine the efficacy of checkpoint inhibitor immunotherapy,nivolumab and 
ipilimumab combination therapy followed by nivolumab monotherapy, or 

 
Page 13 of 52 
nivolumab monotherapy only, in patients with metastatic non-prostate cancer 
harboring loss of CDK12 function. 
2.2.2  To determine the safety and tolerability of nivolumab and ipilimumab combination, 
or nivolumab monotherapy only,therapy followed by nivolumab monotherapy in 
patients with metastatic cancers with loss of CDK12 function. 
2.2.3  To evaluate other measures of clinical efficacy of checkpoint inhibitor 
immunotherapy in metastatic tumors with loss of CDK12 function. 
2.2.4   To assess the Quality of Life (QoL) in subjects treated on protocol therapy. 
2.3 
Exploratory Objectives 
2.3.1 To assess changes in the tumor genome with therapy.  
2.3.2 To profile immune infiltration in tumor biopsies. 
 
2.4 
Primary Endpoint 
The overall response rate (ORR) in subjects with metastatic castration resistant prostate 
cancer whose tumors harbor a genomic change resulting in CDK12 loss of function and 
who are treated with nivolumab and ipilimumab combination therapy followed by 
nivolumab monotherapy, or nivolumab monotherapy only (for applicable cohorts), as 
measured by PSA 50% decline from baseline as determined by PCWG3 criteria.  
2.5 
Secondary Endpoints 
2.5.1 The overall response rate (ORR) in patients with metastatic non-prostate cancer 
harboring loss of CDK12 function, who are treated with nivolumab and ipilimumab 
combination therapy followed by nivolumab monotherapy, or nivolumab 
monotherapy only, as measured by RECIST 1.1 criteria. 
2.5.2 The frequency and severity of adverse events, as assessed by CTCAE version 4.03 
criteria, in patients with metastatic cancer harboring loss of CDK12 function treated 
with nivolumab and ipilimumab combination therapy followed by nivolumab 
monotherapy, or nivolumab monotherapy only,. 
2.5.3 Assess the radiographic progression-free survival (rPFS), progression-free survival 
(PFS), duration of response (DOR) among responders, duration of therapy (DOT), 
time to progression (TTP), overall survival (OS) and objective tumor response in 
patients with measurable disease by RECIST 1.1 criteria. For subjects with 
metastatic CRPC, determine the PSA progression-free survival and time to PSA 
progression by PCWG3 criteria. 
2.5.4 Measure the Quality of Life (QoL) in subjects treated on protocol therapy using 
EORTC-QLQ-C30 and BPI-SF. 
 
 
 
2.6 
Exploratory Endpoints 
 
 
 
 
2.6.1 Tumor genome profiling by integrated DNA and RNA sequencing (including   
molecular tumor burden assessment) at baseline and optionally at progression. 

 
Page 14 of 52 
 
 
2.6.2 Profiling of immune infiltration in tumor biopsies. 
 
 
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled to the study. Study 
treatment may not begin until a subject is enrolled. 
3.1 
Inclusion Criteria 
 
3.1.1 
Age ≥ 18 years and ability to understand and the willingness to sign a written 
informed consent. 
 
3.1.2 
ECOG Performance Status of 0, 1 or 2. 
 
3.1.3 
Subjects must have histologic or cytologic or radiologic evidence of metastatic  
adenocarcinoma of the prostate without small cell histology OR another type of 
metastatic carcinoma. Radiologic or pathologic evidence of metastases is 
allowed. 
 
3.1.4 
All subjects, regardless of cancer type, must have a documented CDK12 loss on 
a CLIA approved, Next Generation Sequencing assay (tissue, cell-free DNA or 
other is allowed) and is willing to provide archival tissue for analysis. CDK12 loss 
will be confirmed by the IND Sponsor (at the University of Michigan) and may 
include deleterious mutations (e.g truncating mutation, inactivating missense 
mutation), rearrangement or deletion. Because it is not always stated explicitly in 
all NGS platforms/assays, the Sponsor Investigator will determine which genomic 
aberrations constitute CDK12 loss. If tissue is unavailable, subject may still 
enroll.  
 
3.1.5 
Subjects with prostate cancer must have documented prostate cancer 
progression within six months prior to screening with PSA progression defined as 
a minimum of two rising PSA levels ≥ 1; at least one week between each 
assessment with a baseline PSA value at screening of ≥ 2 ng/mL, including after 
first generation anti-androgen withdrawal. 
3.1.6 
Subjects with prostate cancer must have ongoing androgen deprivation with total 
serum testosterone < 50 ng/dL (or < 0.50 ng/mL or 1.73 nmol/L)). If the subject is 
currently being treated with LHRH agonists (subjects who have not undergone an 
orchiectomy), this therapy must have been initiated at least 4 weeks prior to 
registration. This treatment must be continued throughout the study. 
3.1.7 
Subjects with non-prostate histologies must have RECIST 1.1-measurable 
cancer on computed tomography (CT) or magnetic resonance imaging (MRI) 
scans. 
3.1.8 
Subjects must have recovered to baseline or ≤ grade 1 CTCAE v 4.03 from 
toxicities related to any prior treatments unless AE(s) are clinically non-significant 
and/or stable. 
3.1.9 
Patients must be ≥ 2 weeks from most recent systemic therapy or most recent 
radiation therapy.  
3.1.10 Women of childbearing potential must have a negative serum or urine pregnancy 
test within 28 days prior to registration. Women of non-childbearing potential are 

 
Page 15 of 52 
defined as those who have no uterus, ligation of the fallopian tubes, are naturally 
postmenopausal for at least 12 consecutive months or have undergone surgical 
removal of the ovaries. 
3.1.11 Female and male subjects of reproductive potential must agree to use an 
adequate method of contraception starting with the first dose of study therapy 
through 5 months (for women) and 7 months (for men) after the last dose of 
study therapy. 
3.1.12 Adequate organ and marrow function as defined below: 
 
System 
Laboratory Value 
Hematological 
Absolute Neutrophil Count 
(ANC) 
≥ 1,000/mm3 
Hemoglobin (Hgb) 
≥ 8 g/dL with or without pRBC transfusion 
Platelets (Plt) 
≥ 100,000/mm3 
Renal 
Calculated or measured 
creatinine clearance 
Serum creatinine <3.0 mg/dl or if elevated, a 
calculated estimated glomerular filtration 
rate (eGFR) of ≥30 mL/min/1.73 m2. 
Hepatic 
Total Bilirubin 
≤ 2.5 × upper limit of normal (ULN) (patients 
with known Gilbert disease who have serum 
bilirubin ≤3x ULN may be enrolled) 
Aspartate aminotransferase 
(AST) 
≤ 2.5 × ULN 
Alanine aminotransferase (ALT) 
≤ 2.5 × ULN 
 
3.2 
Exclusion Criteria 
3.2.1 
Prior treatment with anti-PD-1/PD-L1 and anti-CTLA-4 is NOT allowed. Prior 
intravesical BCG therapy is allowed. 
 
3.2.2 
Treatment with any investigational agent or on an interventional clinical trial 
within 28 days prior to registration on this protocol. 
 
3.2.3 
Prior or concurrent malignancy that has needed active interventional systemic 
therapy in the last 2 years. Adequately treated basal cell or squamous cell skin 
cancer, non muscle-invasive urothelial cancer, in situ cervical cancer, are 
permitted. For subjects in the non-prostate cancer cohort, localized or locally 
advanced prostate cancer definitively treated without recurrence or with 
biochemical recurrence only, or any other cancer fully treated or from which the 
subject has been disease-free for at least 2 years. 
 
3.2.4 
History or risk of any of the following significant autoimmune diseases are 
excluded, including but not limited to systemic lupus erythematosus, rheumatoid 
arthritis, inflammatory bowel disease, vascular thrombosis associated with 
antiphospholipid syndrome, Wegener’s granulomatosis, Sjӧgren’s syndrome, 
Bells’ palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid 
disease, vasculitis, or glomerulonephritis. Vitiligo, mild psoriasis (topical therapy 
only) or hypothyroidism are allowed. No prior history of autoimmune 
pneumonitis allowed. Patients with previous drug-related or radiation therapy-
associated pneumonitis, or other forms of pneumonitis, that has since resolved 
are allowed.  

 
Page 16 of 52 
 
3.2.5 
Need for systemic corticosteroids > 10mg prednisone daily or equivalent 
alternative steroid (except physiologic dose for adrenal replacement therapy) or 
other immunosuppressive agents (such as cyclosporine or methotrexate). 
Topical and inhaled corticosteroids are allowed if medically needed. 
 
3.2.6 
Any history of organ allografts. 
 
3.2.7 
Must not have known active hepatitis B, hepatitis C, or HIV seropositivity. 
Negative PCR suggests infection is not active or latent; however testing is not 
required in the absence of clinical suspicion. 
 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
Patient registration for this trial will be centrally managed by the Coordinating Center of The 
University of Michigan Rogel Cancer Center as described below: 
 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on a Screening and 
Enrollment Log.  
 
It is the responsibility of the local site investigator to determine patient eligibility prior to submitting 
patient registration request to the Coordinating Center. After patient eligibility has been 
determined, a copy of the completed Eligibility Worksheet together with all the pertinent de-
identified source documents will be submitted by the requesting site to the Coordinating Center, 
by email to CTSU-Oncology-Multisite@med.umich.edu.  
 
The Multi-Site Coordinator (MSC) of the Coordinating Center will review the submitted documents 
and process the registration. Sites should inform the Multi-Site Coordinator of a potential 
registration by 5 p.m. on the day prior to registration.  Same day registrations cannot be 
guaranteed.   
 
An email will be sent by the MSC to the requesting site registrar to confirm patient registration 
and to provide the study identification number that has been assigned to the patient. In addition, a 
copy of the completed Eligibility Worksheet signed and dated by the MSC, will be sent back to the 
requesting site registrar. 
 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in a Screening and Enrollment Log. These patients will not 
have study identification number assigned to them, and will not receive study treatment. 
 
5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
Protocol treatment must start within 14 business days of enrollment to the study. 
 
5.1.1 
In this study, Cohort A and Cohort B patients will start treatment with nivolumab 
dosed at 3 mg/kg IV and ipilimumab 1 mg/kg every 3 weeks for up to 4 doses. 
Cohort C patients will receive immunotherapy with nivolumab dosed at a flat 
dose of 480 mg IV every 4 weeks for up to 26 doses or 104 weeks.  
5.1.2.   Cohorts A and B maintenance immunotherapy with nivolumab dosed at a flat 
dose of 480 mg IV every 4 weeks will be continued for up to 23 doses or 92 
weeks. Missed doses of 480 mg Nivolumab due to toxicity or general health 
condition will be skipped. 

 
Page 17 of 52 
 
 
 
5.1.3 
Total protocol therapy for all Cohorts will be up to 104 weeks during treatment. If 
disease progression or recurrence occurs during the follow-up phase, then per 
treating physician discretion, the patient may resume nivolumab 480 mg IV every 
4 weeks until progression if tolerated with axial imaging as per protocol every, 12 
weeks. 
 
5.1.4 
All study therapy will be administered on an outpatient basis.   
 
 
 
Agent 
 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Nivolumab 
(solution for 
injection)  
induction  
Cohort A and 
B only 
Administer 
before other 
immunotherapy 
agents 
3 mg/kg 
up to 4 
doses 
IV infusion over 30 
minutes, +/- 10 
minutes, with a sterile, 
nonpyrogenic, low 
protein binding 0.2 to 
1.2 micrometer in-line  
filter. Follow with 
saline flush. 
Day 1 
3 weeks 
Ipilimumab 
(solution for 
injection) 
induction 
Cohort A and 
B only 
Administer 30 
minutes after 
nivolumab. 
1 mg/kg 
up to 4 
doses 
IV infusion over 90 
minutes, +/- 10 
minutes, through a 
non-pyrogenic, low 
protein-binding in-line 
filter. Separate IV line 
required. 
   
 
Day 1 
 
 
 
 
3 weeks 
 Nivolumab 
(solution for 
injection) 
maintenance 
After induction 
in Cohorts A 
and B; and 
throughout in 
Cohort C 
Administer 
before other 
immunotherapy 
agents 
480 mg 
up to 23 
doses 
(92 
weeks in 
Cohort A 
and B, 
and 104 
weeks in 
Cohort 
C) 
IV infusion over 30 
minutes, +/- 10 
minutes, with a sterile, 
nonpyrogenic, low 
protein binding 0.2 to 
1.2 micrometer in-line 
filter. Follow with 
saline flush. 
Day 1 
4 weeks 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
Table (Section 6.1). Toxicity will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.03. Dose changes of either study drug is 
NOT permitted. Doses can be held however as necessary. Dosing holds should be made 
according to the system showing the greatest degree of toxicity.  
 
Adverse Event Related vs Unrelated Dose Delays: If dose delay is due to an unrelated 
Adverse Event then reason for hold must be documented. Any patient on this protocol will 
be allowed to continue to receive study treatment at the investigator’s discretion, 
regardless of AE relatedness. Do not have to delay dose for unrelated Adverse Event. 
 

 
Page 18 of 52 
5.2.1 Treatment delay for toxicity of more than 84 days from last intended therapy will 
result in treatment discontinuation for the specific drug(s) responsible for the toxicity. If 
ipilimumab is permanently discontinued, then discontinue Nivolumab 3mg/kg. Nivolumab 
480 mg can be continued. 
 
5.2.2 Investigators should consider dose re-calculation of ipilimumab with change in 
weight as per standard of care/institutional guidelines. However, a change in 
weight by 10% or more should lead to a dose re-calculation. 
 
5.2.3 Nivolumab and/or ipilimumab cannot be dose reduced in response to toxicity, 
and can only be held or discontinued as per detailed algorithms for immune-therapy 
toxicity management below.  
 
 
 
 
 
 
 
 
 
NCI CTCAE v 4 Grade 
Nivolumab 
Ipilimumab 
0-1 
No change from original starting 
dose 
No change from original starting 
dose 
2 
Withhold drug, resume treatment 
when adverse reaction improves 
to grade 0 or 1 
Withhold drug, resume treatment 
when adverse reaction improves 
to grade 0 or 1 
3  
Withhold drug, resume treatment 
when adverse reaction improves 
to grade 0 or 1 when given as a 
single agent 
Withhold drug, resume treatment 
when adverse reaction improves 
to grade 0 or 1  
Second episode of grade 3 
or any episode of grade 4 
toxicity 
Permanently discontinue therapy 
and remove subject from trial 
Permanently discontinue therapy 
and remove subject from trial 
 
 
Certain adverse events that are possibly immune mediated warrant special monitoring and management, 
and are outline below to guide investigators. 
 
5.2.4.1 Pulmonary: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue protocol 
therapy. Evaluate with imaging and pulmonary consultation. 
Grade of pneumonitis 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 1 
Radiographic changes only 
• 
Consider delay nivolumab 
or ipilimumab 
• 
Monitor for symptoms 
every 2-3 days 
• 
Consider pulmonary and 
infectious disease 
consultations 
• 
Re-image at least 
every 3 weeks 
If worsens: 
If worsens:  
• 
Treat as Grade 2 or  
 3-4 

 
Page 19 of 52 
 
 
 
 
 
 
 
 
 
 
 
5.2.4.2 Gastrointestinal: 
Rule out non-inflammatory causes. If non-inflammatory is identified, treat accordingly and continue 
protocol theraphy. Opiates/narcotics may mask symptoms of perforation. Infliximab should not be used in 
case of perforation or sepsis. 
 
Grade of diarrhea/colitis 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 1 
Diarrhea:< 4 stools/day 
over baseline;  
Colitis: asymptomatic  
• 
Continue nivolumab 
or ipilimumab per 
protocol  
• 
Symptomatic 
treatment  
• 
Close monitoring for 
worsening symptoms 
• 
Educate patient to report 
worsening immediately 
If worsens: 
• 
Treat as Grade 2 or 3/4 
 
Grade 2 
Diarrhea: 4-6 stools per 
day over baseline; IV 
fluids indicated <24 hrs; 
not interfering with ADL 
• 
Delay nivolumab 
and ipilimumab per 
protocol 
• 
Symptomatic 
treatment 
If improves to grade 1:  
Resume nivolumab or ipilimumab 
per protocol  
 
If persists > 5-7 days or recur: 
Grade 2 
Mild to moderate new 
symptoms 
• 
Delay nivolumab or 
ipilimumab 
• 
Consult pulmonary and 
infectious disease 
• 
Monitor symptoms daily, 
consider hospitalization 
• 
1.0-2.0 mg/kg/day 
methylprednisolone IV or 
oral equivalent 
• 
Consider bronchoscopy 
and/or lung biopsy 
• 
Re-image every 1-3 
days 
If improves:If improves: 
• 
When symptoms 
return to near 
baseline, taper 
steroids over at 
least one month and 
resume nivolumab 
and ipilimumab per 
protocol and 
consider 
prophylactic 
antibiotics  
 
If not improving after 2 
weeks or worsening:  
• 
Treat as Grade 3-4 
If not improving after 
2 weeks or worsening, 
treat as grade 3 or 4 
Grade 3 or 4 
Severe new symptoms; 
New/worsening hypoxia; Life-
threatening 
• 
Discontinue nivolumab or 
ipilimumab 
• 
Hospitalize 
• 
Consult pulmonary and 
infectious disease 
• 
2-4 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
• 
Add prophylactic 
antibiotics for opportunistic 
infections  
• 
Consider bronchoscopy 
and/or lung biopsy 
 
If improves to baseline: 
• 
Taper steroids over 
6 weeks 
 
If not improving after 48 
hours or worsening: 
• 
Add additional 
immunosuppression 
 
 

 
Page 20 of 52 
Grade of diarrhea/colitis 
(NCI CTCAE v4) 
Management 
Follow-up 
Colitis: abdominal pain; 
blood in stool 
 
 
 
 
• 
0.5-1.0mg/kg/day 
methylprednisolone or oral 
equivalent 
• 
When symptoms improve to 
grade 1, taper steroids over at 
least 1 month, consider 
prophylactic antibotics for 
opportunistic infections, and 
resume nivolumab or 
ipilimumab per protocol 
 
If worsens or persists > 3-5 day 
with oral steroids: 
• 
Treat grade 3/4 
 
Grade 3-4 
Diarrhea (G3): ≥7 stools 
per day over 
baseline; incontinence; IV 
fluids ≥24 
hrs; interfering with ADL 
 
Colitis (G3): severe 
abdominal pain, 
medical intervention 
indicated, 
peritoneal signs 
 
G4: life-threatening, 
perforation 
• 
Discontinue nivolumab 
or ipilimumab per 
protocol 
• 
1.0 to 2.0 mg/kg/day       
methylprednisolone           
IV or IV equivalent 
• 
Add prophylactic 
antibiotics for 
             opportunistic     
             infections 
• 
Consider lower 
endoscopy 
 
 
If improves: 
• 
Continue steroids until 
grade 1, then taper over at 
             least 1 month 
If persists > 3-5 days, or recurs 
after improvement: 
• 
Add infliximab 5 mg/kg (if 
no contraindication). 
Note: Infliximab should not be used 
in cases of perforation or sepsis 
 

 
Page 21 of 52 
5.2.4.3 Endocrinopathy: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue protocol 
therapy. Consider visual field testing, endocrinology consultation and imaging. 
 
Endocrinopathy 
Management 
Follow-up 
Asymptomatic thyroid-
stimulating hormone (TSH) 
elevation 
• 
Continue nivolumab or ipilimumab 
• 
If TSH <0.5 x LLN, or TSH >2 x ULN, or consistently out of 
range in 2 subsequent measurements: include free T4 at 
subsequent cyles as clinically indicated; consider 
endocrinology consult 
 
Symptomatic endocrinopathy 
• 
Evaluate endocrine 
function 
• 
Consider pituitary scan 
Symptomatic with abnormal 
lab/pituitary scan: 
• 
Delay study therapy per 
protocol 
• 
1-2 mg/kg/day 
methylprednisolone IV 
or PO equivalent 
• 
Initiate appropriate 
hormone therapy 
No abnormal lab/pituitary 
MRI scan but symptoms 
persist: 
• 
Repeat labs in 1-3 
weeks / MRI in 1 month 
 
If improves (with or 
without hormone 
replacement): 
• 
Taper steroids over at least 1 
month and consider prophylactic 
antibiotics for             
opportunistic infections 
• 
Resume protocol therapy per 
protocol 
• 
Patients with adrenal 
             insufficiency may need to 
             continue steroids with 
mineralocorticoid 
component 
Suspicion of adrenal crisis 
(e.g. severe dehydration, 
hypotension, shock 
out of proportion to 
current illness  
• 
Delay or discontinue nivolumab or ipilimumab per protocol 
Rule out sepsis 
• 
Stress dose of IV steroids with mineralocorticoid activity IV 
fluids 
• 
Consult endocrinologist 
• 
If adrenal crisis ruled out, then treat as above for 
symptomatic endocrinopathy  
 
 
 
 

 
Page 22 of 52 
 
5.2.4.4 Hepatic: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue protocol 
therapy. Consider imaging for obstruction. 
 
Grade of Liver Test 
Elevation 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 1 
AST or ALT > ULN to 3 
x ULN and/or total 
bilirubin > ULN to 1.5 x 
ULN 
• 
Continue nivolumab or 
ipilimumab 
• 
Continue 
liver 
function 
test (LFT) per protocol 
 
If worsening:  
• 
Treat as Grade 2 or 3-4 
Grade 2 
AST or ALT > 3.0 to ≤ 5 
x ULN and/or total 
bilirubin > ULN to 1.5-to 
≤ 3 x  ULN 
• 
Delay nivolumab or 
ipilimumab per protocol 
• 
Increase frequency of 
monitoring to every 3 days  
If returns to baseline: 
• 
Resume routine 
monitoring, resume 
nivolumab or ipilimumab 
 
If persists > 5-7 days or 
worsens:  
• 
0.5-1 mg/kg/day 
methylprednisolone or oral 
equivalent and when LFT 
returns to grade 1 or 
baseline, taper steroids 
over at least 1 month, 
consider prophylactic 
antibiotics for opportunistic 
infections, and resume 
nivolumab and ipilimumab  
Grade 3 or 4 
AST or ALT > 5 x ULN 
and/or total bilirubin > 3 
x ULN 
• 
Discontinue nivolumab or 
ipilimumab* 
• 
Increase frequency of 
monitoring to every 1-2 days 
• 
1.0 to 2.0 mg/kg/day 
methylprednisolone                    
IV or IV equivalent* 
• 
Add prophylactic antibiotics for 
opportunistic infection 
• 
Consult gastroenterologist 
 
If returns to grade 2:  
• 
Taper steroids over at least 
one month 
If does not improve in > 3-5 
days, worsens or rebounds: 
• 
Add mycophenolate 
mofetil 1g twice daily 
• 
If no response within an 
additional 3-5 days, 
consider other 
immunosuppressive 
agents per local guidelines 
*The recommended starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV. 
 

 
Page 23 of 52 
5.2.4.5 Neurological: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue protocol 
therapy. 
 
Grade of neurological 
toxicity 
(NCI CTCAE v 4) 
Management 
Follow-up 
Grade 1 
Asymptomatic or mild 
symptoms; intervention not 
indicated 
• 
Continue nivolumab or 
ipilimumab 
• Continue to monitor the 
patient. 
If worsens:. 
• 
Treat as grade 2 or 3-4 
Grade 2 
Moderate symptoms; 
Limiting instrumental 
ADL 
• 
Delay nivolumab or 
ipilimumab  
• 
Treat symptoms per 
institutional guidelines 
• 
Consider 0.5-1mg/kg 
per day 
methylprednisolone IV 
or oral equivalent 
If returns to baseline: 
• 
Resume nivolumab or 
ipilimumab 
If worsens:  
• 
Treat as Grade 3 - 4 
Grade 3 or 4 
Severe symptoms; 
Limiting self-care ADL; 
Life-threatening 
• 
Discontinue nivolumab 
or ipilimumab  
• 
Consult Neurology 
• 
Treat symptoms per 
institutional guidelines 
• 
1-2mg/kg per day IV 
methylprednisolone or 
IV equivalent 
• 
Add prophylactic 
antibiotics for 
opportunistic infections 
If improves to grade 2:  
• 
Taper steroids over at least 
one month 
If worsens or atypical 
presentation: 
• 
Consider IVIG or other 
immunosuppressive 
therapies per institutional 
guidelines 
 
5.2.4.6 Skin: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue protocol 
therapy 
 
Grade of Rash 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 1-2 
Covering ≤ 30% body 
surface area (BSA)* 
• 
Symptomatic therapy (e.g. 
antihistamines, topical 
steroids) 
• 
Continue nivolumab or 
ipilimumab 
If persists > 1-2 weeks or recurs: 
• 
Consider skin biopsy 
• 
Delay nivolumab or ipilimumab 
• 
Consider 0.5-1mg/kg/day 
methylprednisolone IV or oral 
equivalent. Once improving , 
taper steroids over at least 1 
month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume 
nivolumab or ipilimumab  
If worsens:   
Treat as Grade 3-4 

 
Page 24 of 52 
 
 
 
 
 
 
 
 
 
*Refer to NCI CTCAE v4 for term-specific grading criteria. 
^If SJS/TEN is suspected, withhold I-O therapy and refer patient for specialized care for assessment and treatment. If SJS or TEN is 
diagnosed, permanently discontinue nivolumab and ipilimumab 
 
 
5.2.4.7 Renal: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue protocol 
therapy 
 
Grade of elevation in 
serum creatinine 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 1 
Serum creatinine > ULN 
and > than baseline but ≤ 
1.5 x baseline 
• Continue nivolumab /or 
ipilimumab 
• Monitor serum creatinine 
weekly 
If returns to baseline: 
• 
Resume creatinine 
monitoring per protocol 
If worsens: 
• 
Treat as Grade 2, 3/4 
Grade 2-3 
Serum creatinine > 1.5 x 
baseline to ≤ 6 x ULN 
• Delay nivolumab or 
ipilimumab 
• Monitor serum creatinine 
every 2-3 days 
• 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or 
oral equivalent 
• Consider renal biopsy with 
nephrology consult  
If returns to Grade 1: 
Taper steroids over at least 1 
month, consider prophylactic 
antibotics for opportunistic 
infections, and resume 
nivolumab and ipilimumab and 
routine serum creatine 
monitoring per protocol 
 
If elevations persists > 7days or 
worsen: 
• 
Treat as Grade 4 
 
Grade 4 
Serum creatinine > 6 x 
ULN 
• 
Discontinue nivolumab or 
ipilimumab 
• 
Monitor serum creatinine 
daily 
• 
1-2mg/kg/day 
methylprednisolone IV or 
IV equivalent 
• 
Consult nephrology 
• 
Consult renal biopsy 
If returns to Grade 1: 
• 
Taper steroids over at least 
one month and add 
prophylactic antiobotics for 
opportunistic infections 
 
 
 
 
Grade 3-4 
Covering >30% BSA; 
or life threatening 
consequences*^ 
• 
Delay or discontinue 
nivolumab or ipilimumab 
• 
Consider skin biopsy 
• 
Consult dermatology 
• 
1-2mg/kg/day 
methylprednisolone IV or IV 
equivalent 
If improves to grade 1: 
• 
Taper steroids over at least one 
month and add prophylactic 
antibiotics 
for 
opportunisitic 
infections 
• 
Resume nivolumab or 
ipilimumab  

 
Page 25 of 52 
 
5.2.4.8 Myocarditis: 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue protocol 
therapy 
 
 
 
 
 
 
 
 
 
 
Grade of Rash 
Myocarditis 
(NCI CTCAE v4) 
Management 
Follow-up 
Grade 2 
Symptoms with mild to 
moderate activity or 
exertion 
• 
Delay nivolumab or ipilimumab 
hospitalization with cardiac 
monitoring 
• 
Urgent cardiology consultation 
for evaluation and management  
                   o Troponin and BNP 
              o ECG ±continuous    
cardia monitoring 
                  o Echocardiogram 
                  o Cardiac MRI 
•   Prompt initiation of 2 mg/kg/day 
methylprednisolone IV or equivalent 
• If worsens, intensify 
treatment according to 
grade 
• Upon recovery, taper 
steroids over at least 1 
month with close 
monitoring of troponin 
   and BNP as well as for      
new symptoms 
• Repeat cardiac MRI for 
post treatment 
assessment and 
cardiology follow-up 
• Retreatment may be 
considered after 
recovery and completion of 
steroid taper 
Grade 3: 
Severe with symptoms 
at rest or with minimal 
activity or exertion; 
intervention indicated 
 
 
 
 
Grade 4: 
Life threatening 
consequences; urgent 
intervention indicated 
(e.g., continuous IV 
therapy or mechanical 
hemodynamic support) 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Permanently discontinue 
nivolumab or ipilimumab 
• Hospitalize to intensive cardiac 
monitoring 
o Cardiac evaluation to include: 
o Troponin and BNP 
monitoringECG ± continuous 
cardic monitoring 
o Echocardiogram 
o Cardiac MRI 
o Myocardial biopsy if feasible 
• Immediate initiation of 2 
mg/kg/day methylprednisolone 
IV or 1 g IV bolus 
• Consider adding a second 
immunosuppressive agent 
 
Additionally, for Grade 4: 
• Hospitalize/transfer to institution 
with expertise in intensive 
cardiac monitoring 
• Consider ATG as second agent 
given its immediate effect 
• If no improvement, 
consider additional 
immunosuppression 
• Upon recovery, taper 
steroids over at least 1 
month with close 
monitoring of troponin 
and BNP as well as for 
new symptoms 
• Repeat cardiac MRI for 
post 
treatmentassessments 
and cardiology follow-up 

 
Page 26 of 52 
5.2.4.9 Ocular manifestations: 
Monitor patients for signs or symptoms of ocular toxicity, which may include blurred vision and reduced 
visual acuity. Immune-mediated ocular toxicity may be associated with retinal detachment or permanent 
vision loss. Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. 
Permanently discontinue ipilimumab for immune-mediated ocular disease that is unresponsive to local 
immunosuppressive therapy. If uveitis occurs in combination with other immune-mediated adverse 
reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients 
receiving ipilimumab and may require treatment with systemic steroids to reduce the risk of permanent 
vision loss. 
 
5.2.4.10 Other:  
For rare cases of myotoxicity (myositis, myocarditis, and rhabdomyolysis), some with fatal outcome, have 
been reported with nivolumab or nivolumab in combination with ipilimumab. If a patient develops signs 
and symptoms of myotoxicity, close monitoring should be implemented, and the patient referred to a 
specialist for assessment and treatment without delay. Based on severity of myotoxicity, nivolumab or 
nivolumab in combination with ipilimumab should be withheld or discontinued, and appropriate treatment 
instituted.  
 
5.3 
Concomitant Medications/Treatments 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial. If there is a clinical indication for any medication or vaccination specifically 
prohibited during the trial, discontinuation from trial therapy or vaccination may be required. The 
investigator should discuss any questions regarding this with the Study PI. The final decision on 
any supportive therapy or vaccination rests with the investigator and/or the subject's primary 
physician. However, the decision to continue the subject on trial therapy or vaccination schedule 
requires the mutual agreement of the investigator, the Sponsor-Investigator and the subject. 
  
Use of bisphosphonates/RANKL inhibitors are standard in CRPC and are allowed on the study. 
Starting bisphosphonates if indicated is allowed while on study.  
 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase of this trial:  
 
Antineoplastic systemic chemotherapy or biological therapy except for ongoing androgen 
deprivation therapy (e.g. with LHRH agonist/antagonist)  
 
Immunotherapy not specified in this protocol  
 
Chemotherapy not specified in this protocol 
 
Investigational agents other than checkpoint inhibitor immunotherapy  
 
5 α-reductase inhibitors (e.g., finasteride, dutasteride) 
 
Any herbal product known to decrease PSA levels (e.g. Saw Palmetto and PC-SPES) 
 
Neulasta®  
 
Radiation therapy  
 
Local intervention is discouraged unless medically unavoidable. Radiation therapy to a 
symptomatic solitary lesion/area may be considered on a case-by-case basis after 
consultation with the Principal Investigator (except during screening). Subjects receiving local 
intervention (e.g., palliative radiation) are allowed to continue to receive study treatment at 
the investigator’s discretion. Subjects who receive local intervention may be considered not 
evaluable (and may be assigned a conservative censoring or progression date).  
 
Live vaccines within 30 days prior registration and while participating the trial. Examples of 
live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster, yellow fever, intranasal influenza, rabies, BCG (tuberculosis vaccine), and 
typhoid vaccine. If precluded by local regulations, live vaccines should not be given for 120 
days after the last dose of checkpoint inhibitor immunotherapy is administered.  
 
Systemic glucocorticoids or other immunosuppressive drugs for any purpose other than to 
modulate symptoms from a drug-related AE of immunologic etiology (refer to Section 5.2 – 

 
Page 27 of 52 
Dose Modification). The use of physiologic doses of corticosteroids may be approved after 
consultation with the Study PI.  
o 
Use of prophylactic corticosteroids to avoid allergic and other adverse reactions (e.g., to 
IV contrast dye or transfusions) is permitted. 
 
o 
Use of intermittent inhaled steroids or local injection of corticosteroids into joints is 
permitted upon consultation with the Study PI. 
 
o 
Physiologic doses of prednisone ≤10 mg (or equivalent) per day. 
5.4 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for a 
total of 104 weeks in all from the start of study therapy or until one of the following criteria 
apply: 
 Disease progression as defined in Section 7.0 
 Inter-current illness that prevents further administration of treatment 
 Unacceptable adverse event(s) 
 Patient voluntarily withdraws from treatment  
 General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 
Do not hold scans, continue scan schedule every 12 weeks from cycle 5 day 1 regardless 
of treatment delays thereafter. 
5.5 
Off Treatment Criteria  
Patients will be removed from protocol specified therapy when any of the criteria listed in 
Section 5.4 apply. Document in the source the reason for ending protocol therapy and the 
date the patient was removed from treatment. All patients who discontinue treatment 
should comply with protocol specific follow-up procedures as outlined in Section 5.6. The 
only exception to this requirement is when a subject withdraws consent for all study 
procedures or loses the ability to consent freely. 
5.6 
Duration of Follow-Up 
Patients will be followed every 3 months for 24 months after removal from treatment or 
until death, whichever occurs first. Patients removed from treatment for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event.  
5.7 
Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative 
reasons. The reason(s) for discontinuation from study or study drug therapy will be 
documented and may include: 

 
Page 28 of 52 
5.7.1 
Patient withdraws consent (termination of treatment and follow-up); 
5.7.2 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment; 
5.7.3 
Patient is unable to comply with protocol requirements; 
5.7.4 
Treating physician determines continuation on the study would not be in the 
patient’s best interest; 
5.7.5 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); study patient will undergo the EOT visit and follow-up 
visits excluding tumor biopsy according to the activities in this protocol and study 
procedure assessments. 
5.7.6 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.7.7 
Lost to Follow-up; 
5.7.8 
Termination of the study by The University of Michigan; 
5.7.9 
Patient completes protocol treatment and follow-up criteria. 
5.8 
Patient Replacement 
Patients who do not receive any dose of the study drug will be replaced. 
 
6.0 
STUDY PROCEDURES 
 
6.1  
SCHEDULE OF ASSESSMENTS: 
 
 
Screening 
(within 28 
days) 
C1D1 
C2D1 
C3D1 
C4D1 
D1C5+ 
EOT12 
Follow 
Up8 
Informed Consent 
X 
 
 
 
 
 
 
 
Review Eligibility Criteria  
X 
 
 
 
 
 
 
 
Demographics, Height 
X 
 
 
 
 
 
 
 
Prior and Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
 
Review Adverse Events10 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination, Vital 
Signs1, Weight 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
 
Survival Status 
 
 
 
 
 
 
 
X Q3m 
Laboratory Assessments  
 
Pregnancy Test for 
WOBCP2 
X 
 
 
 
 
 
 
 
CBC with diff, platelets3 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive Metabolic 
Panel, including Alk Phos4 
X 
X 
X 
X 
X 
X 
X 
 

 
Page 29 of 52 
 
Screening 
(within 28 
days) 
C1D1 
C2D1 
C3D1 
C4D1 
D1C5+ 
EOT12 
Follow 
Up8 
LDH 
X 
X 
X 
X 
X 
 
 
 
PSA11 
X 
X 
X 
X 
X 
X 
X 
X 
Testosterone11 
X 
 
 
 
X 
 
X 
 
TSH, free T3, free T4 (If 
Clinically Indicated: FSH, 
LH, ACTH) 
X 
X 
X 
X 
X 
X6 
X 
 
Therapy 
 
Cohorts A and B 
Nivolumab 3 mg/kg IV q3 
wks for up to 4 doses13 
 
 
X 
 
 
 
Cohorts A and B 
Ipilimumab 1 mg/kg IV q3 
wks for up to 4 doses13 
 
 
X 
 
 
 
 
Cohorts A and B  
Nivolumab 480 mg IV q4 
wks for up to 23 doses13 
 
 
X 
 
 
Cohort C 
Nivolumab 480 mg IV q4 
wks14  
 
X 
X 
 
 
Imaging Tumor Assessments 
 
CT chest 
X 
 
 
 
 
X  
(q 12 
wks) 
 
 
CT Abdomen/Pelvis or MRI 
Abdomen/Pelvis 5  
X 
 
 
 
 
X  
(q 12 
wks) 
 
 
Tc99m Bone Scan   (prostate 
only) 
X 
 
 
 
 
X  
(q 12 
wks ) 
 
 
QoL: BPI-SF and EORTC 
QLQ C30 
X 
 
 
 
 
X 
(q 12 
wks) 
 
 
Correlatives 
 
Tumor Tissue Archival 
(CRPC preferred if available) 
X 
 
 
 
 
 
 
 
Tumor Biopsy 
X 
 
 
 
 
 
X7 
 
Research blood 9 
 
X 
X 
X 
 
X  
(q 12 
wks ) 
X 
 
1. Vital signs will include temperature, pulse, respirations, blood pressure; height will be obtained at screening only. 
2. WOCBP: Women of child bearing potential; urine or serum pregnancy test. 
3. CBC with diff includes total WBC, hemoglobin, hematocrit and differential of the WBC including absolute counts. 
4. COMP or Comprehensive metabolic profile includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, AST, ALT, alkaline 
phosphatase, total bilirubin.  
5. With or without intravenous contrast, before or on associated visit. CT or MRI (preferred) brain with  or without IV contrast if 
suspected or known brain metastases. Frequency of tumor assessments will be q12 weeks.  
6. Every 42 calendar days ± 14 business days. May be delayed if infusion is not scheduled within the window.  
7. Optional tissue biopsy collection at progression if subject consents; +/- 14 working days. 
8. Follow up with phone call or with clinic visit. 
9. Blood for research should be collected prior to study treatment on C1D1, C2D1, C3D1 and C5D1, every 12 weeks thereafter and 
end of treatment. 

 
Page 30 of 52 
10. Data on adverse events will be collected from the time of the initial study drug administration through 100 days after the last dose 
of study drug (nivolumab and/or ipilimumab) as described in Section 8.2. 
11. For Cohort A only 
12. End of Treatment Visit should occur within 3-4 weeks of last dose of protocol therapy. 
13. Cohorts A and B (Nivolumab and Ipilimumab: 1 cycle (C) = 21 days (D) for up to 4 doses of Nivolumab (3mg/kg IV) and Ipilimumab 
(1mg/kg IV), then Nivolumab maintenance therapy alone (480mg IV): 1 cycle=4 weeks or 28 days (D). Total treatment time is up to 
104 weeks.    
14. Cohort C (Nivolumab monotherapy): 1 cycle (C) = 28 days (D) of Nivolumab monotherapy (480mg IV) for up to 104 weeks.  
  
NOTE: 
All procedures in study assessments schedule have a window of ± 3 business days unless otherwise 
mentioned. Virtual clinic visits will be allowed per clinician/ subject discretion.  
 
 
7.0 
MEASUREMENT OF EFFECT 
7.1 
Antitumor Effect- Prostate Cancer  
 
While on therapy with either nivolumab alone or in combination with ipilimumab, patients    
with mCPRC will undergo laboratory monitoring on day 1 of each treatment cycle, including 
PSA, repeated every 4 weeks.  
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with study drug. 
 
 
Evaluable for Objective PSA Response.  All patients enrolled in Cohort A who received at 
least 1 cycle(s) of therapy, and who have 2 PSA measurements after protocol therapy 
initiation will be considered evaluable for PSA response.  Patients who exhibit objective or 
clinical disease progression prior to collection of 2 PSA measurements will also be 
considered evaluable. 
7.1.1 PSA Response Rate 
 
Per PCWG3 criteria, PSA response rate will be defined as the proportion of subjects who 
have PSA response as defined by at least 50% decline in PSA level from baseline 
measured twice at least 3 weeks apart. Based on the PCWG3 criteria, a favorable effect 
on PSA may be delayed for ≥ 12 weeks. PSA will be monitored every 4 weeks, but 
treatment will be planned to continue through early rises for 12 weeks unless other 
evidence of progression, such as radiographic progression.  
 
 
Therefore, early rises in PSA before 12 weeks will not be considered when determining 
PSA response.  
7.1.2  Criteria for PSA Progression 
 
For rising PSA after an initial decline from baseline, the PSA is recorded from the start 
of therapy to first PSA increase that is ≥ 25% and ≥ 2ng/mL above the nadir, which is 
confirmed by a second value 4 or more weeks later, confirming a rising trend. If there 
is no initial decline from baseline, PSA progression is defined as ≥ 25% increase and 
≥ 2 ng/mL increase from baseline beyond 12 weeks.  
 
 
Patients who have only documented PSA progression in the absence of radiographic 
or clinical progression may continue on study therapy.  
 
 

 
Page 31 of 52 
 
7.1.3   Duration of Response 
 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for PSA response until the first date that 
PSA progression is documented, or if there is interval development of recurrent 
or progressive disease objectively documented by RECIST 1.1 criteria.  
7.1.4 
Progression-Free Survival 
PSA progression-free survival (PSA-PFS) is defined as the duration of time from 
start of treatment to time of PSA progression as defined above in section 7.1.2 or 
death, the event that occurs first.  Patients who have not experienced either 
event at the time of analysis will be censored at the last PSA measurement date. 
 
Radiographic progression-free survival (rPFS) is defined as the duration of time 
from start of treatment to time of radiographic progression as defined above in 
section 7.1.5 or death, the event that occurs first. Patients who have not 
experienced either event at the time of analysis will be censored at their last 
radiographic scan date. 
 
Progression-Free Survival (PFS) is defined as the duration of time from start of 
treatment to time of first PCWG3 defined progression or death, the event that 
occurs first. Patients who have not experienced either event at the time of 
analysis will be censored at the date of their last progression assessment. 
 
 
7.1.5 
Radiographic Response Criteria  
 
All radiographic response criteria are as per PCWG3 criteria summarized below. 
 
7.1.5.1 Nodal Disease 
Up to five (5) lesions are recorded per site of disease. These will be 
assessed as per RECIST 1.1 with the following PCWG3 caveats: 
 
1. Changes in size are recorded using a waterfall plot 
2. Favorable change is confirmed with a second scan 
3. Complete elimination of disease at any site is recorded 
separately 

 
Page 32 of 52 
4. Only changes in lymph nodes that were ≥1.5 cm in the short axis 
are reported 
5. Changes in pelvic (regional) nodes versus extrapelvic 
(distant/metastatic) nodes are recorded separately 
 
7.1.5.2 Visceral Disease 
Visceral disease includes lesions in lung, liver, adrenal, and CNS sites. 
These will be assessed as per RECIST 1.1 with the following PCWG3 
caveats: 
 
1. Changes in liver, lung, adrenal, and CNS sites are recorded 
separately. 
2. Only changes in lesions ≥1.0 cm in the longest dimension are 
reported 
 
7.1.5.3 Bone Disease 
Bone disease is evaluated as per PCWG3 criteria, with changes 
recorded as improved or stable (no new lesions) or worse (new lesions). 
Additional PCWG3 caveats include: 
 
1. Changes in intensity of uptake alone do not constitute 
progression or regression 
2. No new lesions: continue therapy in absence of other signs of 
progression 
3. New lesions (progression) is defined by the following per 
PCWG3: 
a. Exclude pseudoprogression in the absence of symptoms 
or other signs of progression 
b. At least two new lesions on first post-treatment scan, 
with at least two additional lesions on the next scan (2+2 
rule) 
c. If at least two additional new lesions are seen on the 
next (confirmatory) scan, the date of progression is the 
date of the first post-treatment scan, when the first two 
new lesions were documented 
d. For scans after the first post-treatment scan, at least two 
new lesions relative to the first post-treatment scan 
confirmed on a subsequent scan 
 
7.2 
Antitumor Effect- Non-Prostate Malignancies 
 
 
(For Cohort B only)  
 
For patients with metastatic non-prostate cancer and measurable disease, response and 
progression will be evaluated using the new international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee [34].  Changes in 
only the largest diameter (unidimensional measurement) of the tumor lesions are used in 
the RECIST v1.1 criteria. 
 
 
 
 
Immunotherapy drugs such as nivolumab and ipilimumab can initially cause inflammation 
in the early stages of treatment. Immune-related RECIST (irRECIST) utilizes RECISTv1.1 
but considers an inflammatory response (or “pseudo-progression”) as normal. The main 
difference between RECISTv1.1 and irRECIST is that patients can stay on trial after the 
first progressive disease (PD) assessment (as per RECISTv1.1) if using immune-related 

 
Page 33 of 52 
RECIST criteria. This PD per RECISTv1.1 is then re-labeled as immune related stable 
disease (irSD) per irRECIST and requires addition of unidimensional measurements of all 
new lesions (that meet the definition of target lesion) to be added to the sum of longest 
diameters (SLD) calculation for response assessment. Importantly, immune-related 
progression (irPD) must be confirmed by a follow-up scan at least 4 weeks (within 4-8 
weeks) following the initial PD/irSD assessment in order to take the patient off the trial. 
 
Subjects that are deemed to have clinical progression and unstable should not be 
continued on therapy after PD (per RECISTv1.1) and are therefore not required to have 
repeat tumor imaging for confirmation as per irPD definition. It is at the discretion of the 
site investigator whether to continue a subject on study treatment until repeat imaging is 
obtained. This clinical judgment decision by the site investigator should be based on the 
subject’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data. 
 
Treatment Beyond Progression 
 
Accumulating evidence indicates a minority of subjects treated with 
immunotherapy may derive clinical benefit despite initial evidence of PD. 
 
Subjects treated will be permitted to continue study 
treatment beyond initial RECISTv1.1 defined PD, assessed by the 
investigator, as long as they meet the following criteria: 
 
 
Investigator determined clinical benefit 
 
Tolerance of study drug 
 
Stable performance status 
 
Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (e.g., CNS metastases) 
 
 
 
A radiographic assessment/ scan should be performed within 4-8 weeks 
 
 
of initial investigator-assessed progression to determine whether there 
 
 
has been a decrease in the tumor size or continued PD (termed irPD). 
 
 
The assessment of clinical benefit should be balanced by clinical 
 
 
judgment as to whether the subject is clinically deteriorating and unlikely 
 
 
to receive any benefit from continued treatment. 
 
 
If the investigator feels that the subject continues to achieve clinical 
benefit by continuing treatment, the subject should remain on the trial and continue to 
receive monitoring according to the Study Calendar (see Section 6.1). 
 
 
Immune-related Progressive Disease (irPD): For the subjects who 
continue study therapy beyond progression, further progression is 
defined as an additional 20% increase in tumor burden with a minimum 5 
mm absolute increase from time of initial PD, unequivocal worsening of 
NT lesions, or appearance of new lesions since the last evaluation. This 
includes an increase in the sum of diameters of all target lesions and/ or 
the diameters of new measurable lesions compared to the time of initial 
PD. Study treatment should be discontinued permanently upon 
documentation of further progression (i.e. irPD). 
7.2.1 
Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with study drug. 
 

 
Page 34 of 52 
Evaluable for objective response. All patients enrolled who received at least 1 
cycle(s) of therapy, and who have measurable disease present at baseline and 
have had their disease re-evaluated will be considered evaluable for response. 
These patients will have their response classified according to the definitions 
stated below. (Note: Patients who exhibit objective or clinical disease progression 
prior to the end of cycle 1 will also be considered evaluable.) 
7.2.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
 
 10mm by CT scan (irrespective of scanner type) for studies with a slice 
thickness of <5mm or twice the slice thickness or MRI 
 10mm caliper measurement by clinical exam (lesions which cannot be 
          accurately measured with calipers should be record as non-measurable)          
 20mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
                           
 All tumor measurements must be recorded in millimeters (or decimal fractions 
of centimeters). 
 
 Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15mm in short axis when assessed by 
CT scan (CT scan slice thickness recommended to be no greater than 5 mm). 
At baseline and in follow-up, only the short axis will be measured and 
followed. 
 
 Note: Tumor lesions that are situated in a previously irradiated area will only 
be considered measurable if they have had subsequent progression by at 
least 5mm. 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
CT scan), are considered non-measurable disease. Bone lesions without 
measurable soft tissue component, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast 
disease, abdominal masses (not followed by CT or MRI), and cystic lesions are 
all non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their 
size (non-nodal lesions with the longest diameter), be representative of all 
involved organ(s), but in addition should be those that lend themselves to 
reproducible repeated measurements. If a non-nodal lesion is either not present 
or is initially measured with longest diameter <10mm as a non-target then grows 
to >10mm after baseline, this lesion then becomes a new target lesion as per 
irRECIST criteria. The non-nodal longest diameter is then added to the sum of 
diameters, and patient response is calculated with the new lesion. 
 
Lymph nodes merit special mention since they are normal anatomical structures 
which may be visible by imaging even if not involved by tumor. Pathological 
nodes which are defined as measurable and may be identified as target lesions 
must meet the criterion of a short axis of ≥15mm by CT scan. Only the short axis 
of these nodes will contribute to the baseline sum. The short axis of the node is 

 
Page 35 of 52 
the diameter normally used by radiologists to judge if a node is involved by solid 
tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI 
the plane of acquisition may be axial, sagittal or coronal). The smaller of these 
measures is the short axis. For example, an abdominal node which is reported as 
being 20mm x 30mm has a short axis of 20mm and qualifies as a malignant, 
measurable node. In this example, 20mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10mm but <15 
mm) should be considered non-target lesions. Nodes that have a short axis 
<10mm are considered non-pathological and should not be recorded or followed. 
 
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 as noted above, 
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. If a non-target lymph node grows to 
>15mm after baseline, this node then becomes a new target lesion as per 
irRECIST. The nodal short axis is then added to the sum of diameters, and 
patient response is calculated with the new lesion. 
 
Non-target lesions. All other lesions (or sites of disease) including pathological 
lymph nodes should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required and these lesions should 
be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, 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’). 
7.3 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. Imaging 
based evaluation should always be done rather than clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and >10mm diameter as assessed using calipers (e.g. skin nodules). For the 
case of skin lesions, documentation by color photography including a ruler to estimate the 
size of the lesion is suggested. As noted above, when lesions can be evaluated by both 
clinical exam and imaging, imaging evaluation should be undertaken since it is more 
objective and may also be reviewed at the end of the study. 
 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5mm or less. When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion 

 
Page 36 of 52 
should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for 
body scans). 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, 
it cannot be guaranteed that the same technique and measurements will be taken from 
one assessment to the next. If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT or MRI is advised. If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response or surgical resection is an endpoint. 
 
 
Cytology, Histology: These techniques can be used to differentiate between PR and CR 
in rare cases if required by protocol (for example, residual lesions in tumor types such as 
germ cell tumors, where known residual benign tumors can remain). When effusions are 
known to be a potential adverse effect of treatment (e.g. with certain taxane compounds 
or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any 
effusion that appears or worsens during treatment can be considered if the measurable 
tumor has met criteria for response or stable disease in order to differentiate between 
response (or stable disease) and progressive disease. 
 
7.4 
Response Criteria 
7.4.1 
Evaluation of Target Lesions 
Prior to the first PD assessment, patients will be evaluated according the 
following RECISTv1.1 response: 
 
Complete Response (CR): Disappearance of all target lesions, determined by 
two separate observations conducted not less than 4 weeks apart. 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 LD of target 
lesions (with a minimum absolute increase of 5 mm), taking as reference the 
smallest sum LD recorded since the treatment started, or the appearance of one 
or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR (taking as 
reference the baseline sum LD) nor sufficient increase to qualify for PD (taking as 
reference the smallest sum LD since the treatment started). 
 
For Cohort B only: After the first PD assessment per RECISTv1.1 (=irSD per 
irRECIST), patients will be evaluated for irPD at least 4 weeks apart according to 
the following definition: 
 
Immune-related Progressive Disease (irPD): At least a 20% increase in 
the sum of the LD of target lesions (with a minimum absolute increase of 

 
Page 37 of 52 
5 mm), taking as reference the smallest sum LD recorded since the 
treatment started, or appearance of new lesions since the last 
evaluation. 
7.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes should be non-pathological 
in size (<10 mm short axis).  
 
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. 
 
Although a clear progression on non-target lesions in absence of stable 
target lesions is exceptional, the opinion of the treating physician should prevail 
in such circumstances. 
7.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). The patient's best response assignment will depend on the achievement 
of both measurement and confirmation criteria. 
 
Evaluation as per RECISTv1.1 and irRECIST. 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
per RECIST 
1.1 
Overall 
Response 
per 
irRECIST 
(Cohort B 
only) 
Best Response for 
this Category Also 
Requires: 
CR 
CR 
No 
CR 
N/A 
>4 wks. confirmation 
CR 
CR 
Non-CR/SD 
No 
 
PR 
 
 
N/A 
 
>4 wks. confirmation 
PR 
CR 
Non-CR/PD 
No 
SD 
CR 
Non-CR/PD 
No 
SD 
 
N/A 
documented at least 
once >4 wks. from 
baseline 
PD 
Any 
Any 
 
 
PD 
 
 
 
irSD 
 
>4 wks. from 
baseline;  
Any 
PD* 
Any 
 
Any 
Any 
Yes 
PD 
Any 
Any 
 
N/A 
 
      irPD 
 
No further 
confirmation required 
 
Any 
PD* 
Any 
Any 
Any 
Yes 
 
 

 
Page 38 of 52 
 
 
 
 
 
 
 
 
 
 
 
 
N/A=not applicable 
 
Note: If subjects respond to treatment and are able to have their disease resected, the 
patient’s response will be assessed prior to the surgery 
 
 
7.5 
Duration of Response - Non prostate malignancies 
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). 
 
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.  
7.6 
Progression-Free Survival - Non prostate malignancies 
Radiographic progression-free survival (PFS) is defined as the duration of time from start 
of treatment to time of radiographic progression as defined above in section 7.4 or death, 
the event that occurs first. Patients who have not experienced either event at the time of 
analysis will be censored at their last radiographic scan date. 
 
Progression-free survival (PFS) is defined as the duration of time from start of treatment 
to time of radiographic or clinical progression or death, the event that occurs first. 
Patients who have not experienced either event at the time of analysis will be censored at 
the date of their last progression assessment. 
 
7.7 
 Safety/Tolerability 
Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 4.03 for reporting of non-hematologic 
adverse events (http://ctep.cancer.gov/reporting/ctc.html)). 
8.0 
ADVERSE EVENTS 
8.1 
Experimental Therapy 
For the most recent safety update, please refer to the current Investigator’s Brochure or 
Study Agent Prescribing Information. 
Special Warnings and Precautions for Use 
 
Subjects receiving nivolumab and/or ipilimumab are advised to use two acceptable (to 
treating investigator) methods of birth control (one of which must include a condom as a 
barrier method of contraception) starting at the time of informed consent and continuing 
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment. 

 
Page 39 of 52 
throughout the course of treatment and for at least 5 months (for women) and 7 months 
(for men) after nivolumab and/or ipilimumab immunotherapy is discontinued. 
 
8.2 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is 
done to ensure the safety of subjects enrolled in the studies as well as those who will 
enroll in future studies using similar agents. Data on adverse events will be collected from 
the time of the initial study drug administration through 100 days after the last dose of 
study drug, that is nivolumab and/or ipilimumab. Any serious adverse event that occurs 
more than 100 days after the last study drug dose and is considered related to the study 
drug must also be reported. Serious Adverse Events (SAEs) will continue to be followed 
until: 
 
Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
 
There is satisfactory explanation other than the study drug, nivolumab and/or 
ipilimumab, for the changes observed; or  
 
Death. 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration is considered to be pre-existing in nature. Any known pre-
existing conditions that are ongoing at time of study entry should be considered medical 
history. 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 8.3, 
occurring from the initial study treatment administration through 100 days following the 
last dose of the study treatment must be recorded as an adverse event in the patient’s 
source documents and on the CRF regardless of frequency, severity (grade) or assessed 
relationship to the study treatment. 
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of 
a pre-existing condition that occurs after the patient begins study treatment is also 
considered an adverse event. 
8.3 
Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an experimental 
intervention, whether or not related to the intervention.  
 
Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) procedures 
will not be reported as adverse events. However, the medical condition for 
which the procedure was performed must be reported if it meets the definition of 
an adverse event unless it is a pre-existing (prior to protocol treatment) 
condition. 
 

 
Page 40 of 52 
 
Abnormal laboratory values or test results constitute adverse events if they 
induce clinical signs or symptoms or require therapy. They are to be captured 
under the signs, symptoms or diagnoses associated with them. 
Serious Adverse Event 
An adverse event is considered “serious” if, in the view of either the investigator, it 
results in any of the following outcomes: 
  
 
Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 
 
A life-threatening adverse event 
An adverse even is considered ‘life-threatening’ if, in the view of either the 
investigator [or sponsor], its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event that, had it 
occurred in a more severe form, might have caused death.  
 
 
Inpatient hospitalization or prolongation of existing hospitalization for > 24 
hours. 
 
 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
 
A congenital anomaly/birth defect 
 
 
Important medical event 
Any event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition 
of “Serious Adverse Event”. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room 
or at home; convulsions that do not result in inpatient hospitalization or the 
development of drug dependency or drug abuse. 
 
Previously planned (prior to signing the informed consent form) surgeries should not be 
reported as SAEs unless the underlying medical condition has worsened during the 
course of the study. Preplanned hospitalizations or procedures for preexisting 
conditions that are already recorded in the patient’s medical history at the time of study 
enrollment should not be considered SAEs. Hospitalization or prolongation of 
hospitalization without a precipitating clinical AE (for example, for the administration of 
study therapy or other protocol-required procedure) should not be considered SAEs. 
However, if the preexisting condition worsened during the course of the study, it should 
be reported as an SAE. 
 
Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
 
For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Insert (Label).  
 
For investigational new drugs or devices, those adverse events are described in 
the FDA Investigator’s Brochure.  

 
Page 41 of 52 
 
In clinical research studies, information on expected adverse events is also 
summarized in the protocol and in the consent document.  See section 9.1 for 
the list of expected adverse events related to the drug under study. 
Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the Package 
Insert, Investigator’s Brochure, in the protocol, or in the informed consent document.  
8.4 
Adverse Event Characteristics 
8.4.1 
CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized 
for AE reporting. All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.03. A copy of the CTCAE version 4.03 can be down loaded from the 
CTEP web site. (http://ctep.cancer.gov) 
8.4.2 
Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment.  
Possible – The AE may be related to the study treatment.  
Unlikely – The AE is doubtfully related to the study treatment.  
Unrelated – The AE is clearly NOT related to the study treatment.  
8.5 
Serious Adverse Event Reporting Guidelines 
8.5.1 
Reporting procedures for multi-site trials 
All serious adverse events (SAEs) and unanticipated problems (UPs), regardless 
of causality to study drug, will be reported to the Principal Investigator and also to 
the Coordinating Center.  All SAEs and UPs must be reported to the 
Coordinating Center within 24 hours of first awareness of the event.  Events 
should be reported using the Coordinating Center SAE form as available in the 
study database.  A copy of the Coordinating Center SAE form as available in the 
study database should be sent to the Coordinating Center via fax at 734-232-
0744 or via email to CTSU-Oncology-Multisite@med.umich.edu within 24 hours 
of the site’s knowledge of the event.  
Follow-up information must also be reported within 24 hours of receipt of the 
information by the investigator. 
Participating sites should report all SAEs and UPs to their local IRB per current 
local institutional standards. 
The Coordinating Center will disseminate information regarding SAEs and UPs to 
the participating sites within 5 days of review of the information by the 
Coordinating Center’s Principal Investigator (or designee in the event of 
extended absence) only in the case that the event(s) is believed to be related 
(i.e., possibly, probably, or definitely) to the study drug. The Coordinating Center 
will be responsible for reporting of events to the FDA and supporters, as 
appropriate (outlined below). 
8.5.2 
Reporting procedures to BMS 
All Serious Adverse Events (SAEs) occurring from the initial study treatment 
administration through 100 days following the last dose of the study treatment will 

 
Page 42 of 52 
be reported by the Coordinating Center to BMS Worldwide safety.  Any SAEs 
occurring after 100 days following the last dose of the study treatment that are 
believed to be related to study drug will also be reported to BMS Worldwide 
safety.  
The Coordinating Center will send the initial completed SAE Form within 24 
hours of receipt via email to BMS Worldwide Safety 
(Worldwide.Safety@bms.com; Fax: 609-818-3804).   
If only limited information is initially available or an ongoing SAE changes in its 
intensity or relationship to the study drug, or if new information becomes 
available, a follow-up report will be generated and sent to BMS Worldwide Safety 
within 24 hours of receipt.   
8.5.3 
Reporting procedures to FDA 
In this trial, serious, unexpected adverse events believed to be definitely, 
probably or possibly related to the study treatment will be reported to the Food 
and Drug Administration via the MedWatch 3500A Form. The Michigan IND/IDE 
Assistance Program (MIAP) (University of Michigan) will assist the IND Sponsor 
in reporting SAEs to the FDA that meet the reporting requirements in 21 CFR 
312.32.  This reporting could include the initial report and follow-up reports when 
appropriate for the event.  
8.6 
Routine Reporting 
All other adverse events- such as those that are expected, or are unlikely or definitely not 
related to the study participation- are to be reported annually as part of regular data 
submission. 
8.7 
Reporting of Unanticipated Problems 
There are types of incidents, experiences and outcomes that occur during the conduct of 
human subjects research that represent unanticipated problems but are not considered 
adverse events. For example, some unanticipated problems involve social or economic 
harm instead of the physical or psychological harm associated with adverse events. In 
other cases, unanticipated problems place subjects or others at increased risk of harm, 
but no harm occurs. 
 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse 
event) that may represent an unanticipated problem, the investigator should assess 
whether the incident, experience, or outcome represents an unanticipated problem. The 
incident, experience or outcomes is considered unanticipated if it meets all of the 
following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency); 
2. Related or possibly related to participation in the research; and 
3. Suggests that the research places subjects or others at a greater risk of harm 
than was previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the IRB within 7 calendar days of 
the study team becoming aware of the problem. 
8.8 
Safety Report Reconciliation  
The Sponsor will reconcile the clinical database SAE reports transmitted to BMS Global 
Pharmacovigilance (Worldwide.Safety@bms.com).  Frequency of reconciliation should 
be every 3 months and prior to the database lock or final data summary.  BMS GPV&E 

 
Page 43 of 52 
will email, upon request from the Investigator, the GPV&E reconciliation report.  Requests 
for reconciliation should be sent to aepbusinessprocess@bms.com.  The data elements 
listed on the GPV&E reconciliation report will be used for identification purposes.  If the 
Investigator determines a report was not transmitted to BMS GPV&E, the report should 
be sent immediately to BMS.   
 
 
9.0 
DRUG INFORMATION 
9.1 
Nivolumab  
 
Other names for the drug: Opdivo 
 
 
Description: Injection: 100 mg/10 mL solution in a single-dose vial.  
 
 
Classification - type of agent: Immunomodulatory; checkpoint inhibitor 
 
 
Mode of action: 
Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, 
inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands 
occurs in some tumors and signaling through this pathway can contribute to inhibition 
of active T-cell immune surveillance of tumors. Nivolumab is a human 
immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and 
blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated 
inhibition of the immune response, including the anti-tumor immune response. In 
syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor 
growth.  
Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition 
results in enhanced T-cell function that is greater than the effects of either antibody 
alone, and results in improved anti-tumor responses in metastatic melanoma. In 
murine syngeneic tumor models, dual blockade of PD-1 and CTLA-4 resulted in 
increased anti-tumor activity. 
 
 
Pharmacokinetics:  
Nivolumab pharmacokinetics (PK) were assessed using a population PK approach 
for both single-agent nivolumab and nivolumab with ipilimumab.  
nivolumab as a single agent: The PK of single-agent was studied in patients over a 
dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses of 
nivolumab every 2 or 3 weeks. Nivolumab clearance decreases over time, with a 
mean maximal reduction (% coefficient of variation [CV%]) from baseline values of 
approximately 24.5% (47.6%) resulting in a geometric mean steady state clearance 
(CLss) (CV%) of 8.2 mL/h (53.9%); the decrease in CLss is not considered clinically 
relevant. The geometric mean volume of distribution at steady state (Vss) (CV%) is 
6.8 L (27.3%), and geometric mean elimination half-life (t1/2) is 25 days (77.5%). 
Steady-state concentrations of nivolumab were reached by approximately 12 weeks 
when administered at 3 mg/kg every 2 weeks, and systemic accumulation was 
approximately 3.7-fold. The exposure to nivolumab increased dose proportionally 
over the dose range of 0.1 to 10 mg/kg administered every 2 weeks.  
 
Nivolumab with ipilimumab: The geometric mean (CV%) CL, Vss, and terminal halflife 
of nivolumab were 10.0 mL/h (50.3%), 7.92 L (30.1%), and 24.8 days (94.3%), 
respectively. When administered in combination, the CL of nivolumab was increased 
by 24%, whereas there was no effect on the clearance of ipilimumab. 
 
 
Side effects:  
Nivolumab as a single agent: fatigue, rash, musculoskeletal pain, pruritus, diarrhea, 

 
Page 44 of 52 
nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, 
arthralgia, upper respiratory tract infection, and pyrexia.  
Nivolumab with ipilimumab: fatigue, rash, diarrhea, nausea, pyrexia, vomiting, and 
dyspnea.  
 
 
Drug Interactions:  
No formal pharmacokinetic drug-drug interaction studies have been conducted with 
nivolumab. 
 
 
Storage and stability:  
The product does not contain a preservative. After preparation, store the nivolumab 
infusion either:  
• at room temperature for no more than 8 hours from the time of preparation. This 
includes room temperature storage of the infusion in the IV container and time for 
administration of the infusion or  
• under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the 
time of infusion preparation. Do not freeze. 
 
 
Preparation and Dispensing:  
Visually inspect drug product solution for particulate matter and discoloration prior to 
administration. Nivolumab is a clear to opalescent, colorless to pale-yellow solution. 
Discard the vial if the solution is cloudy, discolored, or contains extraneous 
particulate matter other than a few translucent-to-white, proteinaceous particles. Do 
not shake the vial. 
• Withdraw the required volume of nivolumab and transfer into an intravenous 
container.  
• Dilute nivolumab with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP to prepare an infusion with a final concentration ranging from 1 mg/mL 
to 10 mg/mL.  
• Mix diluted solution by gentle inversion. Do not shake.  
• Discard partially used vials or empty vials of nivolumab.  
 
 
Administration:  
Administer the infusion over 30 minutes through an intravenous line containing a 
sterile, non-pyrogenic, low protein binding in-line filter (pore size of 0.2 micrometer to 
1.2 micrometer). Do not coadminister other drugs through the same intravenous line. 
Flush the intravenous line at end of infusion. 
When administered in combination with ipilimumab, infuse nivolumab first followed by 
ipilimumab on the same day. Use separate infusion bags and filters for each infusion. 
 
 
Availability: Provided by Bristol Myers Squibb, Inc. 
 
Return and Retention of Study Drug: 
 
Handling and disposal of nivolumab should be per institutional guidelines for the 
handling and disposal of biologic and cytotoxic agents  
 
 
Drug Accountability: 
 
The investigator, or a responsible party designated by the investigator, must maintain 
a careful record of the inventory and disposition of nivolumab. The drug 
accountability records will capture drug receipt, drug dispensing, drug return and final 
disposition.   
 
9.2 
Ipilimumab 
 
Other names for the drug: Yervoy 
 

 
Page 45 of 52 
 
Description:  
 
  
 
Injection: 200 mg/40 mL (5 mg/mL) (3)  
 
 
Classification - type of agent: Immunomodulatory; checkpoint inhibitor 
 
 
Mode of action: human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody  
 
 
Pharmacokinetics:  
The pharmacokinetics (PK) of ipilimumab was studied in 785 patients with 
unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg 
once every 3 weeks for 4 doses. The PK of ipilimumab is linear in the dose range of 
0.3 to 10 mg/kg. Following administration of ipilimumab every 3 weeks, the systemic 
accumulation was 1.5-fold or less. Steady-state concentrations of ipilimumab were 
reached by the third dose; the mean Cmin at steady state was 19.4 mcg/mL at 3 
mg/kg and 58.1 mcg/mL at 10 mg/kg every 3 weeks. The mean value (percent 
coefficient of variation) based on population PK analysis for the terminal half-life 
(t1/2) was 15.4 days (34%) and for clearance (CL) was 16.8 mL/h (38%). Specific 
Populations The effects of various covariates on the PK of ipilimumab were assessed 
in population PK analyses. The CL of ipilimumab increased with increasing body 
weight supporting the recommended body weight (mg/kg) based dosing. The 
following factors had no clinically important effect on the CL of ipilimumab: age 
(range: 23 to 88 years), sex, performance status, renal impairment, mild hepatic 
impairment, previous cancer therapy, and baseline lactate dehydrogenase (LDH) 
levels. The effect of race was not examined due to limited data available in non-
Caucasian ethnic groups.  
 
Renal Impairment: No clinically important differences in the CL of ipilimumab were 
found between patients with renal impairment and patients with normal renal function. 
 
Hepatic Impairment: The effect of hepatic impairment on the CL of ipilimumab was 
evaluated in patients with mild hepatic impairment (n=76) compared to patients with 
normal hepatic function (n=708) in the population PK analyses, and no clinically 
important differences in the CL of ipilimumab were found. Ipilimumab has not been 
studied in patients with moderate or severe hepatic impairment.  
 
 
Side effects: Ipilimumab can result in severe and fatal immune-mediated reactions. 
 
 
Drug Interactions: No formal pharmacokinetic drug interaction studies have been 
conducted with ipilimumab. 
 
 
Storage and stability:  
• Store the diluted solution for no more than 24 hours under refrigeration (2°C to 8°C, 
36°F to 46°F) or at room temperature (20°C to 25°C, 68°F to 77°F).   
 
 
Preparation and Dispensing:  
• Do not shake product.  
• Inspect parenteral drug products visually for particulate matter and discoloration 
prior to administration. Discard vial if solution is cloudy, there is pronounced 
discoloration (solution may have pale-yellow color), or there is foreign particulate 
matter other than translucent-to-white, amorphous particles.  
• Allow the vials to stand at room temperature for approximately 5 minutes prior to 
preparation of infusion.  
• Withdraw the required volume of ipilimumab and transfer into an intravenous bag. 
• Dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to 

 
Page 46 of 52 
prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 
mg/mL. Mix diluted solution by gentle inversion.  
• Discard partially used vials or empty vials of ipilimumab. 
 
 
Administration:  
• Do not mix ipilimumab with, or administer as an infusion with, other medicinal 
products.  
• Flush the intravenous line with 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP after each dose.  
• Administer diluted solution over 90 minutes through an intravenous line containing a 
sterile, non-pyrogenic, low-protein-binding in-line filter. 
 
 
Availability: Provided by Bristol Myers Squibb, Inc. 
 
 
Return and Retention of Study Drug:Handling and disposal of ipilimumab should be 
per institutional guidelines for the handling and disposal of biologic and cytotoxic 
agents  
 
 
Drug Accountability:The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of 
ipilimumab. The drug accountability records will capture drug receipt, drug 
dispensing, drug return and final disposition.    
10.0 
CORRELATIVES/SPECIAL STUDIES 
Specimens will be collected for banking and archival purposes. Submission of samples for 
correlative studies is expected of all subjects at baseline and optional tumor biopsy will be 
performed for those who consent to it. 
10.1 
Sample Collection Guidelines 
 
Prior to study enrollment, patients must have documented CDK12 loss on a prior biopsy 
(or cell-free DNA or other is allowed) of primary or metastatic tissue. Metastatic tissue is 
strongly preferred.  
 
Willingness to provide archival tissue submission is mandatory. If archival tissue,  contains 
inadequate tissue for NGS (i.e., less than 30% tumor content) or patient does not consent 
to fresh tissue biopsy, or fresh biopsy is not feasible, then patient may enroll in study if all 
other eligibility criteria are met. In general, visceral metastases are prioritized over soft 
tissue or lymph node, and least preferable are bone metastases.  
 
Refer to Section 6.0 for tumor tissue and blood collection time points and Lab Manual for 
collection and processing details.  
 
 
 
10.2 
Specimen Banking 
Patient samples (tissue and blood) collected for this study will be retained at the 
University of Michigan. Specimens will be stored indefinitely or until they are used up. If 
future use is denied or withdrawn by the patient, best efforts will be made to stop any 
additional studies and to destroy the specimens. 
 
Specimens being stored long-term for potential use not outlined in the protocol are 
subject to University Policy Governing Tissue Sample Collection, Ownership, Usage, and 

 
Page 47 of 52 
Disposition within all UMMS Research Repositories 
https://research.medicine.umich.edu/office-research/biorepository/governance-policies. 
11.0 
STATISTICAL CONSIDERATIONS 
11.1 
Study Design/Study Endpoints 
This is a multi-center, prospective, one arm, 3 cohort study to evaluate the efficacy of 
immunotherapy in patients with metastatic cancers and CDK12  loss. Patients with 
metastatic castration resistant prostate cancer (mCRPC) will be enrolled in Cohort A until 
25 evaluable patients are identified. Once Cohort A is full, mCRPC patients will enroll in 
Cohort C. Patients with other metastatic subtypes will be enrolled in Cohort B. 
 
An Mini-Max Simon Two-Stage design will be used to assess ORR defined as a 50% 
decline in PSA from baseline in CDK12 loss of function metastatic CRPC patients.  It is 
assumed that an ORR of 30% or more would be interesting for further study compared to 
a reference ORR of 10% based on the KEYNOTE-199 trial [35]. Accrual of 25 objective 
PSA response evaluable patients will provide 80% power to detect this difference in ORR 
with a type I error of 5%.  Interim analysis will be completed after 15 objective PSA 
response evaluable patients (Cohort A only).  If 2 or more patients have a PSA response, 
then the 2nd stage will open and accrue 10 more patients. If 6 or more patients out of 25 
have a PSA response, then the treatment will be recommended for further study in this 
population.  
 
Cohort B will accrue 15 patients with non-prostate histology. A reference ORR of 5% is 
assumed in patients with non-prostate histology.  With 15 patients, we have 76% power 
to detect an ORR of 25% with a one-sided type I error of 5%.  If 3 or more responses are 
seen in cohort B then we will conclude that there is preliminary evidence of activity. 
 
Cohort C will accrue 25 mCRPC patients. A reference ORR of 10% is assumed, allowing 
80% power to detect an ORR of 30% or more with a one-sided type I error of 5%. If 6 or 
more patients out of 25 have a PSA response, then the treatment will be recommended 
for further study in this population. 
 
11.2 
Sample Size and Accrual 
The trial is expected to accrue the total study population of 65 patients harboring CDK12 
loss, including 50 objective PSA response evaluable metastatic prostate cancer patients 
and 15 objective response evaluable patients with non-prostate tumor histology over 2 
years.  
11.3 
Data Analyses Plans 
 
Primary Endpoint Analysis:  
The primary endpoint for Cohort A and Cohort C is overall response rate using PSA 
criteria. The primary analysis will include the response count and proportion with the 
associated exact 95% binomial confidence interval in the mCRPC cohort. If stage 2 is 
initiated, then the efficacy analysis methods for the reported response confidence interval 
will be as described by Koyama and Chen [33].  
 
Secondary Endpoint Analysis: 
Efficacy in Cohort B will be described using overall response rate (CR/PR) using RECIST 
1.1 criteria. The response count and proportion will be reported with the associated 95% 
exact binomial confidence interval. 
 

 
Page 48 of 52 
 
Safety and tolerability of, nivolumab and ipilimumab combination therapy followed by 
nivolumab monotherapy, or nivolumab monotherapy only, will be described by the 
frequency and severity of adverse events by CTCAE criteria. The proportion of patients 
removed from treatment due to AEs will be reported.  The number and proportion of 
patients with dose reductions and/or holds will be reported separately and overall.  Each 
measure will be reported for the entire trial and separately by cohort. 
 
 
Secondary efficacy time-to-event endpoints including radiographic progression-free 
survival (rPFS), progression-free survival (PFS), duration of response (DOR) among 
responders, duration of therapy (DOT), time to progression (TTP) and overall survival 
(OS) will be reported using Kaplan-Meier methods. The median, if reached, and the 52-
week event-free proportion with the associated 95% greenwood formula confidence 
interval will be reported for each endpoint. For subjects with metastatic CRPC, PSA 
progression-free survival and time to PSA progression by PCWG3 criteria will also be 
described for Cohort A using the same the Kaplan-Meier measures described previously. 
Objective tumor response in patients with measurable disease by RECIST 1.1 criteria will 
reported separately by location using PCWG3 recommendations and will include waterfall 
plots and counts with proportions and the associated 95% confidence intervals. Each 
endpoint will be reported for all patients if applicable and separately for each cohort.  
 
 
Quality of Life (QoL) in subjects treated on protocol therapy will be described using 
EORTC-QLQ-C30 and BPI-SF measures.  Baseline will be described using means or 
medians with an associated variance statistic.  Change from baseline will be reported at 
each time point thereafter with similar descriptive statistics. Each measure will be 
reported for the overall population and separately by cohort. Each QoL change from 
baseline will be analyzed using a general linear model with repeated measures for an 
association with response. 
 
 
 
 
Exploratory Endpoint Analysis 
 
 
 
 
 
Tumor genome profiling by integrated DNA and RNA sequencing  at baseline and 
optionally at progression will be described using figures representing the profiled patients. 
These figures will order patients by degree of response (PSA response for Cohort A and 
Cohort C; and RECIST response for Cohort B).  A logistic model with response as the 
outcome may be used with specific markers as independent covariates to estimate an 
effect size if a profound pattern is seen.  Differences seen in paired samples (baseline 
and progression) will be described individually and labeled as a responder/non-
responder.  Immune infiltration in tumor biopsies will be described using figures. 
Associations of the profiles with the response will be described using counts and 
proportions. 
 
 
12.0 
DATA AND SAFETY MONITORING 
This study will be monitored in accordance with the NCI approved University of Michigan Rogel 
Cancer Center Data and Safety Monitoring Plan, with oversight by the Rogel Cancer Center Data 
and Safety Monitoring Committee (DSMC). 
 
The Sponsor-Investigator (S-I)/Study Principal Investigator will provide ongoing monitoring of data 
and patient safety in this trial and conduct regular data review with participating sites 
 
The Sponsor-Investigator (S-I)/Study Principal Investigator and/or the Project Manager/Delegate 
will review data and patient safety issues with participating sites per a defined quarterly meeting 
cadence. Depending on the protocol activity, the meeting cadence may be more frequent. This 
data review meeting may be achieved via a teleconference or another similar mechanism to 
discuss matters related to: 

 
Page 49 of 52 
 
 Enrollment rate relative to expectations, characteristics of participants 
 Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
 Adherence to protocol (protocol deviations) 
 Completeness, validity and integrity of study data 
 Retention of study participants 
 
Participating sites are required to ensure all pertinent data for the review period are available in 
the database at the time of the discussion. 
 
Participating sites unable to participate in the data review meeting are required to provide written 
confirmation that their site has reviewed the relevant data and patient safety issues for the review 
period and their site’s data are in alignment with the data reported in the database. Written 
confirmation is to be provided to the Project Manager/Delegate within the timeline requested to 
retain compliance with monitoring timelines. 
 
Documentation of the teleconference or alternate mechanism utilized to review items above is to 
be retained in the Trial Master File.  
 
The Project Manager/Delegate is responsible for collating the data from all participating sites and 
completing the Protocol Specific Data and Safety Monitoring Report (DSMR) form to document 
the data review meeting discussion.  
 
The DSMR will be signed by the Sponsor-Investigator (S-I)/Study Principal Investigator or 
designated Co-Investigator and submitted to the DSMC on a quarterly basis for independent 
review. 
 
13.0 
DATA MANAGEMENT 
All information will be recorded locally and entered into Case Report Forms (CRFs) on the web-
based electronic data capture (EDC) system of the University of Michigan. Online access will be 
provided to each site by the Coordinating Center.  
 
CRFs will be reviewed and source verified by the MSC during annual monitoring visits and prior 
to and between visits. Discrepant, unusual and incomplete data will be queried by the MSC. The 
investigator or study coordinator will be responsible for providing resolutions to the data queries, 
as appropriate. The investigator must ensure that all data queries are dealt with promptly.  
 
The data submission schedule is as follows:  
 
After subject enrollment   
o 
Subject Status 
o 
Demographics 
 
During study participation 
o 
All data should be entered online within 10 business days of data acquisition. 
Information on Serious Adverse Events must be entered within the reporting 
timeframe specified in Section 8 of the protocol.  
  
All study information should be recorded in an appropriate source document (e.g. clinic chart). 
 
14.0 
QUALITY ASSURANCE AND AUDITS 
The Data and Safety Monitoring Committee can request a ‘for cause’ quality assurance audit of 
the trial if the committee identifies a need for a more rigorous evaluation of study-related issues.  
 

 
Page 50 of 52 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the Coordinating Center that such a 
request has been made. 
 
15.0 
CLINICAL TRIAL MONITORING 
Clinical studies coordinated by The University of Michigan Rogel Cancer Center must be conducted 
in accordance with the ethical principles that are consistent with Good Clinical Practices (GCP) and 
in compliance with other applicable regulatory requirements. 
 
This study will be monitored by a representative of the Coordinating Center of the Rogel Cancer 
Center. Monitoring visits will be made during the conduct of the study and at study close-out. 
 
Prior to subject recruitment, a participating site will undergo a site initiation meeting to be conducted 
by the Coordinating Center. This will be done as an actual site visit; teleconference, 
videoconference, or web-based meeting after the site has been given access to the study database 
and assembled a study reference binder.  The site’s principal investigator and his/her study staff 
should make every effort in attending the site initiation meeting. Study–related questions or issues 
identified during the site initiation meeting will be followed-up by the appropriate Coordinating 
Center personnel until they have been answered and resolved. 
 
Monitoring of this study can include both ‘Centralized Monitoring’, the review of source documents 
at the Coordinating Center and ‘On-site Monitoring’, an actual site visit.  The first ‘Centralized’ visit 
should occur after the first subject enrolled completes the first treatment cycle.  The study site will 
send the de-identified source documents to the Coordinating Center for monitoring.  ‘Centralized’ 
monitoring may be requested by the Coordinating Center if an amendment requires changes to the 
protocol procedures. The site will send in pertinent de-identified source documents, as defined by 
the Coordinating Center for monitoring.  
 
The first annual ‘On-site’ monitoring visit should occur after the first five study participants are 
enrolled or twelve months after a study opens, whichever occurs first. The annual visit may be 
conducted as a ‘Centralized’ visit if less than three subjects have enrolled at the study site.  The 
type of visit is at the discretion of the Coordinating Center.  At a minimum, a routine monitoring visit 
will be done at least once a year, or once during the course of the study if the study duration is less 
than 12 months. The purpose of these visits is to verify: 
 
 
Adherence to the protocol 
 
Completeness and accuracy of study data and samples collected 
 
Proper storage, dispensing and inventory of study medication 
 
Compliance with regulations 
 
During a monitoring visit to a site, access to relevant hospital and clinical records must be given by 
the site investigator to the Coordinating Center representative conducting the monitoring visit to 
verify consistency of data collected on the CRFs with the original source data.  While most patient 
cases will be selected from patients accrued since the previous monitoring visit, any patient case 
has the potential for review.  At least one or more unannounced cases will be reviewed, if the total 
accruals warrant selection of unannounced cases.  
 
The Coordinating Center expects the relevant investigational staff to be available to facilitate the 
conduct of the visit, that source documents are available at the time of the visit, and that a suitable 
environment will be provided for review of study-related documents. Any issues identified during 
these visits will be communicated to the site and are expected to be resolved by the site in a timely 
manner.  For review of study-related documents at the Coordinating Center, the site will be required 
to ship or fax documents to be reviewed.   

 
Page 51 of 52 
 
Participating site will also undergo a site close-out upon completion, termination or cancellation of 
a study to ensure fulfillment of study obligations during the conduct of the study, and that the site 
Investigator is aware of his/her ongoing responsibilities. In general, a site close-out is conducted 
during a site visit; however, site close-out can occur without a site visit. 
16.0 
REFERENCES 
 
1. 
Robinson, D., et al., Integrative clinical genomics of advanced prostate cancer. Cell, 
2015. 161(5): p. 1215-28. 
2. 
Robinson, D.R., et al., Integrative clinical genomics of metastatic cancer. Nature, 2017. 
548(7667): p. 297-303. 
3. 
Chila, R., F. Guffanti, and G. Damia, Role and therapeutic potential of CDK12 in human 
cancers. Cancer Treat Rev, 2016. 50: p. 83-88. 
4. 
Teply, B.A. and E.S. Antonarakis, Treatment strategies for DNA repair-deficient prostate 
cancer. Expert Rev Clin Pharmacol, 2017. 10(8): p. 889-898. 
5. 
Joshi, P.M., et al., Ovarian cancer-associated mutations disable catalytic activity of 
CDK12, a kinase that promotes homologous recombination repair and resistance to 
cisplatin and poly(ADP-ribose) polymerase inhibitors. J Biol Chem, 2014. 289(13): p. 
9247-53. 
6. 
Popova, T., et al., Ovarian Cancers Harboring Inactivating Mutations in CDK12 Display 
a Distinct Genomic Instability Pattern Characterized by Large Tandem Duplications. 
Cancer Res, 2016. 76(7): p. 1882-91. 
7. 
Ekumi, K.M., et al., Ovarian carcinoma CDK12 mutations misregulate expression of 
DNA repair genes via deficient formation and function of the Cdk12/CycK complex. 
Nucleic Acids Res, 2015. 43(5): p. 2575-89. 
8. 
Snyder, A., et al., Genetic basis for clinical response to CTLA-4 blockade in melanoma. 
N Engl J Med, 2014. 371(23): p. 2189-2199. 
9. 
Yaghmour, G., et al., Role of Genomic Instability in Immunotherapy with Checkpoint 
Inhibitors. Anticancer Res, 2016. 36(8): p. 4033-8. 
10. 
Brahmer, J.R., et al., Phase I study of single-agent anti-programmed death-1 (MDX-
1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and 
immunologic correlates. J Clin Oncol, 2010. 28(19): p. 3167-75. 
11. 
Beer, T.M., et al., Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus 
Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic 
Chemotherapy-Naive Castration-Resistant Prostate Cancer. J Clin Oncol, 2017. 35(1): p. 
40-47. 
12. 
Graff, J.N., et al., Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate 
cancer. Oncotarget, 2016. 7(33): p. 52810-52817. 
13. 
Basnet, A., et al., A Case of Locally Advanced Castration-resistant Prostate Cancer With 
Remarkable Response to Nivolumab. Clin Genitourin Cancer, 2017. 
14. 
Postow, M.A., et al., Nivolumab and ipilimumab versus ipilimumab in untreated 
melanoma. N Engl J Med, 2015. 372(21): p. 2006-17. 
15. 
Antonia, S.J., et al., Nivolumab alone and nivolumab plus ipilimumab in recurrent small-
cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet 
Oncol, 2016. 17(7): p. 883-895. 

 
Page 52 of 52 
16. 
Wu, Y., et al., The clinical value of combination of immune checkpoint inhibitors in 
cancer patients: A meta-analysis of efficacy and safety. Int J Cancer, 2017. 
17. 
Alexandrov, L.B., et al., Mutational signatures associated with tobacco smoking in 
human cancer. Science, 2016. 354(6312): p. 618-622. 
18. 
Rizvi, N.A., et al., Cancer immunology. Mutational landscape determines sensitivity to 
PD-1 blockade in non-small cell lung cancer. Science, 2015. 348(6230): p. 124-8. 
19. 
Roychowdhury, S., et al., Personalized Oncology Through Integrative High-Throughput 
Sequencing: A Pilot Study. Science Translational Medicine, 2011. 3(111). 
20. 
Cieslik, M., et al., The use of exome capture RNA-seq for highly degraded RNA with 
application to clinical cancer sequencing. Genome Research, 2015. 25(9): p. 1372-1381. 
21. 
Robinson, D., et al., Integrative Clinical Genomics of Advanced Prostate Cancer. Cell, 
2015. 161(5): p. 1215-1228. 
22. 
Mehra, R., et al., Biallelic Alteration and Dysregulation of the Hippo Pathway in 
Mucinous Tubular and Spindle Cell Carcinoma of the Kidney. Cancer Discov, 2016. 
6(11): p. 1258-1266. 
23. 
Cieslik, M., et al., The use of exome capture RNA-seq for highly degraded RNA with 
application to clinical cancer sequencing. Genome Res, 2015. 25(9): p. 1372-81. 
24. 
Koboldt, D.C., et al., VarScan 2: somatic mutation and copy number alteration discovery 
in cancer by exome sequencing. Genome Res, 2012. 22(3): p. 568-76. 
25. 
Ye, K., et al., Pindel: a pattern growth approach to detect break points of large deletions 
and medium sized insertions from paired-end short reads. Bioinformatics, 2009. 25(21): 
p. 2865-71. 
26. 
Lonigro, R.J., et al., Detection of somatic copy number alterations in cancer using 
targeted exome capture sequencing. Neoplasia, 2011. 13(11): p. 1019-25. 
27. 
Dobin, A., et al., STAR: ultrafast universal RNA-seq aligner. Bioinformatics, 2013. 
29(1): p. 15-21. 
28. 
Liao, Y., G.K. Smyth, and W. Shi, The Subread aligner: fast, accurate and scalable read 
mapping by seed-and-vote. Nucleic Acids Res, 2013. 41(10): p. e108. 
29. 
Ritchie, M.E., et al., limma powers differential expression analyses for RNA-sequencing 
and microarray studies. Nucleic Acids Res, 2015. 43(7): p. e47. 
30. 
Smyth, G.K., Linear models and empirical bayes methods for assessing differential 
expression in microarray experiments. Stat Appl Genet Mol Biol, 2004. 3: p. Article3. 
31. 
Law, C.W., et al., voom: Precision weights unlock linear model analysis tools for RNA-
seq read counts. Genome Biol, 2014. 15(2): p. R29. 
32. 
Newman, A.M., et al., Robust enumeration of cell subsets from tissue expression profiles. 
Nat Methods, 2015. 12(5): p. 453-7. 
33. 
 Koyama, T. and H. Chen, Proper inference from Simon's two-stage designs. Stat Med, 
2008. 27(16): p. 3145-54. 
34. 
Eisenhauer, P., et al., New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1). European Journal of Cancer, 2009. 45 (2): p. 228-247. 
35. 
De Bono, J.S.e.a., KEYNOTE-199: Pembrolizumab (pembro) for docetaxel-refractory 
metastatic castration-resistant prostate cancer (mCRPC). . Journal of Clinical Oncology, 
2018. 36.  
 
 

 
Page 53 of 52 
17.0 
APPENDICES 
 
 
APPENDIX A 
 
 
 

 
Page 54 of 52 
APPENDIX B 
Brief Pain Inventory (Short Form)

 
Page 55 of 52 
 
 
 

 
Page 56 of 52 
APPENDIX C 
 
EORTC QLQ-C30 (version 3) 
 
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. 
The information that you provide will remain strictly confidential.  
 
Please fill in your initials:  
Your birthdate (Day, Month, Year):  
 
Today's date (Day, Month, Year):   
 
 
  
 
 
 
 
 
 
 
 
 Not at      A  
  Quite     Very  
  All  
  Little     a Bit     Much  
1. Do you have any trouble doing strenuous activities,  
    like carrying a heavy shopping bag or a suitcase?  
 
 
     1  
      2            3            4  
2. Do you have any trouble taking a long walk?   
 
 
     1            2            3            4  
3. Do you have any trouble taking a short walk outside of the house?  
     1            2            3            4  
4. Do you need to stay in bed or a chair during the day?   
 
     1            2            3            4  
5. Do you need help with eating, dressing, washing  
    yourself or using the toilet?   
 
 
 
 
     1  
      2         3          4 
 
 
 During the past week:  
   Not at      A     Quite    Very  
                 All        Little    a Bit   Much  
 
6. Were you limited in doing either your work or other daily activities?       1  
        2        3           4  
7. Were you limited in pursuing your hobbies or other leisure time 
     activities?   
 
 
 
 
       
 
      1           2         3           4  
8. Were you short of breath?  
 
 
 
 
 
      1           2         3           4  
9. Have you had pain?   
 
 
 
 
 
      1           2         3           4  
10. Did you need to rest?  
 
 
 
 
 
      1           2          3          4  
11. Have you had trouble sleeping?  
 
 
 
 
      1           2          3           4  
12. Have you felt weak?  
 
 
 
 
                   1           2          3           4  
13. Have you lacked appetite?   
 
 
 
 
      1           2          3           4  
14. Have you felt nauseated?  
 
 
 
 
 
      1           2          3           4  
15. Have you vomited?   
 
 
 
 
 
      1           2          3           4  
16. Have you been constipated?  
 
 
 
 
      1           2          3           4  
 
 

 
Page 57 of 52 
During the past week:  
  Not at       A        Quite   Very  
                  All        Little    a Bit  Much  
17. Have you had diarrhea?  
 
 
 
 
 
      1           2          3           4  
18. Were you tired?  
 
 
 
 
 
 
      1           2          3            4  
19. Did pain interfere with your daily activities?   
 
 
      1           2          3            4  
20. Have you had difficulty in concentrating on things,  
like reading a newspaper or watching television?  
 
 
      1           2          3           4  
21. Did you feel tense?   
 
 
 
 
 
      1           2          3           4  
22. Did you worry?  
 
 
 
 
 
 
      1           2          3           4  
23. Did you feel irritable?  
 
 
 
 
 
      1           2          3            4  
24. Did you feel depressed?  
 
 
 
 
 
      1           2          3           4  
25. Have you had difficulty remembering things?  
 
 
      1           2          3            4  
26. Has your physical condition or medical treatment  
interfered with your family life?  
 
 
 
 
      1           2          3           4  
27. Has your physical condition or medical treatment  
interfered with your social activities?  
 
 
 
 
      1           2          3            4  
28. Has your physical condition or medical treatment  
caused you financial difficulties?  
 
 
 
 
      1           2          3           4  
 
 
For the following questions please circle the number between 1 and 7 that best applies to 
you  
 
29. How would you rate your overall health during the past week?  
 
1  
2  
3  
4  
5  
6  
7  
Very poor  
 
 
 
 
 
Excellent  
 
 
30. How would you rate your overall quality of life during the past week?  
 
1  
2  
3  
4  
5  
6  
7  
Very poor  
 
 
 
 
 
Excellent