Conditions: Metastatic Castration Resistant Prostate Cancer Metastatic Cancer Solid Tumor
Keywords: Metastatic Cancer Metastatic Castration Resistant Prostate Cancer mCRPC Immunotherapy CDK12 Solid Tumor
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 56
Healthy volunteers: no

Brief summary:
This study will attempt to determine the efficacy of checkpoint inhibitor immunotherapy with nivolumab and ipilimumab combination therapy followed by nivolumab monotherapy in patients with metastatic prostate cancer and other tumor solid tumor histologies harboring loss of CDK12 function as well as monotherapy nivolumab treatment in patient with metastatic prostate cancer harboring loss of CDK12 function.

Detailed description:
This study investigates the efficacy of checkpoint inhibitor immunotherapy in patients with metastatic cancer with CDK12 mutations. The study includes three cohorts: Cohort A consists of metastatic prostate cancer patients being treated with combination nivolumab and ipilimumab treatment followed by monotherapy nivolumab treatment. Cohort B consists of other solid tumor patients being treated with combination nivolumab and ipilimumab treatment followed by monotherapy nivolumab treatment. As of an amendment approved 03FEB2021 a third cohort was added, Cohort C, which consists of metastatic prostate cancer patients being treated with monotherapy nivolumab treatment.

As of an amendment approved 21JUN2020 the maximum duration of treatment, as well as the anticipated timing for some of the studies outcome measures, were updated from 52 weeks to 104 weeks.

Arms:
arm 1: Patients with metastatic castration resistant prostate cancer (mCRPC) will be enrolled in cohort A. arm 2: Patients with all other metastatic subtypes will be enrolled in cohort B arm 3: Patients with metastatic castration resistant prostate cancer (mCRPC) will be enrolled in cohort C once enrollment to cohort A has been completed.

Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab
Intervention descriptions: intervention 1: Patients in arms Metastatic CRPC and Experimental: Solid Tumors (non-prostate) 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.

Patients in arm Metastatic CRPC will receive therapy with monotherapy nivolumab therapy at flat dose 480 mg IV every 4 weeks for up to 104 weeks of total therapy. intervention 2: Patients in arms Metastatic CRPC and Experimental: Solid Tumors (non-prostate) 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.

Protocol document:
Prot_SAP_000.pdf: 
 
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  
 
 
 
 
 
 
 

ICF_001.pdf: 
 
UMCC 2018.050 
 
 
Immunotherapy in PaƟents with MetastaƟc Cancers and CDK12 MutaƟons 
 
 
NCT03570619 


Page 1 of 25
Consent Subtitle: UMCC 2018.050
UM Consent Version: 23Jul2021
Model Consent Version: 03Mar2021
UNIVERSITY OF MICHIGAN
CONSENT TO BE PART OF A RESEARCH STUDY
INFORMATION ABOUT THIS FORM
You may be eligible to take part in a research study.  This form gives you important information about the study.  
It describes the purpose of the study, and the risks and possible benefits of participating in the study.  
Please take time to review this information carefully.  After you have finished, you should talk to the researchers 
about the study and ask them any questions you have.  You may also wish to talk to others (for example, your 
friends, family, or other doctors) about your participation in this study.  If you decide to take part in the study, you 
will be asked to sign this form.  Before you sign this form, be sure you understand what the study is about, 
including the risks and possible benefits to you.
1.  GENERAL INFORMATION ABOUT THIS STUDY AND THE RESEARCHERS
1.1 Study title: IMPACT: Immunotherapy in Patients with Metastatic Cancers and CDK12 Mutation
1.2 Company or agency sponsoring the study: The University of Michigan 
Financial support for this study is provided by Bristol Myers Squibb (BMS)
1.3 Names, degrees, and affiliations of the researchers conducting the study:
Principal Investigator:  
Ajjai Alva, MD
Department of Internal Medicine, Hematology/Oncology, University of Michigan
2. PURPOSE OF THIS STUDY
2.1 Study purpose: 
Cancer is caused by changes (mutations) to genes that control the way our cells function; especially how they 
repair mistakes that crop up during regular growth and turnover.  Some of these mistakes cause cancer, some 
cause cancer to grow. The normal proof-reading system in the cells tries to fix the DNA mistakes. CDK12 is part of 
the proof-reading system that fixes DNA mistakes.  Cancer cells that carry a broken form of CDK12 cannot correct 
the DNA mistakes well. However, cancer cells that grow due to these mistakes could have a weakness. The 
mistakes in the DNA could mark those cells apart and make them sensitive to a type of treatment called immune 
therapy that is designed to activate the patient’s own immune system to go fight the cancer. Learning more about 
how genes work and how they affect cancer could also lead to improvements in treating cancer.
The purpose of this study is to test the effectiveness (how well the drug works), safety, and tolerability of the 
investigational drug nivolumab as well as the combination of nivolumab plus ipilimumab for metastatic prostate 
cancer and other cancer types that have a broken form (called mutations) of the CDK12 gene.  
Nivolumab and ipilimumab are two immunotherapy drugs that have been approved by the Food and Drug 
Administration (FDA) for the treatment of metastatic melanoma (a type of skin cancer) and kidney cancer.  
Nivolumab is also approved the treatment of previously treated advanced lung, head & neck, liver and kidney 
cancers. Nivolumab and the combination of nivolumab and ipilimumab has not yet been approved for the 
Study ID: HUM00148776   IRB: IRBMED   Date Approved: 4/7/2022   Expiration Date: 3/17/2023


Page 2 of 25
Consent Subtitle: UMCC 2018.050
UM Consent Version: 23Jul2021
Model Consent Version: 03Mar2021
treatment of prostate cancer or other cancers that have CDK12 mutations.  The test used to find out if your 
cancer has the CDK12 mutation has not been approved or cleared by the FDA. 
3. INFORMATION ABOUT STUDY PARTICIPANTS (SUBJECTS)
Taking part in this study is completely voluntary.  You do not have to participate if you don't want to.  You may 
also leave the study at any time.  If you leave the study before it is finished, there will be no penalty to you, and 
you will not lose any benefits to which you are otherwise entitled. 
3.1 Who can take part in this study?
Adult men or women who have metastatic adenocarcinoma of the prostate or other advanced metastatic 
carcinomas that have CDK12 mutations.
There are many other inclusion and exclusion criteria (a sort of checklist) which the doctors will use to determine 
if you can participate in this study.  It is important that you discuss your full medical history and all of your 
medications with your doctor.
3.2 How many people (subjects) are expected to take part in this study?
A total of approximately 65 subjects at several institutions will take part in this study, including approximately 15 
subjects from the University of Michigan.
4.  INFORMATION ABOUT STUDY PARTICIPATION
4.1 What will happen to me in this study?  
The study team will explain the research study and answer any questions you have about the study.  If you want 
to participate in the study, the study team will request you sign the consent form prior to any activities occurring 
that pertain to the study.  Once your consent is obtained, the study team will look through your medical chart, ask 
you questions, and begin scheduling tests and procedures to determine if you are eligible for the study.  The study 
team will inform you of the types of tests and procedures required before the study begins.  
Many of the procedures that will be performed during the study, including routine blood tests, disease 
evaluations, physical examinations, vital signs (blood pressure, heart rate, breathing rate, and temperature) and 
measurement of height and weight, would normally be done as part of your standard of care regardless of study 
participation.  However, some of these may be done more frequently as a result of your participation in this study. 
Tests and procedures that are done more often than your regular medical care because of your study 
participation and that are solely for research purposes will be identified below.  The study staff will inform you of 
the types of tests and procedures you have to undergo during the study.  
During the study you must:

Follow the instructions you are given.

Come to the study center for your visits with the study doctor.

Tell the study doctor or study staff about any changes in your health and/or medications you are taking.

Tell the study doctor or study staff if you want to stop being in the study at any time.
Before starting the study:  Some exams, tests, and procedures including cancer genomic testing, will be required 
to find out if you can be in this study.  If you have had some of the tests recently, they may not need to be 
repeated.  The screening tests and procedures do not have to be completed in one day and you are allowed to 
take breaks if you have multiple procedures in one day.
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The following tests and procedures will be performed during screening and/or at one or more study visits.  Refer 
to the study calendar below for information about which procedures will be performed at certain study visits.

Medical history: including any past treatments, surgeries, infection and autoimmune diseases.

Medications: It is important that you tell your doctor about all of the medications that you have been 
taking, including over the counter medicines, vitamins or herbal treatments.

Physical exam/Vital Signs: including measurement of your height (screening only), weight, blood 
pressure, heart rate, respiratory rate and temperature.

Performance status: Your ability to perform day to day activities and care for yourself 

Routine blood tests (approximately 2 teaspoons): will be drawn for tests to check blood counts, 
chemistry, thyroid health and blood markers for cancer 

Pregnancy test: (urine or blood – approximately 1 teaspoon): if you are a woman able to have children

Scans of your cancer: these could include Computed tomography (CT) of the chest, CT or magnetic 
resonance imaging (MRI) of the upper and lower belly or bone scan (prostate only).  
o
A CT scan uses special x-ray equipment to make detailed pictures of body tissues and organs.  For 
the CT scan, you may be given a “contrast material” (a special dye that makes it easier for doctors 
to see different tissues in your body).  You will be asked to lie still and may be asked to hold your 
breath for a few seconds.  The CT scan is done in the Radiology Department and takes about half 
an hour.
o
A MRI scan takes an image of your head or body to observe the location and size of your tumor.  
For the MRI scan, you may be given a “contrast material” (a special dye that makes it easier for 
doctors to see different tissues in your body).  You will be asked to lie down on a narrow bed 
which will slide into a tunnel that is 6 feet long by 22 inches across and is open at each end.  You 
will be asked to lie quietly for about one hour, during which time you will hear a loud machine-
like noise.  A MRI scan takes about an hour and a half to complete. 
o
Bone scan.  A bone scan is a procedure in which a very small amount of radioactive material is 
injected into a vein in your arm. The radioactive material is then transported by your blood into 
your bones. This will allow the doctor to monitor the cancer in your bones before, during, and 
after you receive the study treatment.

Toxicity evaluation: You will be asked about any side effects or illnesses you experience.

Tumor tissue: Your doctor will check to see if you have enough stored tissue sample of your tumor that 
was collected previously. If you do not have enough stored tissue, you will be asked to undergo a fresh 
tissue biopsy prior to starting treatment.  You may still participate in this study even if you do not have 
enough stored tissue or undergo a fresh tissue biopsy.  An optional tissue biopsy may be collected at end 
of treatment.  You can make your choice in Section 12 for the optional biopsies.  This tumor tissue is for 
research purposes.  
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
Blood for Research (approximately 3-5 tablespoons): Will be drawn for testing for biomarkers (testing of 
substances such as proteins that tell us how the drug is working in your body).  This is for research 
purposes.  

Questionnaire: You will be asked to complete a quality of life questionnaire asking about your symptoms 
and how your disease and symptoms make you feel.  You may find some of the questions uncomfortable 
to answer.  You do not have to answer any question you do not want to answer.  This is for research 
purposes.
Study Intervention (for Research):
If you qualify to participate in the study based on the results of the screening tests and procedures, you will return 
to the study doctor’s clinic.
If you have metastatic adenocarcinoma of the prostate, you may qualify for either Cohort A or C. If you have 
another advanced metastatic carcinoma that have CDK12 mutations, you may qualify for Cohort B.  
For this study, a treatment cycle is defined as 21 days if your study treatment regimen is with nivolumab and 
ipilimumab. If your study treatment is nivolumab only, then a cycle is defined as 28 days.
Cohorts A or B: You will receive the combination of nivolumab and ipilimumab given intravenously (through a vein 
in your arm or port) every three weeks for a maximum of 4 cycles as long as you are tolerating the intervention.  
Beginning with Cycle 5 you will receive nivolumab alone every 4 weeks for up to 92 weeks as long as you are 
tolerating the intervention and your disease hasn’t progressed. Total study therapy duration will last up to 104 
weeks as long as you are tolerating the intervention and disease hasn’t progressed.
Cohort C: You will receive nivolumab-only given intravenously (through a vein in your arm or port) every four 
weeks for a maximum of 26 cycles as long as you are tolerating the intervention. Total study therapy duration will 
last up to 104 weeks as long as you are tolerating the intervention and disease hasn’t progressed.
Follow-up:
If you stop the study intervention for any reason you will be asked to return for end of treatment visit 3-4 weeks 
after your last dose of study intervention.
After you complete the end of treatment you will have an office visit or be contacted by a member of the study 
team every 3 months for up to 2 years from when you stopped the study intervention. 
See the table for a summary of the study intervention and procedures.
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Study Procedures Table:
Procedures
Screening
Cycle 1
Day 1
Cycle 2
Day 1
Cycle 3
Day 1
Cycle 4
Day1
Day 1 of Cycle 5
and beyond
End of 
Treatment 
Visit
Follow 
Up
Medical history
X
Medication review 
X
X
X
X
X
X
X
Toxicity evaluations
X
X
X
X
X
X
X
X
Physical Exam/vital 
signs
X
X
X
X
X
X
X
Performance Status
X
X
X
X
X
X
X
Pregnancy Test 
X
Routine Blood Tests
X
X
X
X
X
X
X
X
Scans/Imaging of your 
cancer
X
X 
Every 12 weeks
Questionnaires
X
X
Every 12 weeks
Archive Tumor Tissue 
submission 
X
Fresh Biopsy
X (optional)
X (optional)
Research blood
X
X
X
X
Every 12 weeks
X
Survival Status
X 
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We will collect and store information about your genes. The DNA contained in your genes holds the instructions 
that your body uses to grow and function. Your genes are responsible for your physical features such as eye color, 
blood type, and how your body breaks down medications. Genes can also be responsible for some medical 
conditions.
Genomic information relates to the structure and function of all of the genetic material in the body.
We will submit your genomic information to a repository to be used for scientific purposes. A repository contains 
information from many people. Some repositories are maintained by the University of Michigan, some are 
maintained by the federal government, and some are maintained by private companies. 
Researchers all over the world can take information from the repository and use it in their studies. Their studies 
may be similar to this one or may be completely different.
Because this research receives funding from the National Institutes of Health (NIH), we will submit your genomic 
information to a public repository approved by NIH. NIH is a national research agency and is part of the federal 
government.
We will label your genomic information with a code, instead of your name or other information that people could 
use to directly identify you. Even so, there is a possibility that when your genomic information is combined with 
other information available to researchers, either now or in the future, they may be able to identify a group you 
belong to (like an ethnic group or a disease population) or, less likely, you personally. NIH prohibits people from 
trying to identify individuals whose genomic information is in an NIH-designated repository.
Researchers will have unrestricted access to your specific genomic information. Unrestricted access means that 
researchers may obtain genomic information from the repository without special approval from NIH.
If you allow us to put your genomic information in the repository, you can change your mind later and ask us to 
remove it. Keep in mind, however, that we cannot take back information that other researchers have already 
obtained from the repository.
OPTIONAL Research Samples Stored for Future Use:
We will keep some of your research blood and tumor tissue, as well as medical information (such as gender, race, 
and how your cancer responded to the study intervention, etc.) so that we may study them in future research. 
The future research may be similar to this study or may be completely different and may include genetic analysis 
on your tissue. Your samples would be kept at the University of Michigan. Samples will be stored indefinitely or 
until they are used up.  
By taking part in this study, you are giving us your permission to use your blood, tumor tissue and medical 
information for future research. Even if you give us permission now to keep some of your blood, tissue and 
medical information, you can change your mind later and ask us to destroy it. Keep in mind, however, that once 
we have analyzed your blood and tissue, we may not be able to take the information out of our research.
We may share your blood, tumor tissue and medical information with other researchers, so that they can use it in 
their research with the overall aim of helping future patients. No identifiable information that could be directly 
linked to you will be provided.  Their research may be similar to this study or may be completely different. Once 
we have shared your blood, tissue and medical information with other researchers, we will not be able to get it 
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back.  Future use of your identifiable data and/or specimens will be conducted in compliance with applicable 
regulatory requirements.
You will not find out the results of future research on your blood and tumor tissue samples. Allowing us to do 
future research on your blood, tissue and medical information will not benefit you directly.
Research can lead to new discoveries, such as new tests, drugs, or devices. Researchers, their organizations, and 
other entities, including companies, may potentially benefit from the future research on your blood, tumor tissue 
and medical information. You will not have rights to these discoveries or any proceeds from them
You will be asked to affirm in Section 12 of this consent form that you understand your participation in this 
Optional sub-study (storage of research samples for future use)
4.2 How much of my time will be needed to take part in this study?  
The initial screening visit will take approximately 2-5 hours.  Each study visit is expected to take approximately 4-6 
hours. 
4.3 When will my participation in the study be over? 
The maximum time you will be in the study is up to 104 weeks of study treatment and will depend on how your 
disease responds to the study intervention and how well you tolerate the study intervention. After you stop 
taking the study intervention you will be asked to come back for an end of treatment visit and then we will follow 
you either by phone or a clinic visit for up to 24 months. Your participation may end sooner if you decide to no 
longer participate, your study doctor feels it is in your best interest to stop your study participation, your disease 
progresses or the study is ended.  You can stop participating at any time.  However, if you decide to stop 
participating in the study, we encourage you to talk to the study doctor and your regular physician first.
4.4 What will happen with my information and/or biospecimens used in this study? 
Your biospecimens and collected information may be shared with Bristol Myers Squibb. 
With appropriate permissions, your biospecimens and collected information may also be shared with other 
researchers, here, around the world, and with companies. 
Your identifiable private information or identifiable biospecimens may be stripped of identifiers and used for 
future research studies or distributed to another researcher for future research studies without additional 
informed consent.
5.  INFORMATION ABOUT RISKS AND BENEFITS
5.1 What risks will I face by taking part in the study?  What will the researchers do to protect me against these 
risks?
The drugs used in the study may cause certain side effects and discomforts. You may have all, some, or none of 
the known side effects. There is also a risk that other rare or unknown side effects may occur. Your doctors and 
nurses will check you closely for side effects, and may give you medicines or other treatments to stop or reduce 
some of these effects. Some side effects may go away soon after the study medication is stopped, but in some 
cases, side effects may be serious, long lasting, and/or permanent. There is even a chance that a side effect may 
cause death. If you have any side effects, it is important that you report them to your study doctor or research 
staff.
We will minimize the risks by monitoring you carefully. We will provide the usual supportive care that would be
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routinely given to someone with your condition. If you have side effects from the study intervention,
we will make appropriate adjustments as defined by the study protocol. You may need to discontinue the
study intervention if the side effects are too serious.
The known or expected risks are:
Side Effects ASSOCIATED WITH NIVOLUMAB
Nivolumab may cause one or more of the side effects listed below.  This information is based on data from cancer 
subjects in other clinical trials with nivolumab.  In addition, there may be side effects that are not yet known that 
may occur.  You should tell your doctor or nurse right away about any possible side effects that you experience.
Very common side effects of nivolumab  are [> 1/10 or ≥ 10%]

Diarrhea

Feeling tired or lack of energy 

Skin itching

Skin rash
Common side effects of nivolumab include: [> 1/100 to <1/10 or ≥ 1% to < 10%] 

Abdominal pain

Alkaline phosphatase increased: lab test result associated with liver or bone abnormalities

Allergic reaction/ hypersensitivity 

ALT increased: lab test result associated with abnormal liver function

Amylase increased: lab test result associated with pancreas inflammation

AST increased: lab test result associated with abnormal liver function

Bilirubin increased (lab test results associated with abnormal liver function)

Chills

Constipation

Cough

Creatinine increased: lab test result associated with decreased kidney function

Decreased appetite

Dizziness or vertigo (feeling off balance which can lead to dizziness)

Dry mouth

Dry skin

Fever

Headache

Increased blood sugar 

Lipase increased: lab test result associated with pancreas inflammation

Inflammation of the colon

Inflammation of the mouth

Infusion related reaction

Loss of color (pigment) from areas of skin

Low levels of sodium in the blood

Low platelet counts (thrombocytopenia): this may increase your risk for skin bruising, nose bleeds, and 
bleeding from the gums

Low red blood cell counts (anemia): this may make you feel weak and tired
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
Lung inflammation (pneumonitis): It is possible that nivolumab may cause inflammation of the tissues of 
the lung.  This adverse effect has been reported in patients treated with nivolumab.  While many patients 
with x-ray or CT abnormalities have not developed any symptoms, some patients have developed mild to 
severe symptoms and in rare cases, death has occurred as a result of their lung inflammation.  Signs and 
symptoms of lung inflammation may include difficulty breathing, pain or discomfort while breathing, 
chest pain, cough, shortness of breath, increased rate of breathing, fever, low blood oxygen levels, or 
fatigue.  

Nausea

Pain in the muscles, bones, ligaments, tendons, and nerves

Reaction related to infusion of the medicine. The symptoms may include but not limited to fever, rash, 
pain, swelling 

Redness of the skin

Shortness of breath

Swelling, including face, arms, and legs (edema)

Thyroid gland function decreased or may be increased; increased thyroid stimulating hormone- a lab test 
result associated with abnormal thyroid function

Thyroid stimulating hormone increased: lab test result associated with abnormal thyroid function

Tingling, burning, numbness or weakness, possibly in arms, legs, hands and feet

Vomiting
Uncommon side effects of nivolumab include: [> 1/1,000 to < 1/100 or ≥ 0.1% to <1%]

Bronchitis: inflammation of the lining of bronchial tubes, which carry air to and from the lungs

Decreased secretion of hormones produced by adrenal glands

Decreased thyroid stimulating hormone - a lab test result associated with abnormal thyroid function

Dehydration

Diabetes: a disease that results in too much sugar in the blood 

Dry eye

Erythema multiforme: a skin disorder that is considered to be an allergic reaction to medicine or an 
infection. Symptoms may include symmetrical, red raised skins areas that can appear all over the body, 
more noticeable on the fingers and toes. These patches often look like “targets” (dark circles with purple-
grey centers)

Hair loss

Heart rate increased

Heart rhythm abnormal

High blood pressure

Hives

Inflammation of the eye

Inflammation of the kidney

Inflammation of the pancreas

Inflammation of the pituitary gland

Inflammation of the stomach

Inflammation of the thyroid gland

Joint pain and stiffness

Kidney function failure, kidney disease

Liver inflammation

Low blood pressure
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
Low white blood cell counts (neutropenia): these put you at higher risk for infection

Pemphigoid: blistering of the skin or mouth caused by the immune system attacking healthy tissue

Respiratory failure: a condition in which not enough oxygen passes from your lungs into your blood, or 
when your lungs cannot properly remove carbon dioxide

Skin disease with thickened patches of red skin, often silvery scales (Psoriasis)

Trouble falling and/or staying asleep (Insomnia)

Underactive function of the pituitary gland situated at the base of the brain

Upper respiratory tract infection: A common viral / bacterial infection that affects the nose, throat, and
airways

Vision blurred
Rare side effects of nivolumab include: [≥ 1/10,000 to < 1/1,000 or ≥ 0.01% to <.1%]

Autoimmune hemolytic anemia: a malfunction of the immune system that produces autoantibodies, 
which attack red blood cells as if they were foreign substances to the body

Cranial nerve disorder

Damage to the protective covering of the nerves in the brain and spinal cord

Diabetes complications resulting in excess blood acids and diabetic coma

Disease caused by the body’s immune system attaching healthy organs

Double vision

Drug induced liver injury

Guillain-Barre syndrome, an autoimmune disorder associated with progressive muscle weakness or 
paralysis

Histiocytic necrotizing lymphadenitis or Kikuchi lymphadenitis: disorder of the lymph nodes which causes 
the lymph nodes to become enlarged, inflamed and painful, commonly affecting lymph nodes of the neck 
and possibly associated with fever or muscle and joint pains

Inflammation of blood vessels

Inflammation of the brain, potentially life-threatening or fatal

Inflammation of the heart

Inflammation of the lining of the brain and spinal cord

Lung infiltrates, associated with infection of inflammation

Muscle inflammation

Myasthenic syndrome (neurologic syndrome characterized by muscle weakness) including myasthenia 
gravis, a nerve disease that may cause weakness of eye, face, breathing, and swallowing muscles.

Pericarditis: a swelling and irritation of the thin saclike membrane surrounding the heart (pericardium)

Polymyalgia rheumatica: an inflammatory disease that causes muscle pain and stiffness, especially in the 
shoulders

Rhabdomyolsis: muscle fiber released into the blood stream which could damage your kidneys

Rosacea: acne-like skin condition resulting in redness of face

Rupture of the intestines/hole in the intestine

Sarcoidosis, a disease involving abnormal collections of inflammatory cells (granulomas) in organs such as 
lungs, skin, and lymph nodes

Severe allergic reaction may include but not limited to high grade fever, rash, swelling and pain

Stevens Johnson syndrome: inflammatory disorder of skin and mucous membrane, resulting in blistering 
and shedding of skin
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
Toxic epidermal necrolysis: a potentially fatal disease characterized by blistering and peeling of the top 
layer of skin resembling a severe burn
The following events have been identified during post-approval use of nivolumab. Because reports are voluntary 
from a population of unknown size, an estimate of frequency cannot be made.
•
Graft-versus-host-disease: a condition that occurs when donor bone marrow or stem cells attack the 
recipient
•
Hemophagocytic lymphohistiocytosis (HLH) syndrome: a disease that may affect your body’s defense 
system, called immune system. Certain white blood cells may attack other blood cells. These abnormal 
blood cells collect in your spleen and liver, causing these organs to enlarge. The symptoms may include 
fever, rash, and low blood cell counts
•
Solid organ transplant rejection
•
Vogt Koyanagi Harada syndrome: a disease that affects the pigmented tissue; this may affect the eye 
leading to swelling, pain and/or blurred vision; the ear leading to hearing loss , ringing in the ears and /or 
the skin leading to loss of skin color
Additional information on pneumonitis: 
Your study doctor and nurse will watch you closely for changes in your ability to breathe and for other signs or 
symptoms that might show you are developing this type of lung inflammation and will perform regular tests 
including physical exams, measurement of oxygen levels through non-invasive testing (i.e., pulse oximeter), blood 
tests, chest x-rays and/or CT scans. Complications, including fatal events, have occurred in patients who received 
allogeneic hematopoietic stem cell transplantation (HSCT) after nivolumab.
 Please inform your study doctor or nurse AT ONCE if you experience any of the following:

Any new or increased shortness of breath;

Any new or increased chest pain;

Any new or increased pain/difficulty while breathing;

Any new or increased cough or any significant change in your type of cough; for example, any new or 
increased mucous or blood in your cough;  

Any change in the amount of oxygen you require;

Any fever, fatigue, or other symptoms that occur at the same time as any changes to your breathing or 
other lung symptoms. 
If you start to develop symptoms, your study doctor will ask you to return to the clinic for additional tests, which 
could include a physical exam, measurement of oxygen levels, blood tests, chest x-rays, and/or CT scans. You will 
be monitored very closely for changes in your overall lung symptoms, monitoring may require hospitalization. You 
may require specific treatment in order to control pneumonitis. You may also be seen by a special doctor called a 
pulmonologist, who has special training to be an expert in how your lungs work.
Prolonged treatment with medicines that suppress inflammation, sometimes needed to manage the side effects 
of nivolumab treatment, may lower your body’s ability to fight off certain infections (i.e., opportunistic infections). 
These infections may require treatment with antibiotic or antifungal medications and may be fatal.
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Additional information on transplant risks:
Complications, including fatal events, have occurred in patients who received allogeneic hematopoietic stem cell 
transplantation (HSCT) before or after nivolumab.
Complications, including rejection, have also been reported in patients who have received an organ or tissue 
transplant. Treatment with nivolumab may increase the risk of rejection of the organ or tissue transplant.
Side Effects ASSOCIATED WITH NIVOLUMAB combined with Ipilimumab
Very common side effects (≥ 1/10 or ≥10%) of nivolumab combined with ipilimumab are:

ALT increased: lab test result associated with abnormal liver function

AST increased: lab test result associated with abnormal liver function

Decreased appetite

Diarrhea

Feeling tired or lack of energy

Fever

Lipase increased: lab test results associated with pancreas inflammation

Nausea

Skin itching

Skin rash

Thyroid function decreased
Common side effects (≥ 1/100 to <1/10 or ≥1% to <10%) of nivolumab combined with ipilimumab include:

Abdominal pain

Alkaline phosphatase increased: lab test result associated with liver or bone abnormalities

Allergic reaction/hypersensitivity 

Amylase increased: lab test result associated with pancreas inflammation

Bilirubin increased: lab test result associated with abnormal liver function

Chills

Constipation

Cough

Creatinine increased: lab test result associated with decreased kidney function

Decreased secretion of hormones produced by adrenal glands 

Dehydration

Diabetes: a disease that results in too much sugar in the blood

Dizziness or vertigo (feeling off balance which can lead to dizziness)

Dry eye

Dry mouth

Dry skin

Hair loss

Headache

Heart rate increased

Increased blood sugar

Inflammation of the colon (may also include small intestine)

Inflammation of the eye
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
Inflammation of the mouth

Inflammation of the pancreas

Inflammation of the pituitary gland

Inflammation of the thyroid gland

Kidney function failure, kidney disease

Joint pain or stiffness

Liver inflammation

Loss of color (pigment) from areas of skin

Low blood pressure

Low levels of sodium in the blood

Low platelet counts (thrombocytopenia): this may increase your risk for skin bruising, nose bleeds, and 
bleeding from the gums

Low red blood cell counts (anemia): this may make you feel weak and tired

Lung inflammation (pneumonitis): it is possible that nivolumab may cause inflammation of the tissues of 
the lung. This adverse effect has been reported in patients treated with nivolumab. While many patients 
with X-ray or CT abnormalities have not developed any symptoms, some patients have developed mild to 
severe symptoms and in rare cases, death has occurred as a result of their lung inflammation. Signs and 
symptoms of lung inflammation may include difficulty breathing, pain or discomfort while breathing, 
chest pain, cough, shortness of breath, increased rate of breathing, fever, low blood oxygen levels, or 
fatigue

Pain in the muscles, bones, ligaments, tendons, and nerves

Reaction related to infusion of the medicine. The symptoms may include but not limited to fever, rash 
pain, swelling

Redness of the skin

Kidney failure or damage to your kidneys

Shortness of breath

Sodium levels in blood low

Swelling, including face, arms, and legs (edema) 

Thyroid gland function may be increased; increased or decreased thyroid stimulating hormone- a lab test 
result associated with abnormal thyroid function

Tingling, burning, numbness or weakness, possibly in arms, legs, hands and feet

Trouble falling and/or staying asleep (insomnia)

Vision blurred

Vomiting
Uncommon (> 1/1,000 to <1/100 or ≥0.1% to <1%) side effects of nivolumab combined with ipilimumab include:

Bronchitis: Inflammation of the lining of bronchial tubes, which carry air to and from the lungs

Cranial nerve disorder

Diabetes complications resulting in excess blood acids and diabetic coma

Disease caused by the body’s immune system attacking healthy organs

Double vision

Drug-induced liver injury

Erythema multiforme: a skin disorder that’s considered to be an allergic reaction to medicine or an 
infection. Symptoms may include symmetrical, red, raised skin areas that can appear all over the body, 
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more noticeable on the fingers and toes. These patches often look like “targets” (dark circles with purple-
grey centers)

Guillain-Barre syndrome, an autoimmune disorder associated with progressive muscle weakness or 
paralysis 

Heart rate increased

Heart rhythm abnormal

High blood pressure

Hives

Inflammation of the brain (potentially life threatening or fatal)

Inflammation of the heart

Inflammation of the kidney

Inflammation of the stomach

Low white blood cell counts (neutropenia): these put you at higher risk for infection

Lung infiltrates, associated with infection or inflammation

Muscle inflammation

Myasthenic syndrome (neurologic syndrome characterized by muscle weakness) including myasthenia 
gravis, a nerve disease that may cause weakness of eye, face, breathing, and swallowing muscles. 

Pemphigoid: blistering of the skin or mouth caused by the immune system attacking healthy tissue

Respiratory failure: a condition in which not enough oxygen passes from your lungs into your blood, or 
when your lungs cannot properly remove carbon dioxide

Rhabdomyolysis: muscle fiber released into the blood stream which could damage your kidneys

Sarcoidosis, a disease involving abnormal collections of inflammatory cells (granulomas) in organs such as 
lungs, skin, and lymph nodes

Psoriasis: characterized by thickened patches of red skin, often silvery scales

Underactive function of the pituitary gland situated at the base of the brain

Upper respiratory infection: a common viral / bacterial infection that affects the nose, throat, and airways
Rare side effects (≥ 1/10,000 to < 1/1,000 or ≥0.01% to <0.1%) side effects of nivolumab combined with 
ipilimumab include:

Autoimmune hemolytic anemia: a malfunction of the immune system that produces autoantibodies, 
which attack red blood cells as if they were foreign substances to the body

Diabetes complications resulting in diabetic coma

Inflammation of blood vessels

Inflammation of the lining of the brain and spinal cord

Pericarditis: a swelling and irritation of the thin saclike membrane surrounding the heart (pericardium)

Rosacea: acne-like skin condition resulting in redness of face

Polymyalgia rheumatica: an inflammatory disorder that causes muscle pain and stiffness, especially in the 
shoulders

Rupture of the intestine/hole in the intestine

Severe allergic reaction may include but not limited to hg

Stevens Johnson syndrome: inflammatory disorder of skin and mucous membranes, resulting in blistering 
and shedding of skin

Toxic epidermal necrolysis: a potentially fatal disease characterized by blistering and peeling of the top 
layer of skin resembling a severe burn
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The following events have been identified during post-approval use of nivolumab or nivolumab combined with 
ipilimumab. Because reports are voluntary from a population of unknown size, an estimate of frequency cannot 
be made.
•
Drug hypersensitivity syndrome: a severe, unexpected reaction to a medicine, which affects several organ 
systems at the same time
•
Graft-versus-host-disease: a condition that occurs when donor bone marrow or stem cells attack the 
recipient
•
Hemophagocytic lymphohistiocytosis (HLH) syndrome: a disease that may affect your body's defense 
system, called immune system. Certain white blood cells may attack other blood cells. These abnormal 
blood cells collect in your spleen and liver, causing these organs to enlarge. The symptoms may include 
fever, rash, and low blood cell counts
•
Solid organ transplant rejection
•
Vogt-Koyanagi-Harada (VKH) disease: a disease that may affect several parts of the body, including the 
eyes, ears, nervous system, and skin. The symptoms may include eye swelling, pain and/or blurred vision; 
hearing loss, ringing in the ears; and /or loss of skin color
Risks of CT Scan
The contrast substance injected during the CT scan may cause pain, burning feeling, sweating and rarely a serious 
allergic reaction that can be serious. If you know you’re allergic to iodine you must inform your doctor 
immediately. The contrast agent used in the CT scan may cause kidney damage, especially if you’re diabetic, 
dehydrated and if you’re older. In addition, your thyroid function may be affected. Please inform your doctor if 
this is the case.
CT imaging uses ionizing radiation, which increases your risk to develop cancer. Everyone is exposed to naturally 
occurring ionizing radiation every day. The amount of radiation exposure from 1 CT scan is approximately 
comparable to 1-3 years of natural background radiation. The estimated additional lifetime risk of developing a 
potentially fatal cancer from a standard CT scan is approximately 1 in 2,000.
Risks of MRI Scan
Contrast is used to improve the pictures of the inside of the body made by the MRI. Common risks of MRI include: 
feeling fearful of being in a small enclosed space (claustrophobia) when you are lying inside the MRI scanner, 
feeling uncomfortable because of the loud noises made by the machines, and feeling uncomfortable with the 
physical sensations you may feel during the process. You are also exposed to some risk because of the injected 
contrast, gadolinium-DTPA, which may cause headache, nausea, and local burning sensation.
The contrast agent, gadolinium has been linked to development of Nephrogenic Fibrosing Dermopathy (NFD) (also 
known as Nephrogenic Systemic Fibrosis (NSF) This causes a thickening of the skin, organs and other tissues, and 
is a rare complication in patients with kidney disease that undergo an MRI with contrast material. To help prevent 
this, we will check how well your kidneys work before you have any MRIs. Because of the use of contrast, all 
female subjects who are able to have children will be required to use adequate birth control. If you have 
implanted metal objects such as a pacemaker, artificial limbs, or metal joints, you will not be able to have an MRI 
done, and may not be able to take part in this research.
Bone Scan
During a bone scan, you will be injected with radioactive material which collects in your bones and then shows up 
on a special camera. This means that you will be exposed to a low level of radiation. The tracer contains about the 
same amount of radiation as an x-ray. The injection of radionuclide may cause some discomfort and bruising. 
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Blood tests
Blood samples will be taken from a vein in your arm during the study. The taking of a blood sample may cause 
some discomfort and bruising, and there is a potential for infection. Other risks, although rare, include dizziness 
and fainting.
Tumor Biopsy
Risks associated with biopsy should be discussed with your study doctor and may include pain, bleeding, spread of 
cancer and infection. It is also possible to have an allergy to the anesthesia used. 

Genetic material, including DNA and RNA, will be obtained from samples, stored in freezers, and used for 
profiling and analyzing your cancer. Specifically, the study includes DNA sequencing of your tumor and 
normal cells as a comparison. The goal is to identify key changes in the genes important to cancer cells 
that could potentially influence clinical decision making for your cancer. However, success or clinical 
benefits from the profiling of your cancer DNA is not guaranteed.

Some cells from your tumor may be grown and used to create cell lines that can be used as an ongoing 
source of genetic material or used for laboratory research. Additional analysis of the sequencing data will 
be used for research purposes, for example to discover new, unknown associations between genes and 
cancer. This type of research may affect the lives of future patients with cancer.

It is possible that a mutation found in the tumor DNA is also a mutation in your normal tissue (inheritable, 
or passed down in families). Your study doctor will discuss this result with you. If your test results show 
that you have gene mutations that are inherited, your doctor should recommend that you meet with a 
genetic counselor. This referral is considered standard care and is not part of this study. 

As with all medical screening tests, there is a chance of a false positive or a false negative result. A “false 
positive” refers to the identification of a genetic change that is not present. A “false negative” is the 
failure to find a genetic change that indeed exists. The tests have been designed to ensure that the 
possibility of incorrect results is low. 
Questionnaires
Filling out the questionnaires could lead you to feel uncomfortable or upset. Please tell the study doctor or study 
staff if you feel uncomfortable or upset while filling out a questionnaire. You have the right to refuse to answer 
any questions. 
Research samples/Loss of Confidentiality
Your samples will be coded, however, there is a risk of loss of confidentiality of your information. If your samples 
are provided to research collaborators the following information may be made available: your diagnosis and 
treatments, the time the samples were collected in relation to your study regimen, your disease status, and 
demographic data (for example gender, race, age, etc.).  Please ask the Study Doctor or Study Coordinator if you 
would like to know more about how your information will be protected.
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Pregnancy
Women
If you are a woman of child bearing potential, you must not have sexual intercourse or you must use reliable birth 
control throughout the study and for 5 months after the last dose of study drugs. The study doctor will discuss 
methods of birth control with you if needed.
If you are pregnant or become pregnant or are nursing a child during the study, there may be risks to your unborn 
baby or nursing child. Some drugs cause premature (early) birth or birth defects. Nobody knows what all of these 
risks are right now.
If you become pregnant or think you may be pregnant during the study, immediately stop using the study drugs 
and contact the study doctor’s office immediately. You must not breast-feed an infant during the study. Please 
also inform the study doctor if you become pregnant up to 5 months after the completion of the study drugs.
If there is ANY chance that you can get pregnant, you must either agree to not have vaginal intercourse or you 
must use TWO types of birth control (one from each list below) AT THE SAME TIME.
You must use two types of birth control at the same time for medical reasons all during study treatment (including 
during temporary breaks from treatment), and for at least 5 months after study treatment has stopped. You must 
talk to the doctor before changing any birth control methods you have already agreed to use.
Primary forms 
Secondary forms
• tubal sterilization (tubes tied) 
• male latex condom with or without spermicide
• partner’s vasectomy 
• diaphragm with spermicide
• intrauterine device 
• cervical cap with spermicide
• vaginal sponge (contains spermicide)
Any birth control method can fail. The reports of birth control failing are more frequent for female patients who 
use only a single form of birth control. Using two forms of birth control at the same time greatly reduces the 
chances of pregnancy.
Men
All men must use an acceptable form of birth control while taking part in the study and for 7 months after 
treatment has stopped because the effects on sperm are not known. Acceptable forms of birth control are male 
latex condom (with or without spermicide) or vasectomy. Also, men should not donate sperm or semen while 
taking part in the study because the effects on sperm are not known.
The study doctor must follow up and document the course and the outcome of all pregnancies, even if you 
withdraw from the study or if the study has finished. If you become pregnant during the study, the study doctor 
or his/her staff will ask to contact you and your pregnancy physician for information about the pregnancy until the 
child is born and may share this information with the sponsor.
Let your study doctor know of any questions you have about possible side effects. You can ask the study doctor 
questions about side effects at any time.
As with any research study, there may be additional risks that are unknown or unexpected.
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5.2 What happens if I get hurt, become sick, or have other problems as a result of this research?
The researchers have taken steps to minimize the risks of this study.  Even so, you may still have problems or side 
effects, even when the researchers are careful to avoid them. Please tell the researchers listed in Section 10 about 
any injuries, side effects, or other problems that you have during this study.  You should also tell your regular 
doctors.
5.3 If I take part in this study, can I also participate in other studies?
Being in more than one research study at the same time, or even at different times, may increase the risks to you.  
It may also affect the results of the studies.  You should not take part in more than one study without approval 
from the researchers involved in each study.  
5.4 How could I benefit if I take part in this study?  How could others benefit?  
You may or may not receive any personal benefits from being in this study.  However, others may benefit from 
the knowledge gained from this study.
5.5 Will the researchers tell me if they learn of new information that could change my willingness to stay in this 
study?
Yes, the researchers will tell you if they learn of important new information that may change your willingness to 
stay in this study. If new information is provided to you after you have joined the study, it is possible that you may 
be asked to sign a new consent form that includes the new information.
6.  OTHER OPTIONS
6.1 If I decide not to take part in this study, what other options do I have?
You do not have to be in this study to get treatment for your cancer.  Other possible options include:

Treatment with standard of care drugs such as: enzalutamide, abiraterone + prednisone, or 
chemotherapy such as docetaxel or cabazitaxel.

You could participate in other research trials, if one is available.

You could choose not to be treated for cancer but you may want to receive comfort care to relieve 
symptoms. 
You should talk to your study doctor and your regular physician about each of your options and their risks and 
benefits before you decide if you want to take part in this study.
7.  ENDING THE STUDY
7.1 If I want to stop participating in the study, what should I do?
You are free to leave the study at any time.  If you leave the study before it is finished, there will be no penalty to 
you. You will not lose any benefits to which you may otherwise be entitled.  If you choose to tell the researchers 
why you are leaving the study, your reasons for leaving may be kept as part of the study record. If you decide to 
leave the study before it is finished, please tell one of the persons listed in Section 10 “Contact Information” 
(below).
7.2 Could there be any harm to me if I decide to leave the study before it is finished? 
If you decide to leave the study early, please notify someone on the study team.  They will instruct you on how to 
stop the study safely and you will be advised whether any additional test may need to be done for your safety.
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7.3 Could the researchers take me out of the study even if I want to continue to participate?
Yes. There are many reasons why the researchers may need to end your participation in the study.  Some 
examples are:

The researcher believes that it is not in your best interest to stay in the study.

You become ineligible to participate.

Your condition changes and you need treatment that is not allowed while you are taking part in the study.

You do not follow instructions from the researchers.

The study is suspended or canceled.
8.  FINANCIAL INFORMATION
8.1 Who will pay for the costs of the study? Will I or my health plan be billed for any costs of the study?  
The study will pay for research-related items or services that are provided only because you are in the study.  If 
you are not sure what these are, see Section 4.1 above or ask the researchers for a list.  If you get a bill you think 
is wrong, call the researchers’ number listed in section 10.1.
Nivolumab and ipilimumab will be provided by BMS free of charge.
 You or your health plan will pay for all the things you would have paid for even if you were not in the study, like:

Health care given during the study as part of your regular care

Items or services needed to give you study drugs or devices (such as the cost of the infusion)

Monitoring for side effects or other problems

Deductibles or co-pays for these items or services

Treatment of complications
If you do not have a health plan, or if you think your health plan may not cover these costs during the study, 
please talk to the researchers listed in Section 10 below or call your health plan’s medical reviewer.
The study team has given you instructions about this research study. It is important that you follow these 
instructions carefully. If you get sick, have a medical complication, or are injured as a result of your being in the 
study, call Dr. Ajjai Alva, at (734) 936-0091 or (734) 936-4000 (24-hour paging). The doctor will either treat you or 
send you to another doctor for treatment. You or your insurance provider will be billed for all costs of treatment 
for sickness or injury caused by the study. It is possible that your insurance will not cover these costs.
By signing this form, you do not give up your legal rights to seek payment if you are harmed as a result of being in 
this study.
8.2 Will I be paid or given anything for taking part in this study?
You will not be paid to take part in this study.
8.3 Who could profit or financially benefit from the study results?
Information obtained from this study may help the supporter BMS and/or the University of Michigan learn more 
about the causes, risks, treatments, or how to prevent this and other health problems.  BMS, the University of 
Michigan, and/or physicians at the university could profit financially from this information. Dr. Alva and Dr. 
Vaishampayan serve as paid consultants to BMS.
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Research can lead to new discoveries, such as new tests, drugs, or devices. Researchers, their organizations, and 
other entities, including companies, may potentially benefit from the use of the data or discoveries. You will not 
have rights to these discoveries or any proceeds from them.  
9. CONFIDENTIALITY OF SUBJECT RECORDS AND AUTHORIZATION TO RELEASE YOUR PROTECTED HEALTH 
INFORMATION
The information below describes how your privacy and the confidentiality of your research records will be 
protected in this study.
9.1 How will the researchers protect my privacy?
The University of Michigan has rules to protect information about you. Federal and state laws also protect your 
privacy. Upon enrolling in this study, you will be assigned a unique identification number. All records related to 
the study will use this identification number instead of your name or other personally identifying information 
whenever possible. We will take measures to protect the privacy and security of all your personal information, but 
we cannot guarantee complete confidentiality of study data.
This research is covered by a Certificate of Confidentiality from the National Institutes of Health. The researchers 
with this Certificate may not disclose or use information, documents, or biospecimens that may identify you in 
any federal, state, or local civil, criminal, administrative, legislative, or other action, suit, or proceeding, or be used 
as evidence, for example, if there is a court subpoena, unless you have consented for this use. Information, 
documents, or biospecimens protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that requires disclosure (such as to 
report child abuse or communicable diseases but not for federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings, see below); if you have consented to the disclosure, including for your medical 
treatment; or if it is used for other scientific research, as allowed by federal regulations protecting research 
subjects. 
The Certificate cannot be used to refuse a request for information from personnel of the United States federal or 
state government agency sponsoring the project that is needed for auditing or program evaluation by the 
SPONSOR which is funding this project or for information that must be disclosed in order to meet the 
requirements of the federal Food and Drug Administration (FDA).  You should understand that a Certificate of 
Confidentiality does not prevent you from voluntarily releasing information about yourself or your involvement in 
this research. If you want your research information released to an insurer, medical care provider, or any other 
person not connected with the research, you must provide consent to allow the researchers to release it.
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, state, or local law 
of the following for example: reporting of child or elder abuse, some communicable diseases, and threats to harm 
yourself or others. 
The Certificate of Confidentiality will not be used to prevent disclosure for any purpose you have consented to in 
this informed consent document.
Medical information created by this research study may become part of your hospital medical record and may be 
forwarded to your primary doctor. Information that does not become part of your medical record will be stored in 
your study file.
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You have the right to request access to your protected health information that is used or shared during this 
research and that is related to your study treatment for your disease, but you may access this information only 
after the study is completed. To request this information, please contact the researchers listed in Section 10 
“Contact Information” (below).
Genetic Risks:
The federal Genetic Information Nondiscrimination Act (GINA) generally makes it illegal for health insurance 
companies, group health plans, and most employers to discriminate against you based on your genetic 
information.  This law does not protect you against genetic discrimination by companies that sell life insurance, 
disability insurance, or long-term care insurance.  Under this law:

Health insurance companies and group health plans may not request your genetic information that we 
obtain from this research

Health insurance companies and group health plans may not use your genetic information when making 
decisions regarding your eligibility or premiums

Employers with 15 or more employees may not use your genetic information that we obtain from this 
research when making a decision to hire, promote, or fire you or when setting the terms of your 
employment
GINA does not apply to the following groups; however, these groups have policies in place that provide similar 
protections against discrimination:

Members of the US Military receiving care through Tricare

Veterans receiving care through the Veteran’s Administration (VA)

The Indian Health Service

Federal employees receiving care through the Federal Employees Health Benefits Plans
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.
9.2 What information about me could be seen by the researchers or by other people?  Why?  Who might see it?
Signing this form gives the researchers your permission to obtain, use, and share information about you for this 
study, and is required in order for you to take part in the study.  Information about you may be obtained from any 
hospital, doctor, and other health care provider involved in your care, including:

Hospital/doctor's office records, including test results (X-rays, blood tests, urine tests, etc.)

Mental health care records (except psychotherapy notes not kept with your medical records)

Alcohol/substance abuse treatment records

HIV/AIDS status

Sexually transmitted disease or other communicable disease status

Health plan/health insurance records

All records relating to your condition, the treatment you have received, and your response to the 
treatment

Billing information

Demographic information

Personal information
There are many reasons why information about you may be used or seen by the researchers or others during or 
after this study.  Examples include:
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
The researchers may need the information to make sure you can take part in the study.  

The researchers may need the information to check your test results or look for side effects.  

University of Michigan, Food and Drug Administration (FDA), and/or other government officials, auditors 
and/or the IRB may need the information to make sure that the study is done in a safe and proper 
manner.   

BMS or safety monitors or committees, may need the information to: 
o
Make sure the study is done safely and properly
o
Learn more about side effects 
o
Analyze the results of the study 

Insurance companies or other organizations may need the information in order to pay your medical bills 
or other costs of your participation in the study.

The researchers may need to use the information to create a databank of information about your 
condition or its treatment.

Information about your study participation may be included in your regular University of Michigan 
medical record.

Federal or State law may require the study team to give information to government agencies. For 
example, to prevent harm to you or others, or for public health reasons. 
The results of this study could be published in an article, but would not include any information that would let 
others know who you are. 
9.3 What happens to information about me after the study is over or if I cancel my permission?
As a rule, the researchers will not continue to use or disclose information about you but will keep it secure until it 
is destroyed.  Sometimes, it may be necessary for information about you to continue to be used or disclosed, even 
after you have canceled your permission or the study is over.  
Examples of reasons for this include:

To avoid losing study results that have already included your information 

To provide limited information for research, education, or other activities (This information would not 
include your name, social security number, or anything else that could let others know who you are.) 

To help the University of Michigan and government officials make sure that the study was conducted 
properly
As long as your information is kept within the University of Michigan Health System, it is protected by the Health 
System’s privacy policies.  For more information about these policies, ask for a copy of the University of Michigan 
“Notice of Privacy Practices.”  This information is also available on the web at 
http://www.uofmhealth.org/patient+and+visitor+guide/hipaa.  Note that once your information has been shared 
with others as described under Section 9.2, it may no longer be protected by the privacy regulations of the federal 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
9.4 When does my permission expire?  
Your permission expires at the end of the study, unless you cancel it sooner. You may cancel your permission at 
any time by writing to the researchers listed in Section 10 "Contact Information" (below).  If you withdraw your 
permission, you may no longer be eligible to participate in this study.
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10. CONTACT INFORMATION
10.1 Who can I contact about this study?
Please contact the researchers listed below to:

Obtain more information about the study

Ask a question about the study procedures or treatments

Talk about study-related costs to you or your health plan 

Report an illness, injury, or other problem (you may also need to tell your regular doctors)

Leave the study before it is finished

Express a concern about the study
Principal Investigator: 
Ajjai Alva, MD
Mailing Address: 
University of Michigan 
1500 East Medical Center Drive, 7316CC
                                           Ann Arbor, MI  48109-5946
Telephone: 
734-936-0091
Emergency Contact:
734-936-4000 (Hospital Operator - 24-hour paging)
You may also express a concern about a study by contacting the Institutional Review Board listed below.
University of Michigan Medical School Institutional Review Board (IRBMED)
2800 Plymouth Road
Building 520, Room 3214
Ann Arbor, MI 48109-2800
Telephone: 734-763-4768  (For International Studies:  US Country Code:  001)  
Fax: 734-763-1234
e-mail: irbmed@umich.edu 
If you are concerned about a possible violation of your privacy or concerned about a study you may contact the 
University of Michigan Health System Compliance Help Line at 1-866-990-0111.
When you call or write about a concern, please provide as much information as possible, including the name of the 
researcher, the IRBMED number (at the top of this form), and details about the problem.  This will help University 
officials to look into your concern.  When reporting a concern, you do not have to give your name unless you want 
to.
11.  RECORD OF INFORMATION PROVIDED
11.1 What documents will be given to me?
Your signature in the next section means that you have received signed and dated copies of all of the following 
documents:

This "Consent to be Part of a Research Study" document.  (Note: In addition to the copy you receive, 
copies of this document will be stored in a separate confidential research file and may be entered into your 
regular University of Michigan medical record.)

Other (specify):
Study ID: HUM00148776   IRB: IRBMED   Date Approved: 4/7/2022   Expiration Date: 3/17/2023


Page 24 of 25
Consent Subtitle: UMCC 2018.050
UM Consent Version: 23Jul2021
Model Consent Version: 03Mar2021
12.  SIGNATURES
Consent/Assent to Participate in the Research Study
I understand the information printed on this form.  I have discussed this study, its risks and potential benefits, 
and my other choices with_________________________________________.  My questions so far have been 
answered.  I understand that if I have more questions or concerns about the study or my participation as a 
research subject, I may contact one of the people listed in Section 10 (above).  I understand that I will receive a 
copy of this form at the time I sign it and later upon request.  I understand that if my ability to consent or 
assent for myself changes, either I or my legal representative may be asked to re-consent prior to my 
continued participation in this study.
Print Legal Name: ________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Consent/Assent for Participating in Optional Biopsies
This study involves optional biopsies.  I understand that it is my choice whether or not to take part in these 
optional biopsies.  I understand that if my ability to consent or assent for myself changes, either I or my legal 
representative may be asked to re-consent prior to my continued participation in this study.
Screening biopsy
_____ Yes, I agree to take part in the optional screening biopsy.
_____ No, I do not agree to take part in the optional screening biopsy.
End of treatment biopsy
_____ Yes, I agree to take part in the optional end of treatment biopsy.
_____ No, I do not agree to take part in the optional end of treatment biopsy.
Print Legal Name: ________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Study ID: HUM00148776   IRB: IRBMED   Date Approved: 4/7/2022   Expiration Date: 3/17/2023


Page 25 of 25
Consent Subtitle: UMCC 2018.050
UM Consent Version: 23Jul2021
Model Consent Version: 03Mar2021
Consent/Assent to Collect and Store OPTIONAL Research Samples for Unspecified Future Research 
This project involves the option to allow the study team to keep your identifiable specimens/data for use in 
future research.  I understand that it is my choice whether or not to take part in this optional research.  I 
understand that if my ability to consent or assent for myself changes, either I or my legal representative may 
be asked to re-consent prior to my continued participation in this study.
_____ Yes, I agree to let the study team keep and store my blood and tissue samples for future research.
_____ No, I do not agree to let the study team keep and store my blood and tissue for future research.
Print Legal Name: ________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Principal Investigator or Designee
I have provided this participant and/or his/her legally authorized representative(s) with information about this 
study that I believe to be accurate and complete.  The participant and/or his/her legally authorized 
representative(s) indicated that he or she understands the nature of the study, including risks and benefits of 
participating.
Printed Legal Name: ________________________________________________________________________
Title: ______________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Study ID: HUM00148776   IRB: IRBMED   Date Approved: 4/7/2022   Expiration Date: 3/17/2023


UMCC 2018.050
PERSONAL CENSUS FORM
Name _______________________________________________
Date ____________________
The National Cancer Institute requires that The University of Michigan Comprehensive Cancer Center 
report race and ethnicity information about people who participate in clinical research to ensure that all 
populations are offered the opportunity to participate. 
 Check here if you do not wish to provide some or all of the information below.
1. What race do you consider yourself to be?

American Indian/Alaska Nativea
(Please select one or more)

Asianb

Black or African Americanc

Native Hawaiian or Other
Pacific Islanderd

Whitee

More than one racef
2. Do you consider yourself to be Hispanicg?
 Yes
 No
________________________________________________________________________
a American Indian or Alaska Native- A person having origins in any of the original peoples of North, Central, or South America, 
and who maintains tribal affiliation or community attachment.
b Asian- A person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent, 
including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand and 
Vietnam.
c Black or African American- A person having origins in any of the black racial groups of Africa.  (Terms such as “Haitian” or 
“Negro” are sometimes used in addition to “Black” or “African American.”)
d Native Hawaiian or Other Pacific Islander- A person having origins in any of the original peoples of Hawaii, Guam, Samoa, or 
other Pacific Islands.
e White- A person having origins in any of the original peoples of Europe, the Middle East, or North Africa.
f More than one race- (It is preferred that this be selected in addition to the selection of the specific races listed above, but 
this may also be solely selected.)
g Hispanic or Latino- A person of Mexican, Puerto Rican, Cuban, Central or South American, or other Spanish culture or origin, 
regardless of race.  The term “Spanish origin” is sometimes used in addition to “Hispanic” or “Latino.”
Study ID: HUM00148776   IRB: IRBMED   Date Approved: 4/7/2022   Expiration Date: 3/17/2023