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UMCC 2018.050 Immunotherapy in Pa�ents with Metasta�c Cancers and CDK12 Muta�ons NCT03570619
protocol umcc 2018.050 [ca209-8jj] impact
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| 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 [ca209-8jj] impact
table of contents

ABBREVIATIONS  
| STUDY SYNOPSIS .                                                                                                                                              |                                                                                                                                                            |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1.0                                                                                                                                                           | BACKGROUND AND RATIONALE                                                                                                                                   |
| D Disease Background .......................................................................................................................................9 |                                                                                                                                                            |
| 1.1                                                                                                                                                           |                                                                                                                                                            |
| 1.2                                                                                                                                                           | Study Agent(s) Background and Associated Known Toxicities                                                                                                  |
| 1.3                                                                                                                                                           | RATIONALE                                                                                                                                                  |
| Exploratory Studies ..........................................................................................................................12              |                                                                                                                                                            |
| 1.4                                                                                                                                                           |                                                                                                                                                            |
| 2.0                                                                                                                                                           | STUDY OBJECTIVES/ENDPOINTS                                                                                                                                 |
| 2.1                                                                                                                                                           | Primary Objective ................................................................................................................................12       |
| 2.2                                                                                                                                                           | Secondary Objectives                                                                                                                                       |
| 2.3                                                                                                                                                           | Exploratory Objectives                                                                                                                                     |
| Primary Endpoint ....................................................................................................................................13       |                                                                                                                                                            |
| 2.4                                                                                                                                                           |                                                                                                                                                            |
| 2.5                                                                                                                                                           | Secondary Endpoints ....................................................................................................................................13 |
| PATIENT ELIGIBILITY.............................................................................................................................14            |                                                                                                                                                            |
| 3.0                                                                                                                                                           |                                                                                                                                                            |
| 3.1                                                                                                                                                           | Inclusion Criteria                                                                                                                                         |
| 3.2                                                                                                                                                           | Exclusion Criteria                                                                                                                                         |
| 4.0                                                                                                                                                           | SUBJECT SCREENING AND REGISTRATION PROCEDURES ..............................................16                                                             |
| TREATMENT PLAN..................................................................................................................................16            |                                                                                                                                                            |
| 5.0                                                                                                                                                           |                                                                                                                                                            |
| 5.1                                                                                                                                                           | Treatment Dosage and Administration ...........................................................................................16                          |
| 5.2                                                                                                                                                           | Toxicities and Dosing Delays/Dose Modifications                                                                                                            |
| Concomitant Medications/Treatments...........................................................................................26                               |                                                                                                                                                            |
| 5.3                                                                                                                                                           |                                                                                                                                                            |
| 5.4                                                                                                                                                           | D Duration of Therapy                                                                                                                                      |
| 5.5                                                                                                                                                           | Off Treatment Criteria .                                                                                                                                   |
| D Duration of Follow-Up                                                                                                                                       |                                                                                                                                                            |
| 5.6                                                                                                                                                           |                                                                                                                                                            |
| 5.7                                                                                                                                                           | Off Study Criteria .                                                                                                                                       |  
__
5.8 Patient Replacement  
| 6.0                                                                                                                                                  | STUDY PROCEDURES .                                                                                                                                       |
|------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|
| MEASUREMENT OF EFFECT                                                                                                                                |                                                                                                                                                          |
| 7.0                                                                                                                                                  |                                                                                                                                                          |
| 7.1                                                                                                                                                  | Antitumor Effect- Prostate Cancer                                                                                                                        |
| 7.2                                                                                                                                                  | Antitumor Effect- Non-Prostate Malignancies ............................................................................32                               |
| Guidelines for Evaluation of Measurable Disease .......................................................................35                            |                                                                                                                                                          |
| 7.3                                                                                                                                                  |                                                                                                                                                          |
| 7.4                                                                                                                                                  | Response Criteria ....................................................................................................................................36 |
| 7.5                                                                                                                                                  | Duration of Response - Non prostate malignancies .....................................................................38                                 |
| 7.6                                                                                                                                                  | Progression-Free Survival - Non prostate malignancies ............................................................38                                     |
| Safety/Tolerability ..............................................................................................................................38 |                                                                                                                                                          |
| 7.7                                                                                                                                                  | ADVERSE EVENTS ......................................................................................................................................38  |
| 8.0                                                                                                                                                  |                                                                                                                                                          |
| 8.1                                                                                                                                                  | Experimental Therapy ......................................................................................................................38            |
| 8.2                                                                                                                                                  | Adverse Event Reporting Requirements ........................................................................................39                          |
| DEFINITIONS                                                                                                                                          |                                                                                                                                                          |
| 8.3                                                                                                                                                  | Adverse Event Characteristics ......................................................................................................41                   |
| 8.4                                                                                                                                                  | Serious Adverse Event Reporting Guidelines ............................................................................41                                |
| 8.5                                                                                                                                                  |                                                                                                                                                          |
| 8.6                                                                                                                                                  | Routine Reporting...........................................................................................................................42           |
| 8.7                                                                                                                                                  | Reporting of Unanticipated Problems                                                                                                                      |
| Safety Report Reconciliation .......................................................................................................42               |                                                                                                                                                          |
| 8.8                                                                                                                                                  | DRUG INFORMATION .............................................................................................................................43         |
| 9.0                                                                                                                                                  |                                                                                                                                                          |
| 10.0   CORRELATIVES/SPECIAL STUDIES ..........................................................................................46                     |                                                                                                                                                          |
| 10.1 Sample Collection Guidelines                                                                                                                    |                                                                                                                                                          |
| 10.2 Specimen Banking                                                                                                                                |                                                                                                                                                          |
| 1.0   STATISTICAL CONSIDERATIONS                                                                                                                     |                                                                                                                                                          |
| 1.1 Study Design/Study Endpoints .....................................................................................................47             |                                                                                                                                                          |
| 1.2 Sample Size and Accrual .............................................................................................................47          |                                                                                                                                                          |  
| __                                                                                                                                                |
|---------------------------------------------------------------------------------------------------------------------------------------------------|
| 1.3   Data Analyses Plans .....................................................................................................................47 |
| 12.0   DATA AND SAFETY MONITORING ...........................................................................................48                   |
| 13.0   DATA MANAGEMENT                                                                                                                            |
| 14.0 QUALITY ASSURANCE AND AUDITS ........................................................................................49                      |
| 15.0 CLINICAL TRIAL MONITORING                                                                                                                    |
| 16.0   REFERENCES                                                                                                                                 |
| 17.0 APPENDICES                                                                                                                                   |
protocol umcc 2018.050 [ca209-8jj] impact
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        |  
| SPGT   | Serum Glutamic Pyruvic Transaminase   |
|--------|---------------------------------------|
| UaP    | Unanticipated Problem                 |
| WBC    | White Blood Cells                     |
| WXS    | Whole Genome Sequencing               |
protocol umcc 2018.050 [ca209-8jj] impact
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.
protocol umcc 2018.050 [ca209-8jj] impact
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  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. |
| Objectives and Endpoints | 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                                                                                                                                                                                            |  
| 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.  25 mCRPC each in Cohorts A and C; and15 of non-prostate in |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| Number of Subjects                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Cohort B, 65 total subjects  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.) |
| Key Inclusion Criteria                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | 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.                                                                                                                                                                                                                                                                                                      |  
| 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. 1. Prior treatment with anti-PD-1/PD-L1 and anti-CTLA4 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.                        |
|------------------------|
| Key Exclusion Criteria |  
| 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 therapyassociated 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.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
|                                                                    | 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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
| Study Product(s), Dose,  Route, Regimen  Duration of Administration | Up to a total of 104 weeks of study treatment and 24 months of  follow up in all Cohorts.  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 |
| Statistical Methodology                                             |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |  
| 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.   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
protocol umcc 2018.050 [ca209-8jj] impact
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].
protocol umcc 2018.050 [ca209-8jj] impact
cdk12

Figure 1 Tepley et al. Treatment strategies for DNA repair-deficient prostate cancer. Expert Rev Clin Pharmacol. 2017 Aug; 10(8):889-898.  
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, 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].
protocol umcc 2018.050 [ca209-8jj] impact
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).
protocol umcc 2018.050 [ca209-8jj] impact
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 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].
protocol umcc 2018.050 [ca209-8jj] impact
1.2 study agent(s) background and

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 wellestablished 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 wellestablished. 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.
protocol umcc 2018.050 [ca209-8jj] impact
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.  
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 singleagent 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.
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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.
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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.
protocol umcc 2018.050 [ca209-8jj] impact
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
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.
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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.
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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.
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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.  
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.
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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 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 | ≥ 1,000/mm3                                                                                                                  |
| (ANC)  Hemoglobin (Hgb)                 | ≥ 8 g/dL with or without pRBC transfusion                                                                                    |
| Platelets (Plt)                         | ≥ 100,000/mm3                                                                                                                |
| Renal Calculated or measured            | Serum creatinine <3.0 mg/dl or if elevated, a                                                                                |
| creatinine clearance                    | 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              | ≤ 2.5 × ULN                                                                                                                  |
| (AST) 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 therapyassociated pneumonitis, or other forms of pneumonitis, that has since resolved are allowed.  
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. 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.
protocol umcc 2018.050 [ca209-8jj] impact
5.0 treatment plan

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.
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4.0 subject screening and registration

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 deidentified 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.
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5.1 treatment dosage and administration

Protocol treatment must start within 14 business days of enrollment to the study.  
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.  
| Cycle                                                                                                                 |                                                 |                                                                                         |                                                                                                                                                                       |          |         |
|-----------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|-----------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------|---------|
| Agent                                                                                                                 | Precautions                                     | Dose                                                                                    | Route                                                                                                                                                                 | Schedule | 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 |
protocol umcc 2018.050 [ca209-8jj] impact
5.2 toxicities and dosing delays/dose

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. 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                                                                               | No change from original starting                                                 |
| dose                                                           | 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                                                                                | Permanently discontinue therapy                                                  |
| and remove subject from trial                                  | 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.
protocol umcc 2018.050 [ca209-8jj] impact
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                                  | Management                                                | Follow-up                |                                  |
|-------------------------------------------------------|-----------------------------------------------------------|--------------------------|----------------------------------|
| (NCI CTCAE v4)  Grade 1                               | -                                                         | Consider delay nivolumab |                                  |
| Radiographic changes only                             | 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 |                                                           |                          |                                  |  
| 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; Lifethreatening                                                                                                                                                                                                                                                                                                                                                       | -                                                            | 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 |                          |
protocol umcc 2018.050 [ca209-8jj] impact
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                                                                            | Management                                       | Follow-up                                                                                               |                                          |
|------------------------------------------------------------------------------------------------------|--------------------------------------------------|---------------------------------------------------------------------------------------------------------|------------------------------------------|
| (NCI CTCAE v4)  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 of diarrhea/colitis                                                                                                     | Management                                                                                                                                                                                   | Follow-up                                                                                                                                                                                                                                                               |
|-------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (NCI CTCAE v4)                                                                                                                |                                                                                                                                                                                              |                                                                                                                                                                                                                                                                         |
| Colitis: abdominal pain;                                                                                                      | -                                                                                                                                                                                            | 0.5-1.0mg/kg/day                                                                                                                                                                                                                                                        |
| blood in stool                                                                                                                | 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                     | -                                                                                                                                                                                            | 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 |
| Colitis (G3): severe  abdominal pain,  medical intervention  indicated,  peritoneal signs  G4: life-threatening,  perforation |                                                                                                                                                                                              |                                                                                                                                                                                                                                                                         |
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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 thyroidstimulating 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                                                                                          |                                                                                                                                                                                                                                                                                                                         |                                                           |
|                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                         |                                                           |
protocol umcc 2018.050 [ca209-8jj] impact
5.2.4.4 hepatic

Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue protocol therapy. Consider imaging for obstruction.  
| 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                                                                                                                                                                                                                                                                                                                                                                | -  | Continue | liver | function |
| ipilimumab                                                                                               | 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.               |                                                                |                                                                                                                                                                                                                                                                                                                                                                                      |    |          |       |          |
protocol umcc 2018.050 [ca209-8jj] impact
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                                                                                                                                                                           | -  | Continue to monitor the |
| ipilimumab                                                  | 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                            | Management                        | Follow-up                                                                                                                                                                                                                                                                                                                                                          |
|------------------------------------------|-----------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (NCI CTCAE v4)  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 |  
| 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 |  
*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
protocol umcc 2018.050 [ca209-8jj] impact
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 | 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                  | -                                                                                                           | Continue nivolumab /or  ipilimumab                                                                                                                                                                                                                                                       |
| -                                                                | Monitor serum creatinine  weekly                                                                            |                                                                                                                                                                                                                                                                                          |
| -                                                                | 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                                                                                                                                                        | 5.2.4.8 Myocarditis: Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue protocol therapy  
| therapy  Grade of Rash  Myocarditis  (NCI CTCAE v4)                                                                                                                                                                                                                                                                                                                                                                                                                                    | Management                                                                                                                                                                                                                                                                                                                                                   | Follow-up                                                               |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------|
| Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                              |                                                                         |
| Symptoms with mild to  moderate activity or  exertion                                                                                                                                                                                                                                                                                                                                                                                                                                  | - 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                                                                                                                                                                                                                                                                                                                                                                                           | -                                                                                                                                                                                                                                                                                                                                                            | 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  - 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 | -                                                                                                                                                                                                                                                                                                                                                            | 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                                                                                                                                                                                                                                                                                 |                                                                         |
| Grade 4:                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                              |                                                                         |
| Life threatening  consequences; urgent  intervention indicated  (e.g., continuous IV  therapy or mechanical  hemodynamic support)                                                                                                                                                                                                                                                                                                                                                      | Additionally, for Grade 4:  - Hospitalize/transfer to institution  with expertise in intensive  cardiac monitoring  - Consider ATG as second agent  given its immediate effect                                                                                                                                                                               |                                                                         |
protocol umcc 2018.050 [ca209-8jj] impact
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.
protocol umcc 2018.050 [ca209-8jj] impact
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.
protocol umcc 2018.050 [ca209-8jj] impact
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 -
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: 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.
protocol umcc 2018.050 [ca209-8jj] impact
6.0 study procedures 6.1 schedule

|                                         | 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                   | X                              | X      | X      | X      | X      | X       | X       |               |
| Medications  Review Adverse Events10    | X                              | X      | X      | X      | X      | X       | X       |               |
| Physical Examination, Vital             | X                              | X      | X      | X      | X      | X       | X       |               |
| Signs1, Weight  ECOG Performance Status | X                              | X      | X      | X      | X      | X       | X       |               |
| Survival Status                         | X Q3m                          |        |        |        |        |         |         |               |
| Laboratory Assessments                  |                                |        |        |        |        |         |         |               |
| Pregnancy Test for                      | X                              |        |        |        |        |         |         |               |
| WOBCP2 CBC with diff, platelets3        | X                              | X      | X      | X      | X      | X       | X       |               |
| Comprehensive Metabolic                 | X                              | X      | X      | X      | X      | X       | X       |               |
| Panel, including Alk Phos4              |                                |        |        |        |        |         |         |               |  
|                                                                                                                                                                                                                                                                                                                          | 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                                                                                                                                                                                                                                                                                                 | X                              | X      |        |        |        |         |         |               |
| Abdomen/Pelvis 5                                                                                                                                                                                                                                                                                                         | (q 12  wks)                    |        |        |        |        |         |         |               |
| Tc99m Bone Scan (prostate                                                                                                                                                                                                                                                                                                | X                              | X      |        |        |        |         |         |               |
| only)                                                                                                                                                                                                                                                                                                                    | (q 12  wks )                   |        |        |        |        |         |         |               |
| QoL: BPI-SF and EORTC                                                                                                                                                                                                                                                                                                    | X                              | X      |        |        |        |         |         |               |
| QLQ C30                                                                                                                                                                                                                                                                                                                  | (q 12  wks)                    |        |        |        |        |         |         |               |
| Correlatives                                                                                                                                                                                                                                                                                                             |                                |        |        |        |        |         |         |               |
| Tumor Tissue Archival                                                                                                                                                                                                                                                                                                    | X                              |        |        |        |        |         |         |               |
| (CRPC preferred if available)  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. |                                |        |        |        |        |         |         |               |  
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.
protocol umcc 2018.050 [ca209-8jj] impact
7.0 measurement of effect 7.1

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.
protocol umcc 2018.050 [ca209-8jj] impact
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.
protocol umcc 2018.050 [ca209-8jj] impact
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.  
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.
protocol umcc 2018.050 [ca209-8jj] impact
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.
protocol umcc 2018.050 [ca209-8jj] impact
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 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
protocol umcc 2018.050 [ca209-8jj] impact
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
protocol umcc 2018.050 [ca209-8jj] impact
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
protocol umcc 2018.050 [ca209-8jj] impact
7.2 antitumor effect- non-prostate malignancies

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 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.
protocol umcc 2018.050 [ca209-8jj] impact
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. 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 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').