Conditions: Advanced Solid Tumor IDH1 Mutation Glioma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
In this study, response to treatment and (progression free and overall) survival will be described and safety events of ivosidenib in combination with nivolumab will be summarized in patients with advanced solid tumors (nonresectable or metastatic) or enhancing gliomas.

Detailed description:
This study will describe the safety, response rate, progression free and overall survival, and summarize safety events of ivosidenib in combination with nivolumab in participants with advanced solid tumors (nonresectable or metastatic) or enhancing gliomas. Participants are required to have a histologically consistent diagnosis of IDH1 gene mutated tumor that is not eligible for curative therapy. Enrolled subjects will receive orally administered ivosidenib dosed daily on 28-day cycles and nivolumab will be infused every 28 days. Participants will be assessed at every visit for adverse events starting from the first dose of study treatment. Assessment (CT or MRI) for evaluation of disease response will be conducted every 8 weeks (±7 days) from the first day of treatment cycle 1 and/or at any time when progression of disease is suspected. A Post-Treatment Follow-Up Visit for safety will occur 28 (+/- 5) days after the last dose of study drug.

Arms:
arm 1: Ivosidenib will be administered concurrently with nivolumab on a Q28 day schedule.

Interventions: intervention 1: ivosidenib and nivolumab
Intervention descriptions: intervention 1: Ivosidenib will be administered orally at a dose of 500 mg (provided as 250 mg strength tablets) daily. The dose may be reduced to 250 mg for patients experiencing more than one event of Grade 2 nausea or vomiting (related or unrelated), or Grade 3 or Grade 4 adverse events. Nivolumab will be administered at 480 mg IV every 28 days.

Protocol document:
Prot_SAP_000.pdf: 
1 
 
Title: Phase II study of IDHl inhibitor ivosidenib and nivolumab in IDHl mutant gliomas and advanced 
solid tumors 
 
 
Corresponding Organization: 
 
Protocol Number: 
IND Number: 
NCT Number: 
Version Date: 
Sponsor-Investigator: 
 
 
 
 
 
 
 
 
 
 
Study Statistician: 
UPMC Hillman Cancer Center 
 
HCC 19-096 / CA209-8U3 
145432 
NCT04056910 
February 01, 2023 
Jason J. Luke, MD, FACP 
Director of the Cancer lmmunotherapeutic Center 
Associate Professor of Medicine 
UPMC Hillman Cancer Center 
5150 Centre Ave., Room 564 
Pittsburgh PA 15232 
Telephone: (412) 647-2811 
Fax: (412) 623-7948 
lukejj@upmc.edu 
 
Daniel Normolle, PhD 
UPMC Hillman Cancer Center Biostatistics Shared Resource Facility 
Sterling Plaza Suite 325 
201 N. Craig St. 
Pittsburgh, PA 15213 
Telephone: (412) 383-1591 
dpn7@pitt.edu 


2 
 
Table of Contents 
i. Abbreviations .................................................................................................................................................................. 7 
ii. Protocol Summary ...................................................................................................................................................... 10 
1.0 Introduction and Study Rationale ......................................................................................................................... 13 
1.1 The T-Cell lnflamedMicroenvironment ................................................................................................................... 13 
1.2 Study Rationale ..................................................................................................................................................... 14 
1.2.1 Rationale for Primary Endpoint .................................................................................................................... 16 
1.3 Cellular Metabolism and Cancer ......................................................................................................................... 17 
1.3.1 Role of lsocitrate Dehydrogenase ................................................................................................................ 17 
1.3.2 Tumorigenesis Hypothesis............................................................................................................................ 18 
1.3.3 IDH Mutations in Gliomas and Solid Tumors .............................................................................................. 18 
1.3.4 Biomarker Research ..................................................................................................................................... 19 
1.4 lvosidenib .............................................................................................................................................................. 19 
1.4.1 Overview ........................................................................................................................................................ 19 
1.4.2 Summary of Nonclinical Information ............................................................................................................ 19 
1.4.3 Summary of Clinical Data ............................................................................................................................. 22 
1.5 Identified Risks of lvosidenib................................................................................................................................ 25 
1.6 Nivolumab (BM-936558) ...................................................................................................................................... 25 
1.6.1 Nivolumab Storage ....................................................................................................................................... 26 
2.0 Trial Objectives and Endpoints ................................................................................................................................ 26 
2.1 Objectives .............................................................................................................................................................. 26 
2.1.1 Primary Objective .......................................................................................................................................... 26 
2.1.2 Secondary Objectives .................................................................................................................................... 26 
2.1.3 Exploratory Objective .................................................................................................................................... 26 
2.2 Study Endpoints .................................................................................................................................................... 27 
2.2.1 Primary Endpoints ......................................................................................................................................... 27 
2.2.2 Secondary Endpoints .................................................................................................................................... 27 
2.2.3 Exploratory Endpoints .................................................................................................................................. 27 
3.0 lnvestigational Plan .................................................................................................................................................. 27 
3.1 Overall Study Design ............................................................................................................................................ 27 
3.2 Rationale for Dose Selected ................................................................................................................................ 29 
3.2.1 lvosidenib ....................................................................................................................................................... 29 
3.2.2 Nivolumab ...................................................................................................................................................... 30 


3 
 
3.3 Criteria for Study Termination ............................................................................................................................. 31 
4.0 Study Population ...................................................................................................................................................... 31 
4.1 Inclusion Criteria .................................................................................................................................................. 31 
4.2 Exclusion Criteria .................................................................................................................................................. 33 
4.3 Subject Recruitment and Registration................................................................................................................. 34 
4.3.1 Registration Procedures .............................................................................................................................. 35 
4.4 Subject Withdrawal Criteria ................................................................................................................................ 35 
4.4.1 Withdrawal from Study Treatment ............................................................................................................. 35 
4.4.2 Study Participation Termination .................................................................................................................. 36 
5.0 Study Treatment ........................................................................................................................................................ 36 
5.1 Description of Study Treatment .......................................................................................................................... 36 
5.2 Study Treatment Packaging and Labeling .......................................................................................................... 36 
5.3 Study Treatment Storage ..................................................................................................................................... 36 
5.4 Study Treatment Preparation and Administration of lvosidenib ....................................................................... 37 
5.5 Criteria for Dose Modification, Discontinuation of Study Treatment, and Continuation Beyond 
Radiographic Progression .................................................................................................................................. 37 
5.5.1 Study Treatment Dose Modification and Discontinuation Criteria ........................................................... 37 
5.5.2 Continuation of Treatment beyond Radiographic Progression ................................................................ 38 
5.6 Guidelines for Management of QT Prolongation................................................................................................ 39 
5.7 Treatment of Study Drug-related Infusion Reactions ........................................................................................ 41 
5.8 Nivolumab AEs .................................................................................................................................................... 43 
5.9 Management of Nivolumab AEs ......................................................................................................................... 45 
5.10 Duration of Subject Participation ...................................................................................................................... 47 
5.10.1 Treatment Duration ................................................................................................................................... 47 
5.11 Treatment Compliance ...................................................................................................................................... 47 
5.12 Study Treatment Accountability ........................................................................................................................ 47 
5.13 Prior and Concomitant Medications and Treatments ...................................................................................... 48 
5.13.1 Prior Medications and Procedures ........................................................................................................... 48 
5.13.2 Concomitant Therapy Requiring Careful Monitoring ................................................................................ 48 
5.13.3 Prohibited Concomitant Therapy .............................................................................................................. 48 
5.13.4 Allowed Concomitant Medications, Procedures, and Treatments.......................................................... 48 
6.0 Study Processes and Assessments .......................................................................................................................... 49 
6.1 Schedule of Events ............................................................................................................................................... 49 


4 
 
6.2 Informed Consent ................................................................................................................................................ 57 
6.3 Gene Mutation Analysis and MolecularCharacterization .................................................................................. 58 
6.4 Safety Assessments ............................................................................................................................................. 58 
6.4.1 Physical Examination and ECOG Performance Status ................................................................................ 58 
6.4.2 Vital Signs and ECG ...................................................................................................................................... 58 
6.4.3 Safety Laboratory Assessments ................................................................................................................... 58 
6.5 Efficacy Assessments ........................................................................................................................................... 59 
6.5.1 Response to Treatment ................................................................................................................................. 59 
6.6 Correlative Studies ............................................................................................................................................... 59 
6.6.1 Nanostring Assays of Paired Samples ......................................................................................................... 59 
7.0 Safety and AEs Assessing, Recording, and Reporting ............................................................................................. 60 
7.1 Definition of AEs .................................................................................................................................................. 61 
7.1.1 AEs ................................................................................................................................................................ 61 
7.1.2 Progression of Underlying Malignancy ........................................................................................................ 61 
7.1.3 Hospitalization or Prolonged Hospitalization ............................................................................................... 62 
7.1.4 Persistent or Recurrent AEs ........................................................................................................................ 62 
7.1.5 Related AEs .................................................................................................................................................. 62 
7.1.6 Serious AEs (SAEs) ....................................................................................................................................... 63 
7.2 Procedures for Reporting AEs and SAEs ............................................................................................................ 64 
7.2.1 Routine AE Reporting .................................................................................................................................... 64 
7.2.2 SAE Reporting ................................................................................................................................................ 64 
7.2.3 Diagnosis versus Signs and Symptoms ........................................................................................................ 65 
7.2.4 AEs Occurring Secondary to Other Events .................................................................................................. 65 
7.2.5 Overdose or Incorrect Administration ......................................................................................................... 67 
7.2.6 Review of Safety Information: Sponsor Responsibilities ............................................................................ 67 
7.2.7 IND Safety Reports ........................................................................................................................................ 67 
7.2.8 Submission of IND safety reports ................................................................................................................. 68 
7.2.9 Follow-up ....................................................................................................................................................... 69 
7.2.10 Disclaimer .................................................................................................................................................... 69 
7.2.11 Reporting adverse events to the responsible IRB .................................................................................... 69 
7.3 Pregnancy Reporting ............................................................................................................................................ 70 
7.3.1 Specific BMS Pregnancy Reporting .............................................................................................................. 71 
7.4 Follow-up of Participants after AEs ................................................................................................................... 71 


5 
 
7.4.1 Investigator  Follow-Up ................................................................................................................................. 71 
7.4.2 Post-study Adverse Events .......................................................................................................................... 71 
7.5 Definition of DLT ................................................................................................................................................. 72 
8.0 Statistical Analysis Plan and Sample Size Justification ............................................................................................. 73 
8.1 Evaluability ............................................................................................................................................................ 73 
8.1.1 Evaluability for Safety .................................................................................................................................. 73 
8.1.2 Evaluability for Efficacy ................................................................................................................................ 73 
8.2 Statistical Analysis Plan ....................................................................................................................................... 73 
8.2.1 Primary Objective: Efficacy .......................................................................................................................... 73 
8.2.2 Secondary Objective: Safety ....................................................................................................................... 74 
8.2.3 Secondary Objective: Longitudinal Clinical Outcomes ............................................................................... 75 
8.2.4 Exploratory Objective: Biomarkers and Response to Treatment. .............................................................. 75 
8.2.5 Stopping Rule for Excess Toxicity .................................................................. Error! Bookmark not defined. 
8.3 Justification of Design .......................................................................................................................................... 75 
9.0 Study Management, Agreement, and Ethical Considerations ............................................................................... 76 
9.1 IRB Approval and Consent ................................................................................................................................... 76 
9.2 FDA Approval ........................................................................................................................................................ 76 
9.3 Required Documentation ...................................................................................................................................... 76 
9.4 Data and Safety Monitoring Plan ........................................................................................................................ 77 
9.5 Amendments to the Protocol .............................................................................................................................. 78 
9.6 Annual IRB Renewals, Continuing Review, and Final Reports ............................................................................ 78 
9.7 Record Retention .................................................................................................................................................. 78 
9.8 Obligations of Study Site Investigators ................................................................................................................ 79 
10.0 References .............................................................................................................................................................. 79 
11.0 Appendix ................................................................................................................................................................. 85 
11.1 Eastern Cooperative Oncology Group Performance StatusScoring ................................................................ 85 
11.2 Prohibited Concomitant Medications ................................................................................................................ 85 
11.3 New York Heart Association Classification ........................................................................................................ 86 
11.4 Fridericia's Formula ............................................................................................................................................ 86 
11.5 Medications Known to Prolong the QT Interval ................................................................................................. 86 
11.6 Representative Examples of Low-Fat and High-Fat, High-Calorie Meals ......................................................... 86 
11.7 National Cancer Institute Common Terminology Criteria for AdverseEvents................................................. 87 
11.8 RECIST vl.1 ......................................................................................................................................................... 87 


6 
 
11.9 RANO Criteria ............................................................................................................................................... 90 
11.10 Patient Pill Diary ........................................................................................................................................ 92 


7 
 
i. Abbreviations 
 
Abbreviation 
Definition 
2-HG 
2-Hydroxyglutarate 
5-FU 
5-Flurouracil 
a-KG 
Alpha-ketoglutarate 
AE 
Adverse event 
AIDS 
Acquired immunodeficiency syndrome 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AML 
Acute myelogenous leukemia 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC0-12h 
Area under the concentration x time curve from Oto 12 h 
BCRP 
Breast cancer resistance protein 
BID 
Twice daily 
BUN 
Blood urea nitrogen 
CxDx 
Cycle X, Day X 
Cl 
Confidence interval 
CIMP 
Cytosine-guanine dinucleotide island methylator phenotype 
 
Cmax 
Maximum concentration 
CpG 
Cytosine-guanine dinucleotide 
CO2 
Carbon dioxide 
CR 
Complete response 
CRA 
Clinical Research Associate 
CSR 
Clinical study report 
CT 
Computed tomography 
ctDNA 
Circulating tumor DNA 
CYP 
Cytochrome P450 
DDI 
Drug-drug interaction 
DLT 
Dose-limiting toxicity 
DME 
Drug-metabolizing enzyme 


8 
 
Abbreviation 
Definition 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EQT 
End of treatment 
GBM 
Glioblastoma multiforme 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GLP 
Good Laboratory Practice 
HBV,HCV 
Hepatitis (B/C) virus 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IDH, IDHl, IDH2 
lsocitrate dehydrogenase protein, 1, 2 
IP 
lnvestigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
LVEF 
Left ventricular ejection fraction 
MRI 
Magnetic resonance imaging 
mSV 
Millisievert 
MTD 
Maximum tolerated dose 
NCICTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PAS 
Pharmacokinetic analysis set 
PD 
Pharmacodynamic 
PFS 
Progression-free survival 


9 
 
Abbreviation 
Definition 
PFS6 
Progression-free survival at six months 
P-gp 
P-glycoprotein 
Pl 
Principal Investigator 
PK 
Pharmacokinetic 
PPS 
Per protocol set 
PR 
Partial response 
PS 
Performance status 
QD 
Once daily 
QTcB, QTcF 
Heart-rate corrected QT interval (using Bazett's /Fridericia's formula) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Safety Analysis Set 
SD 
Stable disease 
 
Elimination half-life 
TEAE 
Treatment-emergent adverse event 
TIS 
Tumor inflamed signature 
TTR 
Time to response 
ULN 
Upper limit of normal 


10
 
ii. Protocol Summary 
 
 
Title 
 
Phase II study of IDHl inhibitor ivosidenib and nivolumab in IDHl mutant 
gliomas and advanced solid tumors 
 
Short Title 
 
Phase II of ivosidenib (AG-120) with nivolumab in IDHl mutant tumors 
 
Protocol Number 
 
HCC 19-096 / CA209-8U3 
 
Phase 
 
Phase II 
 
 
 
Methodology 
 
lnterventional trial comparing response and progression-free survival to 
historical data 
 
Treatment groups: advanced solid tumor and select gliomas harboring an 
IDHl mutation 
 
Estimated Enrollment 
Period 
12 months 
 
Estimated Study 
Duration 
 
 
36 months 
 
 
Study Centers 
 
The UPMC Hillman Cancer Center and Memorial Sloan-Kettering Cancer 
Center 
 
Primary Objective 
• 
To describe the clinical response and six month progression-free 
survival of patients treated with ivosidenib in combination with 
nivolumab 
 
 
Secondary Objectives 
• 
To determine the safety of ivosidenib in combination with nivolumab 
• 
To summarize longitudinal clinical outcomes of patients treated with 
ivosidenib in combination with nivolumab 
 
Exploratory Objective 
• 
To evaluate biomaterial-based biomarkers and determine their 
association with treatment response 


11
 
 
 
 
 
 
Primary Endpoints 
• 
Response 
■ 
Advanced Solid Tumors: Best overall response by 
RECIST 1.1 as detailed in (Section 11.8) 8 weeks after 
the initiation of treatment 
■ 
Glioma: Best overall Response by Response 
Assessment in Neuro-Oncology (RANO), Criteria as 
detailed in  (Section 11.9) 8 weeks after the initiation 
of treatment 
• 
Six Month Progression-Free Survival (PFSG) 
■ 
All tumor types: Survival to six months aftter the 
initiation of treatment without objective tumor 
progression 
 
 
 
 
Secondary Endpoints 
• 
The occurrence of dose-limiting toxicity (DLT), as defined in Section 
7.5, in patients receiving ivosidenib plus nivolumab. 
• 
Adverse Events and Serious Adverse Events related to study 
treatment (per CTCAE vS.0) 
• 
Progression-free Survival (PFS) - Survival after the initiation of treatment 
without objective tumor progression up until 18 months after the last 
participant has initiated treatment 
 
 
Exploratory Endpoints
 
• 
Biomarker Studies - quantitative measures of response biomarkers by 
Nanostring assay (or other  available technologies at the time of 
analysis) 


12
 
 
Number of 
Participants 
 
Eighteen in the first stage and seventeen in the second stage, for a maximum 
of 35 patients 
 
lnvestigational 
Product 
 
lvosidenib, Nivolumab, route of administration: intravenous (IV) and oral 
(po), respectively 
Estimated average 
treatment duration 
per patient 
 
6 months 
Duration of 
Participation 
 
Up to 2 years 
 
Reference therapies 
 
lvosidenib or Nivolumab 
 
 
 
Statistical 
Methodology 
 
An optimal Simon two-stage design is employed, where the primary endpoint 
is a composite of response (RANO for glioma patients or RECIST for solid 
tumor patients) and PFS6. Dose-limiting toxicity (DLT) is monitored 
throughout the trial using a Bayesian beta-binomial model. In secondary 
objectives, adverse events, response over time and progression-free survival 
are assessed. In exploratory objectives, the relationship between baseline 
biomarkers and response are described. 
 
 
Safety Evaluations 
 
Physical examination and ECOG performance status, vital signs, safety 
laboratory assessments (Hematology, chemistry, thyroid studies, pregnancy 
test (all women of child-bearing potential [WOCBP]) must have a negative 
pregnancy test to be eligible. Pregnancy testing to be done every 4 ± 1 
weeks while on study treatment), AEs. 
 
 
 
 
Data and Safety 
Monitoring Plan 
 
Investigator/sub-investigators, regulatory, CRS management, clinical 
research coordinators, clinical research associates, data managers, and clinic 
staff meet regularly in disease center Data Safety Monitoring Boards (DSMB) 
to review and discuss study data to include, but not limited to, serious 
adverse events, participant safety issues, recruitment issues, accrual, 
protocol deviations, unanticipated problems, breaches of confidentiality 
 
Minutes of the disease center DSMB meetings are available to those who 
are unable to attend in person. A formal, sequential decision rule based 
on dose-limiting toxicity will be evaluated after every five participants 
have completed Cycle 1. 


13
 
1.0 Introduction and Study Rationale 
1.1 The T-Cell lnflamedMicroenvironment 
The T cell-inflamed tumor microenvironment has been described as a potential predictive biomarker for 
response to multiple immunotherapies including therapeutic vaccines, anti-cytotoxic T-lymphocyte- 
associated protein (CTLA}-4, and anti-programmed cell death protein 1 (PD-1}/PD-1 ligand 1 (PD-Ll} 
antibodies (Harlin, Meng et al. 2009, Gajewski, Louahed et al. 2010, Ji, Chasalow et al. 2012, Topalian, 
Hodi et al. 2012, Gajewski, Woo et al. 2013, Spranger, Spaapen et al. 2013). Analysis of the tumor 
microenvironment in patients with melanoma suggests that approximately 35-50% of cases show 
evidence of spontaneous priming of anti-tumor T cells, leading to migration of CD8+ effector T cells into 
tumor sites. This phenotype has been designated the T 
cell-inflamed tumor microenvironment and is 
characterized by expression of T cell markers, chemokines 
for T cell recruitment, and transcripts indicative of type I 
interferon (IFN) signaling (Harlin, Meng et al. 2009, 
Gajewski, Louahed et al. 2010, Gajewski, Woo et al. 2013} 
(Figure 1}. 
This phenotype may be most robustly predicted using 
gene expression profiling, which in addition to response 
prediction, may also potentially be useful in identifying 
those that will not respond. Patients harboring non- 
inflamed tumors may require treatment strategies which 
modulate the immune response to facilitate the influx of tumor infiltrating lymphocytes (TIL} and 
conversion from a non-inflamed to an inflamed tumor. 
We have recently expanded this analysis of the T cell-inflamed tumor microenvironment to all tumor 
types via analysis of The Cancer Genome Atlas (TCGA) identifying subsets of inflamed and non-inflamed 
tumors across all histologies (Spranger, Luke et al. 2016) (Figure 2). 
 
 
 
Additionally, our group was the first to identify tumor-intrinsic oncogene signaling pathways mediating 
immune exclusion and resistance to cancer immunotherapy. In a disease-specific fashion, we have 
identified WNT/ -catenin signaling (Spranger, Bao et al. 2015} and phosphatase and tensin homolog 
(PTEN) loss in melanoma as well as fibroblast growth factor receptor 3 (FGFR3} activation in urothelial 
bladder cancer (Sweis, Spranger et al. 2016). To more broadly assess the impact of oncogene signaling 


14
 
1 
pathways on immune exclusion, we recently separated all solid tumors of TCGA into T cell-inflamed and 
2 
non-T cell-inflamed and looked for somatic alterations associated with the non-T cell-inflamed 
3 
phenotype. Utilizing a cut off of at least a 10-sample difference for mutations between non-T cell- 
4 
inflamed and T cell-inflamed, we identified isocitrate dehydrogenase 1 (IDHl) as having the most 
5 
powerful association with non-inflamed tumors (while IDH2 also showed a less powerful association, 
6 
Figure 3). 
7 
8 
9 
These IDHl alterations were present across tumor histologies with the vast majority being identified as 
10 
R132H and minority of R132C (Figure 4). While glioma was the most highly represented tumor type 
11 
others included breast cancer, cholangiocarcinoma, melanoma and other tumor types described 
12 
previously to harbor IDHl alterations. This suggests that IDHl alterations may have a pan-cancer effect 
13 
in driving immune exclusion. 
14 
15 
1.2 Study Rationale 
16 
While PDl-blocking immunotherapy has rapidly changed the landscape of cancer treatment, most 
17 
patients do not benefit from this therapy. This is particularly evident for certain cancers that generally 
18 
display the non-T cell-inflamed tumor microenvironment: gliomas, breast cancers and gastrointestinal 
19 
cancers such as cholangiocarcinomas, among others. Our data suggest that aberrant IDH activity may 
20 
play a role in in limiting the efficacy of immunotherapy and data from other groups appear to 
21 
collaborate this finding. A previous study (Kohanbash, Carrera et al. 2017) described a role for mutant 
22 
IDH in mediating immune exclusion in human glioma samples and recapitulated this effect in an IDH 


15
 
mutant syngeneic mouse model. Mutations in IDH confer gain-of-function activity by converting a- 
ketoglutarate to the oncometabolite R-2-hydroxyglutarate, which coordinates epigenetic changes that 
promote malignant transformation (Dang, White et al. 2009). 
Gene expression profiling of gliomas revealed reduced expression of T cell-associated genes and IFN-y- 
inducible cytokines in the IDH-mutated gliomas compared to gliomas with wild-type IDH. Mice 
possessing gliomas with mutated IDH recapitulated the immunophenotype of human IDH-mutated 
gliomas and demonstrated poor CD8 T cell infiltration. R-2-hydroxyglutarate limited intra-tumoral 
production of chemokines CXCL9 and CXCLl0, resulting in decreased T cell recruitment into IDH- 
mutated gliomas (Kohanbash, Carrera et al. 2017). 
Finally, a selective inhibitor that blocks the ability of mutated IDH-1 to produce the oncometabolite R-2- 
hydroxyglutarate restored chemokine expression, promoted T cell infiltration, and increased the efficacy 
of therapeutic peptide vaccination against gliomas (Figure S) (Dang, White et al. 2009). 
 
Thus, inhibitors of mutant IDH are potential therapeutic candidates to reverse immune evasion in 
gliomas and potentially other tumor types. Collectively, these data indicate that it might be possible to 
therapeutically target mutant IDH1 within a non-inflamed tumor to re-engage anti-tumor immune 
defenses and potentially drive combinatorial benefit with anti-PD1 immunotherapy. 
lvosidenib is a novel, first-in-class compound targeted selectively to inhibit the mutated IDH1 enzyme. 
Small molecule inhibition of the mutant IDH enzyme represents a novel, targeted approach to cancer 
treatment. Direct inhibition of the gain-of-function activity of the IDH1 mutated protein is intended to 
inhibit the production of the oncogenic metabolite 2-HG. lvosidenib has been extensively evaluated in 
nonclinical studies and has been shown in vitro and in vivo to effectively inhibit the gain-of-function 
activity of the mutated protein leading to> 95% inhibition of the production of the potential 
oncometabolite 2-HG. In clinical studies, up to 98% inhibition of plasma 2-HG has been observed in 
participants with solid tumors after QD dosing of ivosidenib. 
Here, we propose a Phase II study of the IDH1 inhibitor ivosidenib and nivolumab in IDH1 mutant 
gliomas and advanced solid tumors to assess toxicity and assess the preliminary activity of this 
combination regimen. We hypothesize that safe doses will be observed for ivosidenib with nivolumab 


16
 
and that a higher overall response rate and improved progression free survival relative to historical 
controls will be seen. Within this study we will integrate detailed immune monitoring, genomic profiling 
of the tumor, and systemic immune response. This study will lay the groundwork for potential 
subsequent randomized studies and has the potential to improve outcomes for a high-need patient 
population through expanding the utility of cancer immunotherapy. 
1.2.1 Rationale for Primary Endpoint 
The primary objectives are detailed in section 2. 
In addition to safety, we propose the two co-primary endpoints of Response Evaluation Criteria in Solid 
Tumors (RECIST) or RANO Criteria for gliomas and six month progression-free survival (PFS). First, we 
propose response as an endpoint based on the low historical response rates seen in the proposed tumor 
histologies. The benefits of anti- PDl therapy, despite their advances across multiple cancers, have not 
appreciably advanced the field for many advanced solid tumors- including those enriched with IDHl 
mutations. In prior analyses of such tumor types, poor response rates correlated with a failure to 
improve overall survival (OS). For example, in the Phase Ill Checkmate 143 study of nivolumab in 
glioblastoma (GBM), the noted response rate of 8% failed to show a survival benefit (Filley, Henriquez et 
al. 2017). Additionally, in breast cancer, the ORR was< 5% in those treated with avelumab anti-PDLl 
therapy (Dirix, Takacs et al. 2018). Within GI malignancies, trials assessing outcomes of 
cholangiocarcinoma and anti-PDl combinations are accruing; however, outcomes for other mismatch- 
repair proficient GI malignancies have been poor and expectations are guarded - the ORR was 0% in 
mismatch-repair proficient colorectal cancer when treated with pembrolizumab (Le, Uram et al. 2015). 
We additionally propose the co-primary endpoint of six-month PFS. This is based on the concern that 
response alone may not adequately capture the clinical benefit the study treatments within certain 
tumor histologies. It has been recognized in the treatment of soft tissue sarcomas that tumors 
responding to therapy may be replaced with fibrotic tissue that can confound RECIST measurements 
(Verweij 2008). Additionally, in the Phase 1 study of ivosidenib in chondrosarcoma, a majority of 
patients achieved stable disease as their best overall response. This suggests a possible cytostatic effect 
of ivosidenib (Tap, et al. 2016) where RECIST response may not reflect the therapeutic effect of the 
study treatments. Given the heterogeneity of the tumor histologies involved, it is difficult to know if 
ivosidenib would have similar cytostatic effect across all tumor types - especially when combined with 
nivolumab. PFS has the potential to capture the benefit of the study treatments across these tumor 
types since the most commonly IDHl mutant tumors included have a PFS of< 4 months. This is based 
the following historical controls: 
• 
Cholangiocarcinoma: A median PFS of 3.2 months (Brieau, Dahan et al. 2015) 
 
• 
Advanced Chondrosarcoma: A median PFS of 3.5 months (Italiano, Le Cesne et al. 2013) 
 
• 
Enhancing glioma: median duration on ivosidenib or AG-881 treatment of 1.9-3 months 
(Mellinghoff, Gregory Cote et al. 2016, Mellinghoff, Penas-Prado et al. 2018) 
This study has selected diverse, aggressive tumor histologies unified by their low anticipated PFS. With 
this in mind, we see that the proposed a doubling of expected PFS to 6 months with combination 
ivosidenib and nivolumab to be a meaningful measure of the efficacy of these drugs. 


17
 
1.3 Cellular Metabolism and Cancer 
1.3.1 Role of lsocitrate Dehydrogenase 
The IDH proteins are critical metabolic enzymes that exist as three isoforms: IDHl, IDH2, and IDH3 
(Figure 1), which all catalyze the oxidative decarboxylation of isocitrate to produce carbon dioxide (CO2) 
and alpha-ketoglutarate (a-KG). IDHl and IDH2 produce adenine dinucleotide phosphate (NADPH) 
whereas IDH3 only produces NADH. 
Cancer-associated mutations have been identified in IDHl and IDH2; however, to date, no mutations 
have been described in IDH3 (Yen, Bittinger et al. 2010). One fundamental difference between IDHl and 
IDH2 is the subcellular localization of the two proteins. IDHl is localized in both peroxisomes and cytosol 
(Geisbrecht and Gould 1999, Yoshihara, Hamamoto et al. 2001). IDH2 is a mitochondrial isoform of IDH 
(Yoshihara, Hamamoto et al. 2001, Wang, Travins et al. 2013). 
The genes encoding IDHl and IDH2 are located on chromosome 2q33.3 and 15q26.1, respectively. 
Mutations in these IDH proteins most commonly lead to alterations affecting arginine-132 (R132H or 
R132C) in IDHl, and the analogous arginine residue (arginine-172 mutated to lysine [R172K]) or arginine- 
140 (R140Q) in IDH2. 
Figure 6: 
Citric Acid Cycle 
 


18
 
1.3.2 Tumorigenesis Hypothesis 
Mutant IDH1 and IDH2 are not catalytically inactive enzymes, but rather possess novel enzymatic 
activities, consistent with a gain-of-function, reconciling the heterozygous nature of the point mutations 
(Dang, White et al. 2009). The mutated proteins themselves have a gain-of-function, neomorphic 
activity, catalyzing the reduction of a-KG to 2-hydroxyglutarate (2-HG) (Dang, White et al. 2009). The 
Sponsor's studies established that purified mutant protein efficiently catalyzes the proposed reduction 
of a-KG to 2-HG, while being unable to synthesize isocitrate (Dang, White et al. 2009). Mutations in IDH1 
and IDH2 are almost always mutually exclusive and occur at very early stages of tumor development 
suggesting that they promote formation and progression of tumors (Welch, Ley et al. 2012). 
Evidence supports that cancer-associated IDH mutations block normal cellular differentiation and 
promote tumorigenesis via the abnormal production of 2-HG, a potential oncometabolite. High levels of 
2-HG have been shown to inhibit a-KG-dependent dioxygenases including histone and 
deoxyribonucleotide demethylases, which play a key role in regulating the epigenetic state of cells 
(Chowdhury, Yeah et al. 2011, Xu, Yang et al. 2011, Koivunen, Lee et al. 2012). Consistent with 2-HG 
promoting tumorigenesis via an effect on chromatin structure, patients with IDH mutations display a 
cytosine-guanine dinucleotide (CpG) island methylator phenotype (CIMP) and several studies have 
shown that overexpression of IDH mutant enzymes can induce histone and deoxyribonucleic acid (DNA) 
hypermethylation as well as impair normal cellular differentiation (Figueroa, Abdel-Wahab et al. 2010, 
Lu, Ward et al. 2012, Turcan, Rohle et al. 2012). 
Clinical studies of several tumor types including glioma and acute myelogenous leukemia (AML) have 
found elevated levels of 2-HG in cells with mutant IDH1 and IDH2 compared to cells with wild-type 
alleles (Gross, Cairns et al. 2010, Ward, Patel et al. 2010). In normal cells, 2-HG is present in low levels. 
However, IDH1/IDH2 mutations in cancer cells result in the excess accumulation of 2-HG to extremely 
high levels, which can alter a number of downstream cellular activities. The elevated levels of 2-HG also 
are present in the sera and urine of some affected patients. Efforts are underway in the ongoing Phase 1 
study (AG120-C-002) to explore the association of plasma and tissue 2-HG with underlying tumor burden 
and tumor response in cholangiocarcinoma, enhancing glioma and other solid tumors. 
1.3.3 IDH Mutations in Gliomas and Solid Tumors 
IDH1 mutations continue to be identified in a variety of solid tumor subtypes, including gliomas, 
chondrosarcomas, and intrahepatic cholangiocarcinomas. Mutations in IDH1 have been found in 
approximately 70% of Grade 2 to 3 gliomas (Yan, Parsons et al. 2009), 50% of chondrosarcomas (Amary, 
Bacsi et al. 2011), and 20% of intrahepatic cholangiocarcinomas (Borger, Tanabe et al. 2012) and a 
smaller percentage of extra-hepatic cholangiocarcinomas (Kipp, Voss et al. 2012). 
IDH1 mutations are found in a high percentage of low-grade (Grade 2/3) oligodendrogliomas and 
astrocytomas as well as secondary glioblastomas. IDH2 mutations occur less frequently. IDHl mutations 
occur early in gliomagenesis and are oncogenic, although the exact mechanism for this is unclear. In 
addition, IDH mutations lead to increased methylation in gliomas. Gliomas with IDH1 and IDH2 
mutations also have a better prognosis than gliomas with IDH WT (Cohen, Holmen et al. 2013). 
IDH1 mutations are relevant therapeutic targets in cholangiocarcinoma as they may play a role in the 
pathogenesis of the disease by blocking the differentiation of liver progenitor cells and promoting 
cellular proliferation (Saha, Parachoniak et al. 2014). The majority of available data suggest IDH1 


19
 
mutations are not associated with prognosis in cholangiocarcinoma unlike IDHl mutations in glioma, 
which are associated with improved outcomes (Goyal, Govindan et al. 2015). 
1.3.4 Biomarker Research 
As described in Section 2.1, the T cell-inflamed phenotype is a potential predictive biomarker for 
response to immunotherapies. In addition to response prediction, this gene signature is also potentially 
useful in identifying those that will not respond. Patients harboring non-T cell-inflamed tumors 
therefore require treatment strategies which may modulate the immune response to facilitate the influx 
of tumor infiltrating lymphocytes (TIL) with the intent to convert from a non-T cell-inflamed to a T cell- 
inflamed tumor. Beyond the tumor microenvironment, aspects of the host (patient) may also have an 
essential impact on immunity in response to immunotherapy. Host factors of interest regarding the 
immune response include circulating immune subsets in the peripheral blood. 
Further, evolving research in the presence circulating tumor DNA (ctDNA) have shown this to be a 
potentially predictive biomarker for patients undergoing anti-PDl therapy (Lee, Long et al. 2017). Given 
that all patients included in this study harbor a known IDHl mutation, this allows for circulating IDHl 
mutated ctDNA to be followed before and during therapy. As has been seen in melanoma patients 
followed for known mutations, changes in ctDNA on therapy can predict tumor response and PFS. 
Considering this background, we propose to collect peripheral blood for plasma, peripheral blood 
mononuclear cells, ctDNA and serum levels of 2-HG. Additionally, for at least the first 10 solid tumor 
patients we propose an analysis of baseline tumor tissue, and an additional tissue analysis at week 5 of 
therapy to assess changes in tumor microenvironment. 
 
Additionally, it is requested that any patients who undergo tumor biopsy as part of their standard care 
during the study have any available tissue forwarded for analysis in comparison of pre-administration 
and on-/post-treatment tumor microenvironmental factors. 
 
1.4 lvosidenib 
1.4.1 Overview 
lvosidenib is a potent and selective inhibitor of the IDHl mutant protein with no significant off-target 
activity observed. The compound has been demonstrated to reduce 2-HG levels by> 95%, to reverse 
growth factor-independent growth in vitro, and to induce differentiation in leukemia cell models. Clinical 
data in patients with advanced hematologic malignancies harboring an IDHl mutation (AG120-C-001) 
and with advanced solid tumors harboring an IDHl mutation (AG120-C-002) have shown the compound 
to be well tolerated at total daily doses up to 1200 mg with clinical activity observed in both solid and 
liquid tumors. The 500 mg dose level of ivosidenib was expanded and selected for future studies based 
on the available pharmacokinetic (PK)/pharmacodynamic (PD), safety profile, and preliminary clinical 
activity observed. In 2018, ivosidenib was approved by the US Food and Drug Administration (FDA) for 
the treatment of patients with relapsed refractory AML with and IDHl mutation. 
1.4.2 Summary of Nonclinical Information 
Details of the nonclinical development program for ivosidenib are provided in the Investigator's 
Brochure. A summary of the key information is provided below. 


20
 
1.4.2.1 PK Drug Interactions 
In vitro studies showed that ivosidenib is predominantly metabolized by cytochrome P450 3A4 (CYP3A4) 
and, therefore, co-administration with inhibitors or inducers of CYP3A4 has the potential to affect 
ivosidenib exposure. Co-administration of 250 mg ivosidenib with a strong CYP3A4 inhibitor 
itraconazole) increased single-dose AUC of ivosidenib by 169% with no change in Cmax- Based on 
physiologically based PK (PBPK) simulations, co-administration with ivosidenib and a strong CYP3A4 
inhibitor (itraconazole) or moderate CYP3A4 inhibitor (fluconazole) is predicted to increase ivosidenib 
steady-state Cmax by up to 52% and AUC by up to 90%. Increased ivosidenib plasma concentrations may 
increase the risk of QTc interval prolongation. 
Consider alternative therapies that are not strong or moderate CYP3A4 inhibitors during treatment with 
ivosidenib. If concomitant use of strong or moderate CYP3A4 inhibitors (eg, strong inhibitors such as: 
posaconazole, voriconazole, itraconazole, erythromycin, clarithromycin, and moderate inhibitors such 
as: fluconazole, erythromycin, isavuconazole, diltiazem, and grapefruit juice) is unavoidable, monitor 
participants for increased risk of QTc interval prolongation (refer to Section 6.4 for QTcF risk 
management and the monitoring plan in ivosidenib protocols). Based on a PBPK simulation, 
coadministration of ivosidenib with a strong CYP3A4 inducer (rifampin) is predicted to decrease 
ivosidenib steady-state AUC by 33% and Cmaxby 19%. Avoid coadministration of strong CYP3A4 inducers 
with ivosidenib. 
lvosidenib is an inducer of CYP3A4 and may also induce CYP2B6, CYP2C8, and CYP2C9. Coadministration 
of ivosidenib with narrow therapeutic index drugs that are extensively metabolized by CYP3A4 (eg, 
cyclosporine, fentanyl, everolimus, tacrolimus, sirolimus) or CYP2C9 (eg, phenytoin, warfarin) may result 
in decreased concentrations of these drugs. Investigators should consider alternative therapies that are 
not sensitive substrates of CYP3A4 or CYP2C9 during treatment with ivosidenib. Participants should be 
monitored for loss of therapeutic effect of these medications if coadministration with ivosidenib cannot 
be avoided. 
 
International normalized ratio (INR) levels should be monitored more frequently in participants 
receiving warfarin (a CYP2C9 substrate) during initiation or discontinuation of ivosidenib. 
lvosidenib is a weak direct inhibitor of CYP2C8, CYP2C19, CYP2D6, and CYP3A4/5 with ICsovalues > 50 
µM and shows little or no evidence of direct inhibition of CYP1A2, CYP2B6, or CYP2C9. lvosidenib did not 
show time- or metabolism-dependent inhibition of any of the CYP enzymes evaluated and therefore, the 
likelihood of inhibition of CYP enzymes by ivosidenib is extremely low. 
 
lvosidenib is a substrate for P-glycoprotein (P-gp), but not for BCRP or hepatic transporters OATP1B1 
and OATP1B3. lvosidenib does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, and OCT2 at clinically 
relevant concentrations. lvosidenib is an inhibitor of OAT3. A PBPK simulation predicted an increase 
(<30%) in the AUC of a sensitive OAT3 substrate, suggesting that the potential for clinically relevant drug 
interactions due to the inhibition of OAT3 appears to be low. 
 
lvosidenib does not contain ionizable groups under physiological condition and its aqueous 
solubility is pH independent. Thus, gastric acid reducing agents (eg, proton pump inhibitors, 
H2-receptor antagonists, and antacids) do not affect ivosidenib exposure. 


21
 
Co-administration of ivosidenib may decrease the concentrations of hormonal contraceptives. 
 
1.4.2.2 Safety Pharmacology and Toxicology 
The toxicity profile of ivosidenib has been evaluated in vitro in the bacterial reverse mutation assay and 
in vivo in Sprague Dawley rats and cynomolgus monkeys. The compound was not mutagenic and was 
well tolerated at estimated efficacious exposures with a potential 4-fold therapeutic window. 
Safety pharmacology 
Individual animals with possible ( 30 ms) and probable ( 60 ms) test article-related QT prolongation 
corrected for heart rate using Bazett's formula (QTcB) (Morganroth 2001} have been noted in both the 
28-day and 3-month Good Laboratory Practice (GLP) cynomolgus monkey studies at free maximum 
concentration (Cmax) values 0.7-fold the C2Dl 500 mg free Cmax human exposure (500 mg is the dose 
selected for the expansion phase of the ongoing Phase 1 clinical trial, Study AG120-C-001). In addition, 
prolonged QTcB was observed at the 45 and 135 mg/kg dose levels in a non-GLP single dose monkey CV 
safety pharmacology study, in which group mean Cmaxvalues were similar to that of individual animals in 
the 28-day and 3-month repeat-dose studies. 
Toxicology 
In GLP 28-day repeat-dose toxicology studies, oral doses of ivosidenib administered twice daily (BID) at 
the projected human efficacious exposure were well tolerated by both rats and monkeys. In rats, 
significant findings at 100 mg·kg-1-day-1were limited to minimal alterations in clinical pathology 
parameters, liver and thyroid findings consistent with autoinduction of metabolism, and splenic 
extramedullary hematopoiesis. In monkeys, significant findings at 30 mg·kg-1-day-1were limited to 
gastrointestinal clinical observations and sporadic emesis. In both species, all significant effects at 
projected efficacious exposures were reversible over the 14-day recovery period. 
In the GLP 28-day rat study, dose-limiting toxicity (DLT) occurred at a dosage of 2000 mg·kg-1-day-1. At 
this dose level, significantly reduced exposures were observed, from 15-fold the projected efficacious 
exposure on Day Oto 5.4- to 7.8-fold on Day 27, which were consistent with autoinduction of 
metabolism. Most of the unscheduled deaths occurred early in the study, between Days 2 and 6, 
suggesting that these early mortalities were being driven by the higher exposures. The cause of this 
early DLT was multifactorial and included moderate, bridging, centrilobular hepatocellular degeneration 
and necrosis with additional contributing factors being tubular necrosis in the kidney; cortical and 
medullary tubular vacuolation in the kidney; atrophy of small intestines; hypocellularity, hemorrhage 
and necrosis of the femoral and/or sternal bone marrow; and erosions of the glandular stomach. 
When DLT occurred later in the dosing period (the minority of the early mortality), it was due to 
mucosaI atrophy of the intestines, erosions and ulcerations of the glandular stomach and/or rectum, 
and lymphoid depletion and necrosis in lymphoid organs with renal tubular necrosis being an additional 
contributing factor. Exposures at this time were likely closer to the Day 27 exposures. The Day 27 
ivosidenib area under the concentration x time curve from Oto 12 h (AUCo-12h) value for this dosage was 
69500 and 101000 h-g-1-mL-1, in males and females, respectively, which is 1.2- and 1.8-fold the human 
AUC0-10h, respectively. The next lower dose level tested in rats (500 mg·kg-1-day-1) resulted in an AUC0-12h 
values of 30100 and 59000 ng·h-1-mL-1in males and females, respectively, which is 0.5- and 1-fold the 
human AUC0-10h- No early mortality occurred and this exposure level was tolerated. All significant 
findings at this dose level were reversible. 


22
 
In the GLP 3-month rat study, ivosidenib was well tolerated at dosage levels of 20, 100, and 500 mg-kg- 
1·day-1in rats and resulted in no test article-related deaths. Test article-related effects were qualitatively 
similar at 100 and 500 mg·kg-1-day-1. Most findings had resolved during the 4-week recovery period. At 
500 mg·kg-1·day-1,the Day 90 mean plasma AUC0-12h values were 29000 and 62000 ng·h-1-mL-1in males 
and females, respectively (0.5- and 1.1-fold the human AUCo-1oh value), and at 100 mg·kg-1-day-1were 
12100 and 20000, respectively (0.2- and 0.3-fold the human AUC0-1oh value). At 500 mg·kg-1-day-1,the 
Day 90 mean plasma Cmaxvalues were 4650 and 9710 ng/ml in males and females, respectively, and at 
100 mg·kg-1-day-1were 2770 and 5660 ng/ml, respectively. The Day 90 mean plasma AUC0-12h values at 
20 mg-kg-1-day-1were 6880 and 7090 ng·h-1-mL-1in males and females, respectively (0.1-fold the human 
AUC0-10h value), and the Day 90 mean plasma Cmaxvalues were 1320 and 1580 ng/ml, respectively. The 
findings observed in the 3-month rat study are largely consistent with those noted at tolerable doses in 
the 28-day study with the exception of the novel finding of a higher potassium fractional urine 
excretion. 
In the GLP 28-day monkey study, DLT occurred in male monkeys at an AUC0-12h value of 235000 (at a 
dose of 270 mg·kg-1-day-1), which is 4.1-fold the human AUC0-10h value. The cause of DLT was general 
malaise characterized by poor body condition and gastrointestinal clinical signs leading to emesis and 
secondary aspiration. In females at the same dose level, ivosidenib was tolerated and the Day 27 AUC0- 
12h value was 109000 ng·h-1-mL-1, which is 1.9-fold the human AUC0-10h value. The dosage of 270 mg·kg- 
1·day-1was associated with significant weight loss and moribundity; higher total, direct, and indirect 
bilirubin and triglycerides; lower hemoglobin and hematocrit values; lower phosphorous levels; lower 
albumin and total protein; higher mean specific gravity and lower total urine volume; ventricular 
bigeminy; prolonged QTcB in females; higher liver weights; and hepatocellular hypertrophy. All 
significant findings were reversible following the recovery period, with the exception of the 
cardiovascular findings, for which recovery was not assessed because the affected animals were 
assigned to the primary necropsy. 
In the GLP 3-month monkey study, ivosidenib at dosage levels of 30, 90, and 180 mg·kg-1-day-1for up to 
92 consecutive days was well tolerated at all dosage levels and resulted in no test article-related deaths. 
Test article-related effects included diarrhea in males at 30 mg-kg-1-day-1and females at 180 mg·kg- 
1·day-1,and hepatocellular hypertrophy and higher liver weights at 30 mg·kg-1-day-1. Likely test article- 
related prolongations of QTcB were noted in individual animals in the 90 and 180 mg-kg-1-day-1dose 
groups at free Cmax exposure margins 1.3-fold that of the human 500 mg Cmax value. All test 
article-related changes resolved during the recovery period. The 180 mg·kg-1-day-1dose level was 
associated with gender combined Day 90 mean plasma Cmax and AUC0-12h values of 14800 ng/ml and 
134000 ng·h-1-mL-1, respectively (2.3-fold the human AUC0-10h value). The findings observed in the 3- 
month monkey study are largely consistent with those noted at tolerable doses in the 28-day study. 
1.4.3 Summary of Clinical Data 
The ivosidenib clinical development program was initiated in March 2014 with two Phase 1 dose 
escalation studies, AG120-C-001 and AG120-C-002. Refer to the Investigator's Brochure for further 
details on each of these studies. 
 
1.4.3.1 Study AG120-C-002 
Study AG120-C-002 is evaluating the safety, PK, PD biomarker patterns, and clinical activity of 
ivosidenib in participants with advanced solid tumors, including cholangiocarcinoma, with an IDHl 


23
 
mutation. The primary objectives of the study are to assess the safety and tolerability of treatment 
with ivosidenib administered daily as a single agent dosed orally in participants with advanced solid 
tumors, including glioma, and to determine the maximum tolerated dose(s) (MTD[s]) and/or the 
recommended Phase 2 dose(s) of ivosidenib in this population. The initial dosing regimen was 100 mg 
BID and doses up to 1200 mg once daily (QD) were assessed in a 3+3 dose escalation design; based on 
the favorable PK profile showing a long elimination half-life (t½), BID dosing was discontinued after the 
first cohort and a QD dosing regimen was implemented. The study is divided into a dose escalation 
phase, followed by an expansion phase to allow for a more robust evaluation of the safety profile and 
preliminary assessment of clinical activity. This study is currently ongoing. 
Efficacy data for Study AG120-C-002 were analyzed separately based on the underlying disease 
and specific response criteria, including Response Evaluation Criteria in Solid Tumors 
(RECIST), Response Assessment in Neuro-Oncology (RANO), Response Assessment in Neuro- 
Oncology for low grade glioma (RANO-LGG): cholangiocarcinoma, chondrosarcoma, or 
glioma. As of March 10, 2017, 73 participants with cholangiocarcinoma received ivosidenib in the dose 
escalation and expansion cohorts, with 62 participants receiving ivosidenib at 500 mg QD. Overall, 5% 
(n=4) experienced a confirmed partial response and 56% (n=41) experienced stable disease. 
The 6-month PFS rate was 38.5% and the 12-month PFS rate was 21% (Lowery, Abou-Alfa et al. 2017). 
As of September 23, 2016, 21 participants with chondrosarcoma had been treated with ivosidenib 
and 20 were efficacy-evaluable. Eleven (55%) participants experienced stable disease as their best 
overall response; the remaining participants experienced disease progression (30%) or were not 
assessed (15%). The 3-month PFS rate was 58% with a median ivosidenib treatment duration of 
2.6 months (range, 0 to 24 months) (Tap, et al. 2016). 
 
As of May 12, 2017, 66 participants with glioma had been treated with ivosidenib and enrollment of 
this subset was complete; of these participants, 35 had non-enhancing glioma. Two of these 35 
participants (6%) had a minor response according to RANO-LGG. Twenty-nine (83%) participants had 
stable disease and 4 (11%) had progressive disease as their best response; the median treatment 
duration for non-enhancing glioma was 16 months with 63% of participants being treated for ;?:1 
year. Volumetric analysis (conducted centrally) demonstrated stabilization or a decrease in tumor 
growth rate compared to the pretreatment rate in glioma participants with non-enhancing disease 
receiving ivosidenib (Mellinghoff and Gilbertson 2017). 
Treatment with ivosidenib has been well tolerated; no DLTs have been reported. Overall, 101 (83%) of 
122 participants have reported treatment-emergent AEs (TEAEs). To date, the most commonly reported 
AEs have been nausea (20%), fatigue (12%), diarrhea, (11%), prolonged QT interval (10%), and vomiting 
(10%). There was no evidence for an increase in the incidence of these commonly reported events with 
dose. 
Two deaths within 30 days of study treatment termination have been reported in the 400 mg dose 
cohort. One was due to anemia and the other occurred due to acute respiratory failure. Both deaths 
were assessed as unrelated to study treatment. A total of 20 (16%) of the 122 participants have 
experienced serious AEs (SAEs). No individual SAE was reported in more than 1 participant, and 
none of these SAEs were assessed to be related to ivosidenib. The only SAE experienced by more 
than one participant was headache (2 participants, 2%); additional SAEs were reported in 1 


24
 
participant each. Only an event of supraventricular extrasystoles was assessed as possibly related to 
study treatment. 
Preliminary analysis of PK data at the 100 mg BID and, 300, 400, 500, 600, 800, 900, and 1200 mg QD 
dose levels demonstrated excellent oral ivosidenib exposure that on Cycle 1, Day 15 (C1D15) and Cycle 
2, Day 1 (C2Dl) was above the predicted efficacious exposure of 12.9 h·µg-1-mL-1 that was associated 
with 97% tumor 2-HG inhibition (direct IDHl pathway inhibition PD biomarker) in nonclinical models; 
meant½was from 38.4 to 86.2 h, which enables a QD oral dosing schedule. Evaluation of 2-HG as a 
direct inhibition of the IDHl pathway PD biomarker response following ivosidenib dosing in the 100 
mg BID and 300, 400, 500, 600, 800, 900, and 1200 mg QD dose cohorts demonstrated sustained 
reduction in 2-HG plasma levels (up to 100% inhibition) by C2Dl at all dose levels. 
As of April 14, 2016, 48 participants with cholangiocarcinoma have been treated, including 24 
participants in the dose escalation phase and 24 in the expansion phase. At the time of the data cutoff, 
23 of the 48 participants remain on treatment and 25 have discontinued {19 due to disease progression 
and 2 each due to AE, withdrawal of consent, and other reasons). The overall safety profile of ivosidenib 
remains consistent with that reported in the most recent Investigator's Brochure. Of the 48 
cholangiocarcinoma participants, 38 were evaluable for the analysis of efficacy (ie, had a baseline tumor 
measurement and at least 1 post-baseline response assessment or discontinued earlier). 
Three participants {8%) with cholangiocarcinoma receiving ivosidenib (1 at 300 mg and 2 at 500 mg) had 
an objective partial response, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 
vl.1 (Appendix 11.8). In addition, 22 participants {58%) had stable disease (SD), and 11 participants 
{29%) experienced disease progression as best response. Two participants {8%) were not assessed for 
response (discontinued treatment prior to a response assessment). At the 6-month time point, 60% of 
participants were progression free (PFS6) as assessed by the Kaplan-Meier method. As of the data 
cutoff, three participants remained on study drug> 1 year with an overall best response of SD. 
There were no dose limiting toxicities. Based on the available PK (suggesting less than dose proportional 
increase in exposure beyond 500 mg and maximal plasma 2-HG suppression at 500 mg) and following 
review of data from the dose escalation phase of this study, ivosidenib 500 mg QD was determined to be 
a safe and potentially effective dose for further study. 
 
1.4.3.2 Study AG120-C-001 
Study AG120-C-001 is evaluating the safety, PK, PD biomarker patterns, and clinical activity of ivosidenib 
in participants with advanced AML and related hematologic malignancies that harbor an IDHl mutation. 
The primary objectives of the study are to assess the safety and tolerability of treatment with ivosidenib 
administered daily in participants with advanced hematologic malignancies, to determine the MTD 
and/or the recommended Phase 2 dose of ivosidenib in this population, and to assess the preliminary 
clinical activity of ivosidenib in participants with relapsed or refractory AML with an IDHl mutation. The 
initial dosing regimen was BID; based on the favorable PK profile showing a long t½, BID dosing was 
discontinued after the first cohort and a QD dosing regimen was implemented. Similar to the AG120-C- 
002 study, this study is divided into a dose escalation phase, followed by an expansion phase to allow for 
a more robust evaluation of the safety profile and preliminary assessment of clinical activity. This study 
is currently ongoing and has served as the basis for the 2018 FDA approval of ivosidenib in relapsed 
refractory AML. A summary of the data from this study is provided in the Investigator's Brochure for 


25
 
ivosidenib. 
1.5 Identified Risks of lvosidenib 
A summary of AEs reported in> 10% of participants overall is presented in Table 25 of the Investigator's 
Brochure. As of January 16, 2019, 165 (98.2%) of the 168 participants had reported at least one AE. The 
most commonly reported AEs (> 20% of participants) across all 168 participants were fatigue (33.9%), 
nausea (29.2%), diarrhea (26.2%), and vomiting (20.2%). 
AEs of Grade 3 in severity have been reported in 59 (35.1%) of the 168 participants as 
of the data cutoff date. Grade 3 AEs reported in> 2 participants included ascites, hyponatremia, 
and hypophosphatasemia (five participants each); anemia (four participants); and abdominal pain, 
headache, hyperglycemia, and pulmonary embolism (three participants each). 
As of the data cutoff date, AEs leading to discontinuation of study treatment were reported for two 
participants (cystitis and hyponatremia in one participant and hydronephrosis in the other). All events 
leading to discontinuation were assessed as unrelated to ivosidenib. No dose-limiting toxicities 
have been reported in the study and the MTD was not reached. 
1.6 Nivolumab (BM-936558) 
Nivolumab (also referred to as BMS-936558 or MDX1106) is a human monoclonal antibody (mAb, 
immunoglobulin (lg)G4-S228P) that targets the PD-1 (CD279) cell surface membrane receptor. PD-1 is a 
negative regulatory molecule expressed by activated T and B lymphocytes. Binding of PD-1 to its ligands, 
PD-Ll and PD-L2, results in the downregulation of lymphocyte activation. Inhibition of the interaction 
between PD-1 and its ligands promotes immune responses and antigen-specific T-cell responses to both 
foreign antigens as well as self-antigens. Nivolumab is expressed in Chinese hamster ovary cells and is 
produced using standard mammalian cell cultivation and chromatographic purification technologies. The 
clinical study product is a sterile solution for IV administration. 
The PK, clinical activity, and safety of nivolumab have been assessed in participants with non-NSCLC, 
MEL, and clear-cell RCC in addition to other tumor types. Nivolumab is being investigated both as 
monotherapy and in combination with chemotherapy, targeted therapies, and other immunotherapies. 
Opdivo® (nivolumab) is approved for the treatment of unresectable or metastatic MEL in multiple 
countries including Japan (Jul-2014), the US (Dec-2014), and the European Union (EU) (Jun-2015). 
Nivolumab is also approved for the treatment of metastatic squamous (SQ) NSCLC in the US (Mar-2015). 
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 12,300 participants treated to date. 
For monotherapy, the safety profile is similar across tumor types. There is no pattern in the incidence, 
severity, or causality of AEs to nivolumab dose level. In Phase 3 controlled studies, the safety profile of 
nivolumab monotherapy is acceptable in the context of the observed clinical efficacy and is manageable 
using established safety guidelines. Clinically relevant AEs typical of stimulation of the immune system 
were infrequent and manageable by delaying or stopping nivolumab treatment and timely 
immunosuppressive therapy or other supportive care. 


26
 
In several ongoing clinical studies, the safety of nivolumab in combination with other therapeutics such 
as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and targeted therapies is being explored. 
Most studies are ongoing and, as such, the safety profile of nivolumab combinations continues to 
evolve. The most advanced combination under development is the nivolumab and ipilimumab 
combination therapy, which is approved in participants with unresectable or metastatic MEL and being 
studied in multiple tumor types. Results to date suggest that the safety profile of nivolumab and 
ipilimumab combination therapy is consistent with the individual mechanisms of action of nivolumab 
and ipilimumab. The nature of the AEs is similar to that observed with either agent used as 
monotherapy; however, both frequency and severity of most AEs increase with the combination. 
Detailed descriptions of the chemistry, pharmacology, efficacy, and safety of nivolumab are provided in 
the nivolumab Investigator Brochure (1B). 
1.6.1 Nivolumab Storage 
The product does not contain a preservative. 
After preparation, store the OPDIVO infusion either: 
 
• 
at room temperature for no more than 8 h from the time of preparation. This includes room 
temperature storage of the infusion in the IV container and time for administration of the 
infusion or 
• 
under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 h from the time of infusion 
preparation. 
Do not freeze. 
Detailed descriptions of the chemistry, pharmacology, efficacy, and safety of nivolumab are provided in 
the nivolumab 1B. 
 
2.0 Trial Objectives and Endpoints 
2.1 Objectives 
2.1.1 Primary Objective 
The primary objective of the study is: 
• 
To describe the clinical response and six-month progression-free survival of patients treated with 
ivosidenib in combination with nivolumab 
2.1.2 Secondary Objectives 
The secondary objectives of the study are: 
• 
To determine the safety of ivosidenib in combination with nivolumab 
 
• 
To summarize longitudinal clinical outcomes of patients treated with ivosidenib in combination 
with nivolumab 
2.1.3 Exploratory Objective 
 
• 
To evaluate biomaterial-based biomarkers and determine their association with treatment 


27
 
response. 
 
2.2 Study Endpoints 
 
2.2.1 Primary Endpoints 
 
• 
Response 
 
■ 
Advanced Solid Tumors: Best overall response by RECIST 1.1 as detailed in  {Section 11.8) 
8 weeks after the initiation of treatment 
■ 
Glioma: Best overall Response by Response Assessment in Neuro-Oncology {RANO), 
Criteria as detailed in  (Section 11.9) 8 weeks after the initiation of treatment 
• 
Six-Month Progression Free Survival (PFSG) 
 
■ 
All tumor types: All tumor types: Survival to six months after the initiation of 
treatment without objective tumor progression 
 
 
2.2.2 Secondary Endpoints 
■ 
The occurrence of dose-limiting toxicity {DLT), as defined in Section 7.5, in patients receiving ivosidenib 
plus nivolumab. 
• 
Adverse events in patients receiving the combination of ivosidenib and nivolumab based on 
CTCAEvS.0 
• 
Progression Free Survival (PFS) - Survival with freedom from objective tumor progression from time of 
first treatment until up to 18 months after the last participant has initiated treatment. 
2.2.3 Exploratory Endpoints 
• 
The association between response biomarkers and clinical outcomes in patients treated 
with combination ivosidenib and nivolumab. 
 
3.0 lnvestigational Plan 
 
3.1 Overall Study Design 
This is a Phase II study of orally administered ivosidenib in patients with advanced solid tumors 
{nonresectable or metastatic) or enhancing gliomas. Participants are required to have a histologically 
consistent diagnosis of IDH1 gene-mutated tumor that is not eligible for curative therapy. Participants 
must have received appropriate standard of care treatment options {in the opinion of the treating 
investigator). 
Each participant's course of treatment will be comprised of the following periods: 
Pre-Treatment/Screening Period: Following informed consent, all potential participants will undergo 
Screening procedures to determine eligibility within 28 days prior to the start of study treatment on 
Cycle 1, Day 1 (C1D1), with the exception of baseline radiographic scans, which should be performed 
within 21 days prior to C1D1. In patients with advanced solid tumors excluding brain tumors, a tumor 
biopsy will be collected if not done so before screening. A second biopsy will be taken at the end of the 
first cycle of nivolumab (approximately week 4 ± 10 days). Additional Screening procedures are detailed 
in the study calendar in Section 6.1 


28
 
Treatment Period and End of Treatment Visit: Participants who meet all study eligibility criteria will be 
eligible to start study treatment (criteria detailed in Section 4). Daily study treatment will begin on ClDl 
with planned concurrent dosing of ivosidenib and nivolumab. Cycles are 28 days (±2 days) in duration 
and dosing is continuous. lvosidenib will be dosed daily on 28-day cycles and nivolumab will be infused 
IV every 28 days. All participants will continue to receive best supportive care according to institutional 
practice throughout the study, regardless of treatment arm. Study visits will be conducted every other 
week during Cycles 1-3 (Days 1 and 15), and Day 1 of each cycle thereafter. An end of treatment (EOT) 
Visit will be performed on the last day of study treatment (within 5 to 33 days of last dose of either 
study treatment to accommodate for potential dosing delays of up to 28 days). 
 
Dosing 
Drug 
ivosidenib 
nivolumab 
Dose Level 1 
500 mg daily 
480 mg IV q4 
Dose Level -1 
250 mg daily 
480 mg IV q4 
 
 
Schedule of Administration: lvosidenib will be administered concurrently with nivolumab beginning on 
ClDl to patients with an IDHl mutant solid tumor or glioma selected by CUA certified sequencing for 
IDHl R132 mutations. Should toxicity monitoring suggest and intolerable dose, a dose de-escalation 
approach will be employed according to the above dose levels. Dosing will be continuous (once daily) on 
a 28-day cycle. After confirmation of tolerable dose, ivosidenib will be continued throughout the rest of 
the trial. Nivolumab will be dosed concurrently at 480 mg IV q4 weeks starting on ClDl. After collecting 
baseline peripheral blood, a research biopsy will also be collected in at least the first 10 patients with 
advanced solid tumors - ie, not in glioma - in whom a biopsy is deemed safe by the treating physician, 
pending available funding. lvosidenib will then be administered concurrently with nivolumab on a Q28 
day schedule. A second biopsy will be taken at the end of the first cycle of nivolumab (approximately 
week 4), pending funding. Treatment with ivosidenib will continue indefinitely per treating investigator 
discretion. 
 
Nivolumab will be given for up to 1 year. Either agent will be discontinued upon severe toxicity, 
confirmed disease progression, confirmed pregnancy, death, withdrawal of consent, or if the participant 
is lost to follow-up. 
Radiographic assessment (CT or MRI) for evaluation of disease response will be conducted every 8 
weeks (±7 days) from C1D1, independent of dose delays and/or dose interruptions, and/or at any time 
when progression of disease is suspected. For participants who discontinue study drugs for reasons 
other than disease progression or start of another anticancer agent, an assessment will be conducted at 
the EOT Visit. Target and non-target lesion selection and objective tumor response assessments per 
Response Evaluation Criteria in Solid Tumors (RECIST) vl.1and RANO criteria for glioma patients. 


29
 
Participants will be assessed at every visit for AEs and concomitant medications, starting from the first 
dose of study treatment. Toxicity severity will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Additional physical exam and 
laboratory will be conducted at each visit as detailed in the  study assessments and biomarker table. 
Participants may continue with their assigned study treatment until disease progression, development 
of unacceptable toxicity, confirmed pregnancy, death, withdrawal of consent, the participant is lost to 
follow-up, or the Lead Principal Investigator (Pl} ends the study, whichever occurs first. For participants 
who are determined to be on ivosidenib upon radiographic disease progression and demonstrate clinical 
benefit, treating investigators, with consult from the Lead Pl, may keep the participants on ivosidenib 
after the disease progression. 
Post-Treatment Follow-up Visit: A Post-Treatment Follow-Up Visit for safety will occur 28 days (no more 
than 33 days) after the last dose of study drug. Every effort must be made to perform protocol-specified 
evaluations unless consent to participate in the study is withdrawn. Assessments to be performed at the 
Follow-up Visit are included under  study assessments. If a participant's dose is interrupted for 28 days 
and then the participant discontinues study participation, the EOT Visit will serve as the Post-Treatment 
Follow-up Visit. 
PFS Follow-up: Participants who discontinue study treatment for reasons other than disease progression 
or withdrawal of consent will be followed in PFS follow-up (every 8 weeks through week 48, and every 8 
weeks thereafter) until documented disease progression, death, or the initiation of new cancer therapy. 
If a participant begins a new anticancer therapy during PFS follow-up, information on the new anticancer 
therapy will be collected. 
End of Study: End of study is defined as the point in time when all participants have died, withdrawn 
consent, or been lost to follow-up. 
3.2 Rationale for Dose Selected 
3.2.1 lvosidenib 
lvosidenib is FDA approved for relapsed refractory IDHl mutated AML. Data have shown ivosidenib to 
be well tolerated at total daily doses up to 1200 mg in solid tumors (AG120-C-002) and in hematologic 
malignancies (AG120-C-001}; the MTD was not reached in either study. As of a 16 January 2016, 
122 participants have been treated with ivosidenib in the AG120-C-002 study, of which 84 participants 
received 500 mg QD; 119 participants have been treated with ivosidenib in the AG120-C-001 study, of 
which 89 participants received 500 mg QD. Based on a review of the available safety, PK/PD, and clinical 
activity data observed during dose escalation, 500 mg QD was selected as the ivosidenib dose for the 
expansion phases of both of these trials. 
In these studies, there have been minimal dose interruptions, and without an apparent dose 
relationship for any commonly reported TEAEs or Grade 2:3 TEAEs. No DLTs have been reported in Study 
AG120-C-002. Dose-limiting toxicities of Grade 3 rash and Grade 3 QT prolongation were observed in the 
1200 mg QD and 800 mg QD cohorts respectively in Study AG120-C-001; however, expansion of these 
dose cohorts did not result in identification of the MTD. 
Plasma ivosidenib exposure increased in a less than proportional manner across doses from 100 mg BID 


30
 
to 1200 mg QD, nearing a plateau at 500 mg QD, in both solid tumors and hematologic malignancies. 
Sustained and consistent plasma 2-HG inhibition was observed with plasma 2-HG levels reduced to the 
normal range of healthy volunteers (up to 98.0% inhibition in solid tumors, 99.7% in hematologic 
malignancies) at all doses, with no apparent dose response. The 500 mg QD dose has shown a maximum 
PD effect based on 2-HG levels for the majority of participants. 
For Study AG120-C-002, efficacy data were analyzed separately based on the underlying disease and 
specific response criteria: cholangiocarcinoma, chondrosarcoma, or glioma (see Section 5.4.2 in 
Investigator's Brochure 7.0 for greater detail). As of March 10, 2017, 73 participants with 
cholangiocarcinoma received ivosidenib in the dose escalation and expansion cohorts, with 62 
participants receiving ivosidenib at 500 mg QD. Overall, 5% (n=4) experienced a confirmed partial 
response and 56% (n=41) experienced stable disease. The 6-month progression-free survival (PFS) rate 
was 38.5% and the 12-month PFS rate was 20.7%. As of 23 September 2016, 21 participants with 
chondrosarcoma had been treated with ivosidenib and 20 were efficacy-evaluable. Eleven (55%) 
participants experienced stable disease as their best overall response; the remaining participants 
experienced disease progression (30%) or were not assessed (15%). The 3-month PFS rate was 58% with 
a median ivosidenib treatment duration of 2.6 months (range, 0 to 24 months). 
As of May 12, 2017, 66 participants with glioma have been treated with ivosidenib and enrollment of 
this subset was complete; of these participants, 35 had non-enhancing glioma. Two of these 35 
participants (6%) had a minor response according to RANO-LGG. Twenty-nine (83%) participants had 
stable disease and 4 (11%) had progressive disease as their best response; the median treatment 
duration for non-enhancing glioma was 16 months with 63% of participants being treated for 1 year. 
Volumetric analysis (conducted centrally) demonstrated stabilization or a decrease in tumor growth rate 
compared to the pretreatment rate in glioma participants with non-enhancing disease receiving 
ivosidenib. 
3.2.2 Nivolumab 
Nivolumab is approved as monotherapy for multiple solid tumors (NSCLC, melanoma, RCC, HCC) and in 
combination with ipilimumab for melanoma and RCC at doses of 480mg IV Q4 weeks. PPK analyses have 
shown that the PK of nivolumab is linear with proportional exposure over a dose range of 0.1 to 10 
mg/kg, and no differences in PK across ethnicities and tumor types were observed. Nivolumab 
clearance and volume of distribution were found to increase as the body weight increases, but less than 
proportionally with increasing weight, indicating that milligram/kilogram dosing represents an over- 
adjustment for the effect of body weight on nivolumab PK. The PPK model previously developed using 
data from NSCLC participants has recently been updated, using data from 1,544 participants from 7 
studies investigating nivolumab in the treatment of MEL, NSCLC, and RCC. 
In this dataset, the median (minimum - maximum) weight was 77 kg (35 to 160 kg) and thus, an 
approximately equivalent dose of 3 mg/kg for an 80-kg participant, nivolumab 240 mg q2w was selected 
for future studies. To predict relevant summary exposures of nivolumab 240 mg q2w, the PPK model 
was used to simulate nivolumab 3 mg/kg q2w and 240 mg q2w. In the simulations, the simulated 
participant populations consisted of 1,000 participants per treatment arm randomly sampled from 
aforementioned pooled database of cancer participants. Because no differences in PK were noted 
across ethnicities and tumor types, these simulated MEL and NSCLC data will be applicable to 
participants with other tumor types. The simulated measure of exposure of interest, time-averaged 


31
 
concentrations for 240 mg q2w are predicted to be similar for all participants in reference to 80 kg 
participants receiving 3 mg/kg q2w. 
Nivolumab is safe and well tolerated up to 10 mg/kg q2w dose level. AEs have been broadly consistent 
across tumor types following monotherapy and have not demonstrated clear dose-response or 
exposure-response relationships. Additionally, the simulated median and 95th prediction interval of 
nivolumab summary exposures across body weight range (35 to 160 kg) are predicted to be maintained 
below the corresponding observed highest exposure experienced in nivolumab (ie, 95th percentile 
following nivolumab 10 mg/kg q2w from Study CA209003). Thus, while participants in the lower body 
weight ranges would have greater exposures than 80 kg participants, the exposures are predicted to be 
within the range of observed exposures at doses (up to 10 mg/kg q2w) used in the nivolumab clinical 
program and are not considered to put participants at increased risk. 
For participants with greater body weights, the simulated ranges of exposures are also not expected to 
affect efficacy because the exposures predicted following administration of a 240 mg q2w are on the 
flat part of the exposure- response curves for previously investigated tumors, MEL and NSCLC. Given 
the similarity of nivolumab PK across tumor types and the similar exposures predicted following 
administration of 240 mg flat dose compared to 3 mg/kg, it has been expected that the safety and 
efficacy profile of 240 mg nivolumab will be similar to that of 3 mg/kg nivolumab. 
More recently, data on the clinical pharmacokinetics, safety, and efficacy of 480 mg IV over 30 min every 
4 weeks has been collated and reviewed across tumor types, leading to FDA approval for the 480 mg 
dosing regimen. Hence, combination dosing of nivolumab for this study will be 480mg IV Q 4 weeks. 
lnvestigational supply is being provided for this study. Please reference the nivolumab 1B for dosing 
information and proper storage conditions. 
3.3 Criteria for Study Termination 
In the event of such action, written notification documenting the reason for study termination will be 
provided to each Local Investigator. The study will be terminated if any of the following circumstances 
occur: Determination of unexpected, significant, or unacceptable risk to participants. Failure to enter 
participants at an acceptable rate. Insufficient adherence to protocol requirements. Plans to modify, 
suspend, or discontinue the development of the study treatment. Other administrative reasons. 
 
4.0 Study Population 
4.1 Inclusion Criteria 
1. Be:::: 18 years of age. 
2. Have a histopathological diagnosis (fresh or banked tumor biopsy sample, preferably collected 
within the last 3 years) of an advanced solid tumor for which curative treatment is not available 
and have undergone appropriate standard of care treatment options (in the opinion of the 
treating investigator). 
3. Have a documented IDH1 gene-mutated disease (from a fresh tumor biopsy or the most recent 
banked tumor tissue available) based on CLIA certified sequencing (R132C/L/G/H/S mutation 
variants tested). 


32
 
• 
For glioma, must have both 1) contrast enhancing disease and 2) WHO 2016 grade 2 
4. Have an ECOG PS score of O or 1 (Appendix 11.1) 
5. Have at least one evaluable and measurable lesion as defined by RECIST vl.1 (solid tumors) or 
Response Assessment in Neuro-Oncology (RANO) Criteria (glioma). 
6. Have recovered from toxicities associated with prior anticancer therapy to baseline or :5 grade 1 unless 
stabilized under medical management per investigator. 
7. Have adequate bone marrow function as evidenced by: 
• 
Absolute neutrophil count l,500/mm3 or 1.5 x 109/L 
• 
Hemoglobin 8 g/dL 
• 
Platelets 100,000/mm3 or 100 x 109/L 
8. Have adequate hepatic function as evidenced by: 
• Serum total bilirubin :5 2 x upper limit of normal (ULN), unless considered due to Gilbert's 
disease 
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) :5 5 x ULN in the 
presence of liver metastases (or primary hepatic tumor) OR :5 2x ULN within glioma 
patients 
9. Have adequate renal function as evidenced by: 
• 
Serum creatinine < 1.5 x ULN OR Creatinine clearance 50 ml/min based on the Cockroft- 
Gault glomerular filtration rate (GFR) estimation: (140-Age) x (weight in kg) x (0.85 if 
female)/72 x serum creatinine 
10. Be able to understand and willing to sign the informed consent form (or have legal 
representation) and to comply with scheduled visits, treatment plans, procedures, and 
laboratory tests, including serial peripheral blood sampling, biopsies, and urine sampling, 
during the study. A legally authorized representative may consent on behalf of a participant 
who is otherwise unable to provide informed consent if acceptable to and approved by the 
IRB/Independent Ethics Committee (IEC). 
11. Female participants with reproductive potential must have negative serum pregnancy testing 
within 72 h prior to the initial administration of study drug, then every 4 weeks±l week, or a 
negative confirmation from an obstetrician in case of equivocal serum pregnancy results. Females 
of reproductive potential are defined as sexually mature women who have not undergone a 
hysterectomy, bilateral oophorectomy, or tubal occlusion or who have not been naturally 
postmenopausal (ie, who have not menstruated) for at least 24 consecutive months (ie, have not 
had menses at any time in the preceding 24 consecutive months). 
Men with partners who are women with reproductive potential must agree that they or their 
partners will use two effective forms of contraception (including at least one barrier form) when 
engaging in reproductive sexual activity. Women of child-bearing potential (WOCBP) receiving 
nivolumab will be instructed to adhere to contraception for a period of 7 months after the last 
dose of nivolumab. Men receiving nivolumab and who are sexually active with WOCBP will be 
instructed to adhere to contraception for a period of 7 months after the last dose of nivolumab. 


33
 
Effective forms of contraception are defined as hormonal oral contraceptives, injectables, 
patches, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal ligation, 
condoms with spermicide, or male partner sterilization. 
4.2 Exclusion Criteria 
Participants who meet any of the following criteria will not be enrolled in the study: 
1. Received a prior IDH inhibitor. 
2. Received systemic anticancer therapy or an investigational agent< 2 weeks prior to Day 1). In 
addition, the first dose of study treatment should not occur before a period?: 5 half-lives (ti/2) 
of the investigational agent has elapsed. 
3. For solid tumor patients: received radiotherapy to metastatic sites of disease< 2 weeks prior to 
Day 1 and for glioma patients have received radiation within 3 months prior. 
4. For solid tumor patients, have underwent hepatic radiation, chemoembolization, and 
radiofrequency ablation< 4 weeks prior to Day 1. 
5. Participants must not have a diagnosis of immunodeficiency or is receiving systemic steroid 
therapy at a dose of> 10 mg prednisone daily or equivalent at time of first dose of study 
treatment. 
6. Participants must not have active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic 
corticosteroids replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered 
a form of systemic treatment. 
7. Participants must not have a known history of non-infectious pneumonitis that required steroids for 
treatment. 
8. Participants must not have evidence of interstitial lung disease. 
9. For solid tumor patients, have known symptomatic brain metastases requiring steroids. 
Participants with previously diagnosed brain metastases are eligible if they have completed their 
treatment and have recovered from the acute effects of radiation therapy or surgery prior to 
study entry, have discontinued corticosteroid treatment for these metastases for at least 1 week 
and have radiographically stable disease for at least 1 month prior to study entry. 
10. Have a history of another primary cancer that is active requiring treatment, progressing or for 
which the treating investigator believes will make disease assessment unreliable. 
11. Have evidence of intracranial or intra-tumoral hemorrhage either by MRI or 
computed tomographic (CT) scan. Participants with resolving post-surgical changes, punctate 
hemorrhage, or hemosiderin are eligible. 
12. Underwent major surgery within 4 weeks of Day 1 or have not recovered from post-surgery 
toxicities. 
13. Are pregnant or breastfeeding. 


34
 
14. Are taking known strong CYP3A4 inducers or sensitive CYP3A4 substrate medications with a 
narrow therapeutic window (Appendix 11.2), unless they can be transferred to other 
medications within 2'.5 t112 prior to dosing. 
15. Are taking P-glycoprotein (P-gp) transporter-sensitive substrate medications with a narrow 
therapeutic window (Appendix 11.2), unless they can be transferred to other medications 
within 2'. 5 t112 prior to administration of study treatment. 
16. Have an active infection requiring systemic anti-infective therapy or with an unexplained fever> 
38.5°C within 7 days of Day 1 (at the discretion of the treating investigator) participants with 
tumor fever may be enrolled). 
17. Have any known hypersensitivity to any of the components of ivosidenib or nivolumab. 
18. Have significant active cardiac disease within 6 months prior to the start of study treatment, 
including New York Heart Association (NYHA) Class Ill or IV congestive heart failure (Appendix 
11.3); myocardial infarction; unstable angina; and/or stroke. 
19. Have a heart-rate corrected QT interval (using Fridericia's formula) (QTcF) (Appendix 11.4) 2'. 480 
ms or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart 
failure, hypokalemia, family history of long QT interval syndrome). Bundle branch block and 
prolonged QTcF interval are permitted with approval of the Pl. 
20. Are taking medications that are known to prolong the QT interval (Appendix 11.5), unless 
they can be transferred to other medications within 2'. 5 t112 prior to dosing or unless the 
medications can be properly monitored during the study. (If equivalent medication is not 
available, QTcF should be closely monitored.) 
21. Have known active hepatitis B (HBV) or hepatitis C (HCV) infections, known positive human 
immunodeficiency virus (HIV) antibody results, or acquired immunodeficiency syndrome 
(AIDS)-related illness. Participants with a sustained viral response to HCV treatment or immunity 
to prior HBV infection will be permitted. Participants with chronic HBV that is adequately 
suppressed per institutional practice will be permitted. 
22. Have any other acute or chronic medical or psychiatric condition, including recent (within 
12 months of Day 1) or active suicidal ideation or behavior, or a laboratory abnormality that may 
increase the risk associated with study participation or investigational product administration or 
may interfere with the interpretation of study results and, in the judgment of the treating 
investigator, would make the participant inappropriate for entry into this study. 
23. Have known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric 
resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other conditions that 
limit the ingestion or gastrointestinal absorption of drugs administered orally. Gastroesophageal 
reflux disease under medical treatment is allowed (assuming no drug interaction potential). 
24. Have been committed to an institution by an order issued either by the judicial or administrative 
authorities. 
4.3 Subject Recruitment and Registration 


35
 
Participants who are candidates for enrollment into the study will be evaluated for eligibility by the 
treating investigator to ensure that the inclusion and exclusion criteria have been satisfied and that the 
participant is eligible for participation in this clinical study. 
4.3.1 Registration Procedures 
When registering a participant, patients must not start protocol treatment prior to registration. The 
registration will be conducted using a clinical trials management system. 
Registration will require the following information: 1) protocol name and number; 2) date treatment 
begins; 3) participant name; 4) date of birth; 5) participant hospital medical record number; 6) primary 
study physician; 7) confirmation of eligibility; 8) copies of the informed consent signature page; 9) 
verification that the informed consent was signed. 
4.4 Subject Withdrawal Criteria 
Participants have the right to withdraw from the study at any time for any reason. A participant's 
discontinuation of study treatment or withdrawal from the study will not jeopardize the relationship 
with their healthcare providers or affect their future care. Participants may choose to discontinue study 
treatment but agree to remain on study for follow-up contact. This decision must be recorded in writing 
at the study site. 
Should a participant decide to withdraw, all efforts will be made to complete and report the 
protocol-defined study observations as completely as possible and to determine the reason for 
withdrawal. 
4.4.1 Withdrawal from Study Treatment 
Participants may discontinue or be discontinued from study treatment at any time. In this situation, a 
participant without documented progressive disease by the treating investigator should be followed for 
tumor assessments until the development of progressive disease and/or survival. Participants will be 
discontinued from study treatment for the following reasons: 
• 
Grade 4 QTcF prolongation. 
• 
Disease progression (participants who are, in the opinion of the treating investigator, benefiting 
from treatment [e.g., slow progression or immune-related response evaluation] may be allowed 
to continue on study treatment) 
• 
Severe or unacceptable toxicity 
• 
Death 
• 
Lead Investigator decision 
• 
Subject decision to withdraw from treatment 
• 
Protocol violation: non-adherence to study treatments as required for evaluability (detailed in 
section 8.1.1) or other protocol requirements. 
• 
Confirmed pregnancy (study therapy should be immediately interrupted based upon a positive 
urinary human chorionic gonadotropin [hCG] test, and permanently discontinued if confirmed 
by a serum -hCG test) 
• 
Lost to follow-up 
All AEs should be followed until resolution or for a period of 28 days from the last dose of study 
treatment, whichever is shorter. If the participant withdrew from treatment because of an AE, every 


36
 
effort must be made to perform protocol-specified safety follow-up procedures. All SAEs that occur up 
to 100 days post last dose of nivolumab must be reported to BMS World Wide Safety. 
4.4.2 Study Participation Termination 
Participants who discontinue treatment without disease progression or death will continue to be 
followed for PFS every 8 weeks after the EOT Visit (±5 days) until disease progression, death, start of 
subsequent anticancer therapy, or withdrawal of consent until 6 months after the last enrolled patient 
begins treatment. Participants will be terminated from the study for the following reasons: 
• 
Death 
• 
Withdrawal of consent for follow-up 
• 
Loss to follow-up 
• 
Termination of the study 
 
5.0 Study Treatment 
5.1 Description of Study Treatment 
lvosidenib will be administered orally at a dose of 250 mg or 500 mg (provided as 250 mg strength 
tablets) daily. 
Nivolumab will be administered at 480 mg IV every 28 days. 
5.2 Study Treatment Packaging and Labeling 
lvosidenib will be supplied in appropriate containers with child resistant closures and labeled 
appropriately as the investigational product for this study. 
Packaging and labeling will be prepared to meet all regulatory requirements. 
 
5.3 Study Treatment Storage 
lvosidenib and nivolumab must be stored according to the package label. 
lvosidenib should be stored in a secure area according to local regulations. It is the responsibility of the 
local Pl to ensure that ivosidenib is only dispensed to study participants. lvosidenib must be dispensed 
only from official study site by authorized personnel according to local regulations. 
The product storage manager should ensure that the study treatment is stored in accordance with the 
environmental conditions (temperature, light, and humidity). If concerns regarding the quality or 
appearance of the study treatment arise, the study treatment should not be dispensed. 
lnvestigational product (IP) documentation must be maintained and includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, administration, 
and as applicable, storage temperatures, reconstitution, and use of required processes (e.g., required 
diluents, administration sets). A temperature excursion form will be provided at study activation. All 
temperature excursion must be reported to BMS. 
Storage facilities for controlled substances must be securely locked and substantially constructed, with 
restricted access to prevent theft or diversion, as applicable by local regulations. 
Details regarding preparation and administration are provided in the site training materials for AG-120. 


37
 
For nivolumab, investigational supply is being provided for this study. Please only refer to the nivolumab 
IB for drug storage, preparation, and administration guidelines to include in the protocol. 
5.4 Study Treatment Preparation and Administration of lvosidenib 
Daily treatment with ivosidenib will begin on C1D1. Dosing is continuous; there are no planned inter- 
cycle rest periods. Participants should be instructed to take their QD dose at approximately the same 
time each day. 
Participants should be instructed to swallow tablets whole and to not chew the tablets. Participants may 
take ivosidenib tablets with or without food. Participants should be advised that if ivosidenib tablets are 
taken with food, the participant should avoid grapefruit or grapefruit products and avoid consuming a 
high-fat meal. 
If the participant forgets to take the daily dose, then they should take ivosidenib within 12 h after the 
missed dose. If more than 12 h have elapsed, then that dose should be omitted, and the participant 
should resume treatment with the next scheduled dose. 
Participants will continue to receive best supportive care throughout the study, regardless of treatment 
arm. Participants may continue with their assigned study treatment until any of the conditions for 
withdrawal of study treatments are met - as detailed in Section 4.4.1. For participants who are 
determined to be on ivosidenib upon radiographic disease progression and demonstrate clinical benefit, 
Pis, with consult from the Sponsor, may keep the participants on ivosidenib after the disease 
progression. 
5.5 Criteria for Dose Modification, Discontinuation of Study Treatment, and Continuation Beyond 
Radiographic Progression 
5.5.1 Study Treatment Dose Modification and Discontinuation Criteria 
5.5.1.1 Dose Modifications and Delays 
Dose reductions or dose escalations of nivolumab are not permitted. Nivolumab may continue if the 
ivosidenib is held unless the hold of ivosidenib is for more than 28 days. If a safety issue arises that is related 
to nivolumab, the nivolumab should be withheld or permanently discontinued (Section 5.9). In such a case, 
continuing ivosidenib may be allowed after consultation with the Pl. 
For any AE, including AEs not specifically mentioned in Table 1, the treating investigator may decide to 
delay dosing or modify the dose of ivosidenib based on clinical judgment. Dose modifications of 
ivosidenib from 500 mg to 250 mg will be permitted on study for management of AEs (Table 1). If more 
than one AE occurs that would require a dose modification, upon resolution of all AEs to baseline or 
Grade 1, ivosidenib should be dose reduced to 250 mg. Dose reductions below 250 mg are not 
permitted. If the AE is thought to be related to the ivosidenib, the nivolumab will continue to be dosed 
as per protocol schedule. 
Dose delays for reasons other than management of AEs are discouraged. Dose delays up to 28 days will 
be permitted at the discretion of the lead investigator. 
If the participant cannot resume ivosidenib within 28 days, the participant should be discontinued from 
both study medications. If ivosidenib is discontinued, the participant will complete the EOT and Follow- 
up Visits, and then enter PFS follow-up (if disease has not progressed). Exemptions may be considered 


38
 
for those participants who are determined by the investigator to have received clinical benefit from 
treatment. If a dose is delayed for the management of an AE, the participant should resume the study at 
the next planned visit within a dosing cycle. This determination will be at the discretion of the treating 
physician. 
 
Table 1: Management of lvosidenib-related Adverse Events (AEs) 
 
AEs
Action
Grade 2 nausea or 
vomiting (related or 
unrelated) 
• 
Consider holding dose of ivosidenib until resolution of AE to Grade 
1 within 28 days of supportive therapy. 
 
• 
Manage with supportive therapy according to the institutional standard 
of care. 
• 
May resume ivosidenib at same dose. 
Grade 3 AEs (related, 
first event) 
• 
Hold dose of ivosidenib until resolution to Grade 1 or baseline within 
28 days of supportive therapy and then resume dose. 
• 
Manage with supportive therapy according to the institutional standard 
of care. 
• 
If the Grade 3 AE recurs (a second time), consider reducing ivosidenib 
to 250 mg. Re-escalation may be permitted after discussion with the 
Lead Investigator. 
• 
If the Grade 3 AE recurs (a third time) despite dose reduction of 
ivosidenib, then consider discontinuing ivosidenib in consultation with the 
Lead Investigator. 
Grade 4 AEs (related, 
first event) 
• 
Hold ivosidenib 
 
• 
Manage with supportive therapy according to the institutional standard 
of care. 
 
• 
If the AE resolves to Grade 1 or baseline within 28 days, then 
restart ivosidenib dosing at 250 mg in consultation with the Lead 
Investigator. 
 
• 
If the AE does not resolve to Grade 1 or baseline within 28 days, consider 
discontinuing study treatment in consultation with the Lead Investigator. 
 
• 
If the Grade 4 AE recurs (a second time), despite dose reduction, 
ivosidenib should be discontinued in consultation with the Lead 
Investigator. 
*See Table 2 for specific dose modifications for QTcF prolongation. 
 
5.5.2 Continuation of Treatment beyond Radiographic Progression 


39
 
Accumulating evidence indicates that a minority of participants treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD. 
• 
Participants will be permitted to continue treatment beyond initial RECIST Version 1.1 (solid tumors) 
or Response Assessment in Neuro-Oncology (RANO) (gliomas)-defined PD, assessed by the 
investigator, if they meet the following criteria: 
• 
Investigator-assessed clinical benefit 
• 
Tolerance of study drug 
• 
Stable performance status 
• 
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of PD (e.g., CNS metastases). 
A radiographic assessment/scan should be performed within 6 weeks of initial investigator-assessed 
progression to determine whether there has been a decrease in the tumor size or continued PD. The 
assessment of clinical benefit should be balanced by clinical judgment as to whether the participant is 
clinically deteriorating and unlikely to receive any benefit from continued treatment. 
If the treating investigator deems that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the study and continue to receive monitoring according to 
the study schedule. 
For the participants who continue study treatment beyond progression, further progression is defined 
as an additional 10% increase in tumor burden with a minimum 5 mm absolute increase from time of 
initial PD. 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. Treatment should be discontinued 
permanently upon documentation of further progression. 
New lesions are considered measurable at the time of initial progression if the longest diameter is at 
least 10 mm (except for pathological LNs, which must have a short axis of at least 15 mm). Any new 
lesion considered non-measurable at the time of initial progression may become measurable and, 
therefore, included in the tumor burden if the longest diameter increases to at least 10 mm (except for 
pathological LNs, which must have a short axis of at least 15 mm). In situations where the relative 
increase in total tumor burden by 10% is solely due to inclusion of new lesions, which become 
measurable, these new lesions must demonstrate an absolute increase of at least 5 mm. 
5.6 Guidelines for Management of QT Prolongation 
The following are guidelines for the management of AEs of special interest based on the ivosidenib non- 
clinical and clinical safety findings in participants with solid tumors to date. 
Prolongation of QTcF interval has been observed in monkeys at relatively high doses of ivosidenib (see 
Section 7.2.7.1) and has been identified as an expected risk of treatment with ivosidenib (see the 
Investigator's Brochure, Version 7.0). Cumulatively, QT prolongation has been experienced by 37 (17%) 
of the 223 participants in Study AG120-C-001 (8 participants [4%] had SAEs) and by 17 (10%) of the 168 
participants in Study AG120-C-002 (no SAEs reported). There has been one report of QT prolongation in 
Study AG120-221-C-001, as of April 18, 2017. 
Participants may be at increased risk for the development of QT prolongation when treated with 
ivosidenib in combination with fluoroquinolones, azole antifungal agents, or serotonin (5-HT3) 


40
 
antagonists. Investigators need to be vigilant; refrain from administering concomitant medications 
associated with QT prolongation and if no other therapeutic options are available, monitor participants 
receiving study treatment with the combination of these drugs, and evaluate ECG and electrolytes 
(including potassium, magnesium, and calcium) particularly in participants presenting with nausea, 
vomiting, or diarrhea. 
Participants who experience prolongation of the QTcF interval to> 480 ms (CTCAE Grade;::: 2} while 
receiving study treatment, should be promptly evaluated for causality of the QTcF prolongation and 
managed according to the following guidelines and Table 2: 
• 
Levels of electrolytes (potassium, calcium, and magnesium) should be checked and 
supplementation given to correct any values outside the normal range. 
• 
Concomitant therapies should be reviewed and adjusted as appropriate for medications 
with known QT prolonging effects. 
• 
If no other cause is identified and the treating investigator believes it is appropriate, 
particularly if QTcF remains elevated (after above measures have been implemented, or as 
determined by the Investigator}, study treatment may be interrupted, and an ECG should be 
rechecked in approximately 1 week after the QTcF prolongation was first observed or more 
frequently as clinically indicated. If QTcF has recovered or improved and the Investigator 
believes it is safe to do so, re-challenge with study treatment should be considered if held. 
• 
ECGs should be conducted at least weekly (eg, at every scheduled visit) for 2 weeks 
following QTcF reduction 
480 ms. 
Participants who experience prolongation of the QTcF interval to> 500 ms (CTCAE Grade;::: 3} while 
receiving study treatment, should be promptly evaluated for causality of the QTcF prolongation and 
managed according to the following guidelines and Table 2: 
• 
Levels of electrolytes (potassium, calcium, and magnesium) should be checked and 
supplementation given to correct any values outside the normal range. 
• 
Concomitant therapies should be reviewed and adjusted as appropriate for medications 
with known QT prolonging effects. 
• 
If no other cause is identified and the treating investigator believes it is appropriate, 
particularly if QTcF remains elevated (after above measures have been implemented, or as 
determined by the Investigator}, study treatment may be interrupted, and an ECG should be 
rechecked in approximately 1 week after the QTcF prolongation was first observed or more 
frequently as clinically indicated. If QTcF has recovered or improved and the Investigator 
believes it is safe to do so, re-challenge with study treatment should be considered if held. 
• 
ECGs should be conducted at least weekly (eg, at every scheduled visit) for 2 weeks 
following QTcF reduction 
480 ms. 


41
 
Table 2: Management of QT Prolongation by CTCAE Grade 
 
CTCAE Grade 
Management 
Grade 2 
(QTcF > 480 and :5 500 ms) 
• 
The dose of study treatment may be reduced to 250 
mg QD without interruption of dosing. The dose of 
study treatment may be re-escalated to the prior dose 
in 
14 days after QT prolongation has decreased to 
:5Grade 1. 
Grade 3 
(QTcF > 500 ms on at least two 
separate ECGs) 
• 
Hospitalization for continuous cardiac monitoring and 
evaluation by a cardiologist should both be 
considered. 
• 
Dosing with study treatment will be interrupted. If 
QTcF returns to within 30 ms of baseline or< 450 ms 
for males and< 470 ms for females within 14 days, 
treatment may be resumed at a reduced dose of 250 
mg. 
• 
The dose of study treatment cannot be re-escalated 
following dose reduction for Grade 3 QTcF 
prolongation unless the prolongation was associated 
with an electrolyte abnormality or concomitant 
medication. 
Grade 4 
(QTcF > 500 ms or> 60 ms change 
from baseline with Torsades de 
pointes or polymorphic ventricular 
tachycardia or signs/symptoms of 
serious arrhythmia) 
• 
Participants should be admitted to a hospital for 
continuous cardiac monitoring and discharged only 
after review by a cardiologist. 
• 
Dosing with study treatment should be permanently 
discontinued. 
 
 
5.7 Treatment of Study Drug-related Infusion Reactions 
Nivolumab and the combination therapies may induce infusion or hypersensitivity reactions. If such 
a reaction were to occur, it may manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgia, hypo- or hypertension, bronchospasm, or other symptoms. 
Infusion reactions should be graded according to CTCAE vs guidelines. Any Grade 3 or Grade 4 infusion 
reaction should be reported within 24 h to the Pl or designee and reported as an SAE if it meets the 
criteria. 
The nivolumab 30-min infusion will be administered first, with a 30-min rest, followed by the 
administration of ivosidinib. It may be unclear if an infusion reaction is due to the combination 
therapy, nivolumab, or to both study drugs. Therefore, one set of treatment recommendations 
(based on the most conservative treatments for infusion reactions due to either study drug) is 


42
 
provided below and may be modified based on clinical judgment, local treatment standards and 
guidelines, and/or specific symptoms, as appropriate: 
For Grade 1 symptoms: Mild reaction (e.g., localized cutaneous reactions including mild 
pruritus, flushing, rash), requires infusion rate to be decreased; intervention may be indicated. 
Decrease the rate of the study drug infusion until recovery from symptoms. 
Remain at bedside and monitor the participant's vital signs until resolution of symptoms. 
Diphenhydramine 50 mg may be administered at the discretion of the treating physician. 
When symptoms resolve, restart the infusion at the original infusion rate. 
If a participant has an infusion reaction with nivolumab, combination therapy can be given (without 
prophylactic medications) if the infusion reaction resolves within 3 h. For scheduling purposes, infusion 
may be given the next day. Prophylactic pre-infusion medications should be given prior to all subsequent 
nivolumab infusions. 
If a participant has an infusion reaction, prophylactic pre-infusion medications should be given prior to 
all subsequent infusions. 
The following prophylactic pre-infusion medications are recommended prior to future infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol (acetaminophen) 325 to 1,000 mg at least 
30 min before additional study drug administrations. 
For Grade 2 symptoms: Moderate reaction (i.e., any symptom not listed above [mild symptoms] or 
below [severe symptoms] such as generalized pruritus, flushing, rash, dyspnea, and hypotension with 
systolic blood pressure (BP) > 80 mmHg), requires infusion interruption but responds promptly to 
symptomatic treatment (e.g., antihistamines, nonsteroidal anti-inflammatory drugs, narcotics, 
corticosteroids, IV fluids); prophylactic pre-infusion medications indicated for 24 h. 
Interrupt the study drug infusion. 
Begin an IV infusion of normal saline, and treat the participant with diphenhydramine 50 mg IV (or 
equivalent) and/or paracetamol (acetaminophen) 325 to 1,000 mg. 
Remain at bedside and monitor the participant's vital signs until resolution of symptoms. Corticosteroid 
therapy may be administered at the discretion of the treating physician. 
When symptoms resolve, restart the infusion at 50% of the original infusion rate; if no further 
complications ensue after 30 min, the rate may be increased to 100% of the original infusion rate. 
Monitor the participant closely. If symptoms recur, immediately discontinue the infusion; no further 
study drug will be administered at that visit. Administer diphenhydramine 50 mg IV and remain at 
bedside and monitor the participant until resolution of symptoms. 
If a participant has an infusion reaction with nivolumab infusion, combination therapy 
infusion can be given (without prophylactic medications) if the infusion reaction resolves 
within 3 h. For scheduling purposes, the combination therapy infusion may be given the next 
day. Prophylactic pre-infusion medications should be given prior to all subsequent nivolumab 
infusions. 


43
 
If a participant has an infusion reaction with a combination therapy, prophylactic pre-infusion 
medications should be given prior to all subsequent infusions. 
The following prophylactic pre-infusion medications are recommended prior to future infusions: 
diphenhydramine 50 mg (or equivalent} and/or paracetamol (acetaminophen} 325 to 1,000 mg should 
be administered at least 30 min before additional study drug administrations. If necessary, 
corticosteroids (up to 25 mg of SoluCortef or equivalent} may be used. 
The amount of study drug infused must be recorded. 
For Grade 3 or Grade 4 symptoms: Severe reaction such as bronchospasm, generalized urticaria, systolic 
BP< 80 mmHg, or angioedema; Grade 3 symptoms including prolonged symptoms, which require 6 or 
more hours to respond to symptomatic medication and/or discontinuation of infusion; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae, such as 
renal impairment, pulmonary infiltrates; Grade 4: life-threatening; pressor or ventilation support 
indicated. 
Immediately discontinue the study drug infusion. No further study drug will be administered. The 
amount of study drug infused must be recorded on the case report form (CRF}. 
Begin an IV infusion of normal saline, and treat the participant as follows: Recommend bronchodilators, 
epinephrine 0.2 to 1.0 mg of a 1:1,000 solution for SC administration or 0.1 to 0.25 mg of a 1:10,000 
solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent}, as needed. 
Remain at bedside and monitor the participant's vital signs until recovery from symptoms. 
The participant should be monitored until the investigator is comfortable that the symptoms will not 
recur. 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or generalized 
pruritus within 1 week after treatment}, symptomatic treatment may be given (e.g., oral antihistamine, 
or corticosteroids}. 
5.8 Nivolumab AEs 
Nivolumab treatment should be permanently discontinued for the following: 
Any Grade 2 drug-related uveitis, eye pain, or blurred vision that does not respond to topical therapy 
and does not improve to Grade 1 severity within the OR requires systemic treatment 
Any Grade 3 non-skin, drug-related AE lasting> 7 days or recurs, with the following exceptions for 
laboratory abnormalities, diarrhea, drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity 
reactions, infusion reactions, and endocrinopathies: 
• 
Grade 3 drug-related diarrhea, uveitis, pneumonitis, bronchospasm, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation. 
• 
Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation. 


44
 
• 
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation except 
for the following: 
o 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation 
o 
Any drug-related liver function test (LFT) abnormality that meets the following 
criteria require discontinuation: 
■ 
Grade 3 drug-related AST, ALT, or total bilirubin requires 
discontinuation 
■ 
Concurrent AST or ALT> 3x ULN and total bilirubin > 2x ULN 
Any drug-related Grade 4 endocrinopathy and Grade 3 adrenal insufficiency requires discontinuation. 
Any Grade 4 drug-related AE or laboratory abnormality (including but not limited to creatinine, AST, ALT, 
or total bilirubin), except for the following events, which do not require discontinuation: 
• 
Grade 4 neutropenia ::; 7 days 
• 
Grade 4 lymphopenia or leukopenia 
• 
Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms 
or clinical manifestations of pancreatitis 
• 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 h of their onset 
Any drug-related Grade 4 endocrinopathy and Grade 3 adrenal insufficiency requires discontinuation. 
Any event that leads to delay in dosing lasting> 8 weeks from the previous dose requires 
discontinuation, with the following exceptions: 
• 
Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. 
• 
Dosing delays lasting > 8 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the Lead Investigator. 
Prior to re-initiating treatment in a participant with a dosing delay lasting> 6 weeks, the Lead 
Investigator must be consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed. Periodic study visits to assess safety and laboratory studies should also continue every 6 weeks 
or more frequently if clinically indicated during such dosing delays. 
Any AE, laboratory abnormality, or intercurrent illness, which presents a substantial clinical risk to the 
participant with continued nivolumab dosing as assessed by the treating investigator. 


45
 
5.9 Management of Nivolumab AEs 
Participants should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids. Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might require 
additional supportive care. The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to nivolumab. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
• 
Pneumonitis: 
o 
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o 
For Grade 3-4 events, immediately treat with IV steroids. Administer additional anti- 
inflammatory measures, as needed. 
o 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
• 
Diarrhea/Colitis: 
Participants should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus). 
o 
All participants who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o 
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o 
For Grade 3 or 4 diarrhea/colitis that persists> 1 week, treat with IV steroids followed 
by high dose oral steroids. 
o 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
o 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
• 
For TlDM or Grade 3-4 hyperglycemia 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 
hyperglycemia associated with metabolic acidosis or ketonuria. 


46
 
Evaluate participants with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide. 
• 
Hypophysitis: 
o 
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
o 
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
• 
Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor participants for changes in thyroid 
function (at the start of treatment, periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
o 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
■ 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy. 
■ 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyronine, is indicated per standard of care. 
o 
Grade 3-4 hyperthyroidism 
■ 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
• 
Hepatic: 
o 
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
■ 
Treat with IV or oral corticosteroids 
o 
For Grade 3-4 events, treat with IV corticosteroids for 24 to 48 h. 
o 
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Renal Failure or Nephritis: 
 
o 
For Grade 2 events, treat with corticosteroids. 
o 
For Grade 3-4 events, treat with systemic corticosteroids. 


47
 
o 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
5.10 Duration of Subject Participation 
5.10.1 Treatment Duration 
Treatment with ivosidenib and nivolumab will continue until any of the conditions for withdrawal of 
study treatments are met - as detailed in 4.4.1. 
Following discontinuation of study treatment, participants are to attend a Follow-up Visit at least 
28 days and no more than 33 days after the last dose for study assessments. When study treatment is 
withheld from a participant to resolve toxicity and the participant does not subsequently restart 
treatment, EOT is defined as the date when the study drug was first held. Participants should proceed 
with EOT assessments, safety and PFS follow-up. If the decision to not restart study treatment occurs 
outside of the 28-day safety follow-up window, the participant should proceed with PFS follow-up. 
5.11 Treatment Compliance 
Participants will be dispensed the appropriate number of labeled bottle(s) of ivosidenib for at least 
28 days of dosing on Day 1 of each cycle. The ivosidenib should be taken at approximately the same 
time each day. On clinic days, the ivosidenib should be taken any time prior to the nivolumab 
infusion. The participant will be asked to return all bottles and unused tablets (or empty bottles) on 
Day 1 of each cycle or at their next study visit for assessment of compliance with the dosing regimen. 
Participants will be given a dosing diary for each treatment cycle. They should record relevant 
information regarding their study treatment in the diary (e.g., confirmation that each daily dose was 
taken, reasons for missed doses). Treatment compliance will be assessed based on return of unused 
drug and the dosing diary. 
5.12 Study Treatment Accountability 
Accountability for the study treatment at the study site is the responsibility of the Investigator. The 
Investigator will ensure that the study treatment is used only in accordance with this protocol. Where 
allowed, the Investigator may choose to assign drug accountability responsibilities to a pharmacist or 
other appropriate individual. 
The Investigator or delegate will maintain accurate drug accountability records indicating the drug's 
delivery date to the site, inventory at the site, use by each participant, and disposal of the drug. These 
records will adequately document that the participants were provided the doses as specified in the 
protocol and should reconcile all study treatment Accountability records will include dates, quantities, 
batch/serial numbers, expiration dates (if applicable), and participant numbers. 
Study treatment must not be used for any purpose other than the present study. Study treatment 
that has been dispensed to a participant and returned unused must not be re-dispensed to a 
different participant. 
Participants will receive instructions for home administration of study treatment along with a diary to 
record the date and time of each dose, as well as the number of tablets taken. 
All unused and used study treatment should be retained at the site until they are inventoried and 
verified by study site personnel and/or the study monitor. All used, unused, or expired study treatment 


48
 
will be returned to the Drug Manufacturer or its designee or if authorized, disposed of at the study site 
per the site's Standard Operating Procedures (SOPs) and documented. All material containing ivosidenib 
will be treated and disposed of as hazardous waste in accordance with governing regulations. 
5.13 Prior and Concomitant Medications and Treatments 
5.13.1 Prior Medications and Procedures 
All medications administered, and procedures conducted within 28 days prior to the first day of study 
treatment administration are to be recorded in the medical record. In addition, all prior treatments for 
the underlying malignancy should be recorded. 
5.13.2 Concomitant Therapy Requiring Careful Monitoring 
Concomitant use of drugs with a potential QT prolongation should be avoided and replaced with 
alternative treatments. If this is not possible, participants receiving these drugs should be adequately 
monitored. 
These medications include but are not limited to: 
• Fluoroquinolones such as ciprofloxacin and moxifloxacin 
• Azole antifungals such as fluconazole and posaconazole 
• Serotonin (S-HT3) antagonists such as granisetron and ondansetron 
Other examples of drugs known to prolong the QT interval are listed in Appendix 11.5. 
5.13.3 Prohibited Concomitant Therapy 
Anticancer therapy other than the treatment outlined in the protocol is not permitted during the study. 
If alternative therapy is required for treatment of the participant's disease, the participant should be 
discontinued from the study treatment. 
5.13.4 Allowed Concomitant Medications, Procedures, and Treatments 
Medications and treatments other than those specified above are permitted during the study. All 
intercurrent medical conditions and complications of the underlying malignancy will be treated at the 
discretion of the Investigator according to acceptable local standards of medical care. 
If clinically indicated, palliative biliary decompression procedures will be permitted on-study after 
discussion with the Pl. 
Participants should receive analgesics, antiemetics, anti-infectives, antipyretics, blood products, and any 
other best supportive care measures (excluding anticancer therapy) as necessary, assuming no drug 
interaction potential. 
Growth factors (granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony- 
stimulating factor [GM-CSF]) can be used to support participants who have developed dose-limiting 
Grade 4 neutropenia or Grade 3 neutropenia with fever and/or infection. The use of erythropoiesis 
stimulating agents is permitted according to the American Society of Clinical Oncology Guidelines (Rizzo, 
Brouwers et al. 2010). 
All concomitant medications and any procedures performed during the study, including those used to 
treat AEs, are to be recorded. 


49
 
6.0 Study Processes and Assessments 
6.1 Schedule of Events 
Table 3 provides the schedule of assessments for this study. Pre-screening or screening for IDH1 will 
occur via CLIA certified standard of care sequencing. After obtaining written informed consent for the 
study overall, all participants will undergo Screening procedures to determine eligibility within 28 days 
prior to the start of study treatment on C1D1. Participants are to attend study center visits as outlined in 
the Schedule of Assessments (Table 3). 
An EOT Visit will be conducted as soon as possible after discontinuing study treatment (within 5 days of 
last dose of study treatment, if study drug dosing has not been delayed); in addition, participants are to 
attend a Follow-up Visit 28 days (no more than 33 days) after the last dose of study treatment for final 
safety assessments. If a participant's dose is held and it is subsequently decided to discontinue 
treatment, the EOT Visit should be conducted as soon as possible, within 28 days (and no more than 33 
days) after the last dose of study drug. 


Table 3: Study Calendar Showing Schedule of Assessments 
 
fisit/Cycle: 
 
Post 
Screening 
Cycle 1
(±2 days) 
Cycle 2
(±2 days) 
Cycle 3
(±2 days) 
Cycle 4+7
(±2 days)
EOT 
Treatment 
I PFS Follow- up 
Follow-up 
Study Day: 
D-28 
D1 
D15 
D1 
D15 
D1 
D15 
D1 
D+28 
 
Informed 
Consent 
 
X 
 
 
 
 
 
 
 
 
 
Review Entry 
Criteria 
 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Disease History 
X 
 
 
 
 
 
 
 
 
 
Medical and Surgical 
History 
 
X 
 
 
 
 
 
 
 
 
 
Medication 
History 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Complete Physical 
Exam 
 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Symptom Directed 
Physical Exam 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Vital Signs 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
IECG 
X 
I 
X 
I 
X 
I 
X 
I 
X 
X 
 
X 
X 
 
 
 
 
53 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


55
 
 
 
Visit/Cycle: 
 
I 
Screening 
 
I 
 
I 
Cycle 1
(±2 days) 
 
 
PFS 
Follow- up 
 
Post
Cycle 2
(±2 days) 
Cycle 3
(±2 days) 
Cycle 4+7
(±2 days)
EOT 
Treatment 
Follow-up 
I
Study Day: 
D-28 
D1
D15
D1
D15
D1
D15
D1 
D+28 
 
 
Correlative Blood - 
ctDNA 
 
 
 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
2-HG PD Analysis 
(plasma)4 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Stool 
 
X 
 
 
 
 
 
 
 
 


I 
reening 
 
 
PFS 
Follow- up 
 
Post
Cycle 1
(±2 days) 
Cycle 2
(±2 days) 
Cycle 3
(±2 days) 
Cycle 4 +7
(±2 days) 
EOT 
Treatment 
Follow-up 
I
I
D-28 
D1
D15 
D1 
D15
D1 
D15 
D1 
D+28 
 
Registration and Treatment: 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
X 
 
Tumor Assessments 
X 
 
 
8 weeks(± 7 days) after Cycle 1 including EOT and PFS follow-up 
Other Clinical Assessments 
X 
X 
X 
X 
X 
 
X 
X 
xs 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 


57
 
Abbreviations: D = Day; DNA= deoxyribonucleic acid; ECOG = Eastern Cooperative 
Oncology Group; EQT= end of treatment; PFS = progression-free survival; PS= performance 
status; RECIST = Response Evaluation Criteria in Solid Tumors 
 
Archival tissue to be submitted on all patients. At least 10 (solid tumor) patients to be biopsied, pending 
funding 
2Female participants with reproductive potential must have negative serum pregnancy testing within 24 h prior 
to the initial administration of study drug, then every 4 ± 1 week, or a negative confirmation from an 
obstetrician in case of equivocal serum pregnancy results. Females of reproductive potential are defined as 
sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal 
occlusion or who have not been naturally postmenopausal (ie, who have not menstruated) for at least 24 
consecutive months (ie, have not had menses at any time in the preceding 24 consecutive months). 
3 
 ctDNA to be collected C1D1, C1D15, C3D1, C4D1 (time of pt response assessment) and at time of 
progression. PBMCs to be collected C1D1, C1D15, C2D1, C3D1, C4D1 (time of pt response assessment) and at 
time of progression. 
Germline DNA to be collected C1D1 
Serum to be drawn C1D1, C1D15, C2D1, C3D1, C4D1 (time of pt response assessment) and at the time of 
progression. 
4Modification for 2-HG levels: Drawn on C1D1 (as baseline), at 1 month (C2D1), 3 months (C4D1) and at time 
of disease progression 
5Submit all required materials (eligibility checklist, source documentation, and signed consent form) to confirm 
eligibility and required pre-study procedures to the CRA a minimum of 48 h prior to the participant's 
scheduled therapy start date. Full details listed in  Registration Procedures 
 
Note that nivolumab will be dosed Q28 days via IV infusion, while ivosidenib will be continuous PO daily 
dosing 
After cycle 3 (i.e., from C4 onwards), study visits will be monthly. 
8 
SAEs occurring within 100 days post last study drug dose must be reported to BMS World Wide 
Safety and Agios 
9 
Specific imaging modalities detailed under section 6.5 (Efficacy Assessments) 
10 
As clinically indicated 
11 
See Section 1.3.4 for research blood draw time points 
12 
See Section 6.4.3 - Safety Laboratory Assessments 
 
6.2 Informed Consent 
A complete description of the study is to be presented to each potential participant and a signed and 
dated informed consent is to be obtained before any study specific procedures are performed. A legally 
authorized representative may consent on behalf of a participant who is otherwise unable to provide 
informed consent if acceptable to and approved by the site's Institutional Review Board 
(IRB)/lndependent Ethics Committee (IEC). 
Demographic Data and Medical, Surgical, and Medication History 
Subject demographic data, including gender, date of birth, age, race, and ethnicity, will be obtained 
during Screening, according to applicable local regulations. 
A complete medical and surgical history, including the site of underlying sites of malignancy and the 
date of confirmation of the histologic diagnosis of the underlying malignancy will be obtained during 
Screening. The medical history is to include all relevant prior medical history as well as all current 


58
 
medical conditions. 
All medications administered and procedures conducted within 28 days prior to C101 should be 
reported in the medical record. In addition, all prior treatment regimens for the underlying malignancy 
will be reported. 
6.3 Gene Mutation Analysis and Molecular Characterization 
Tissue from a pre-treatment fresh or banked tumor biopsy will be required for all screened participants. 
Corresponding pathology report is also required if available. 
6.4 Safety Assessments 
 
6.4.1 Physical Examination and ECOG Performance Status 
A complete physical examination, including assessment of weight, will be obtained at Screening, C1D1, 
C301 and every Day 1 of each cycle thereafter, EOT and post treatment follow up visit and PFS follow 
up. A symptom directed physical examination should be completed on C1D15, C2D1, and C2D15. Height 
will be obtained at the Screening Visit only. Participants should be monitored for rash at physical 
examinations and during assessments of adverse reactions. 
Determination of ECOG PS will be performed at Screening, on Day 1 of each treatment cycle thereafter, 
at the EOT Visit, at the Post Treatment Follow-up Visit, and PFS follow up. See Appendix 11.1 for ECOG 
PS scoring. 
6.4.2 Vital Signs and ECG 
Vital signs, including systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature, 
will be obtained at Screening, Days 1 and 15 of Cycles 1 and 2, on Day 1 of each treatment cycle 
thereafter, EOT and post treatment follow up Visit and PFS follow up. Assessments should be 
conducted while the participant is seated or supine. 
 
ECG will be obtained at Screening, Days 1 and 15 of Cycles 1 and 2, on Day 1 of each treatment cycle 
thereafter, EOT and post treatment follow up Visit. Refer to section 5.7 for management of QT 
prolongation. 
6.4.3 Safety Laboratory Assessments 
Clinical laboratory evaluations are to be performed by the local laboratory. 
Clinical laboratory evaluations are to be conducted according to the Schedule of Assessments (Table 3). 
Clinical laboratory evaluations may be collected up to 24 h prior to study visit as long as the labs were 
collected within the visit window (±2 days). In addition, all clinically significant laboratory abnormalities 
noted on testing will be followed by repeat testing and further investigated according to the judgment 
of the Treating Investigator. 
The safety laboratory parameters to be evaluated by the Treating Investigator are: 
Hematology: Hemoglobin, red blood cell (RBC) count, white blood cell (WBC) count and differential{% 
neutrophils, % bands), platelet count with differential 
Chemistry: Sodium, potassium, calcium, magnesium, phosphorus, albumin, glucose, blood urea nitrogen 
(BUN), creatinine, uric acid, lactate dehydrogenase (LOH), alkaline phosphatase (ALP), AST, ALT, total 
bilirubin, direct bilirubin 


59
 
Thyroid Studies: Thyroid stimulating hormone (TSH), total triiodothyronine (T3, If TSH is abnormal}, free 
thyroxine (T4, If TSH is abnormal) 
Blood for hematology and chemistries is to be obtained at screening, Cl - C3 days 1 and 15, on Day 1 of 
every treatment cycle thereafter, and at the EOT Visit. If assessments for hematology and serum 
chemistry were performed within 3 days prior to ClDl, these do not need to be repeated at the ClDl 
Visit. 
Pregnancy Test: All WOCBP must have a negative pregnancy test to be eligible. Pregnancy testing to be 
done every 4 weeks±l week while on study treatment. 
Adverse Events 
 
All AEs will be graded using the NCI CTCAE version 5 grading system (Appendix 11.7). 
6.5 Efficacy Assessments 
 
6.5.1 Response to Treatment 
The efficacy of ivosidenib and nivolumab will be evaluated by assessing response to treatment according 
to RECIST vl.1 (Appendix 11.8) or RANO Criteria (Appendix 11.9) (Eisenhauer, Therasse et al. 2009). 
Radiographic assessments (CT or MRI) to obtain tumor measurements are to be conducted every 8 
weeks (±7 days) from ClDl, independent of dose-delays and/or dose interruptions, and/or at any time 
when progression of disease is suspected. CT imaging of the chest, abdomen, and pelvis (torso) with 
triphasic IV contrast (30 millisieverts [mSv] per scan) should be performed at baseline and on study for 
solid tumor patients (not glioma patients). For participants with allergy to IV iodine contrast, CT of the 
chest without IV contrast and MRI of the abdomen with IV contrast should be performed at baseline and 
on study. For patients with solid tumors, brain scans with CT (2 mSv per scan) or MRI should be 
performed at baseline in participants with known treated brain metastases and on study at the same 
imaging time points as Torso imaging. 
 
For the glioma cohort, MRI with contrast is required for baseline and response assessments, and CT is 
only allowed if an MRI is contraindicated (in the view of the treating physician). Bone scans (4 mSv per 
scan) will be performed at baseline if disease is suspected and on study as appropriate as the same 
imaging time points as Torso imaging. Any ancillary findings on the radiographic assessments will be 
communicated to the appropriate physician for notification to the participant. The same method (CT or 
MRI) should be used consistently for any given participant. For participants who discontinue study drug 
for reasons other than disease progression, an assessment will be conducted at the EOT Visit and every 
8 weeks thereafter (with the exception of those participants who initiate a new cancer therapy after 
discontinuing study treatment) until any of the conditions for withdrawal of study treatments are met - 
as detailed in 4.4.1. 
6.6 Correlative Studies 
 
6.6.1 Nanostring Assays of Paired Samples 
Morphologic predictors of response include expression of PD-Ll, an interferon gamma target indicative 
of an active inflammatory response to tumor, and the presence of tumor infiltrating CD8 T cells, 
dendritic cells, and NK cells of particular phenotypes. The therapeutic hypothesis for this study centers 
on the possibility that treatment with ivosidenib will either induce or augment an antitumor 
inflammatory response, and/or will induce production of neoantigen presenting MHC class I in the 


60
 
tumor. 
The primary goal of the biopsy analysis is to determine whether the tumor has sustained an infiltration 
by innate and adaptive immune cells, and/or increased tumor expression of antigen expression 
apparatus such as components of MHC Class I, consistent with the therapeutic hypothesis. The 
secondary goal is to determine whether either the baseline level of inflammatory infiltrate or the level 
induced by ivosidenib treatment is predictive of immediate an extended response to the combination of 
ivosidenib with nivolumab. 
The primary assays for analysis of the paired biopsies are the Nanostring 10 360 assay, an extensively 
validated transcript profiling assay used for semi-quantitative cell enumeration and transcriptional 
response in biopsies (Danaher, Warren et al. 2017), as well as immunofluorescence based direct 
enumeration of immune cells and their spatial co-localization. Assay is subject to change based on 
available technologies at the time of analysis. 
The primary hypothesis for statistical analysis of the paired biopsies is to accept or reject the hypothesis 
that the tumor inflammation signature (TIS, or T cell-inflamed GEP), a function calculated from the 
abundance of 18 transcripts detected in the sample (Table below), has changed in the tumor due to 
therapy. This function is highly correlated with anti-PDl antibody treatment outcome (Ayers, Lunceford 
et al. 2017). 
 
Table 4: Eighteen Component Transcripts of Tumor Inflamed Signature (TIS) Score 
 
TIGIT 
PD-Ll 
PSMBlO 
STATl 
CD27 
CXCR6 
IDO1 
HLADRBl 
CD8A 
CMKLRl 
CXCL9 
HLAE 
PD-L2 
NKG7 
HLADQAl 
 
LAG3 
CCIS 
CD276 
 
 
Several outcomes may be envisaged: 
• 
lvosidenib causes an increase in TIS in a subset of patients and that increase is associated with 
an increase in PFS. 
• 
Baseline TIS is associated with PFS, and changes induced ivosidenib treatment are not 
associated with changes in PFS. 
• 
lvosidenib does not affect TIS in any patient. 
 
7.0 Safety and AEs Assessing, Recording, and Reporting 
AEs will be monitored throughout the study (once participants have received study drug); SAEs that are 
assessed as related to study treatment that occur> 100 days post treatment also are to be reported. 
All AEs should be monitored until they are resolved or are clearly determined to be due to a 
participant's stable or chronic condition or intercurrent illness(es). 
Adverse Event Reporting Period 


61
 
Investigators will seek information on AEs at each participant contact, as outlined below. All AEs, 
whether reported by the participant or noted by study personnel, will be recorded in the participant's 
medical record. 
After informed consent has been obtained but prior to initiation of study drug, only SAEs caused by a 
protocol-mandated intervention should be reported (e.g., SAEs related to invasive study procedures 
such as biopsies). 
After initiation of study drug, all AEs and SAEs regardless of attribution will be collected at every visit 
until 100 days following the last administration of study treatment or until study 
discontinuation/termination or until initiation of subsequent anticancer therapy, whichever occurs first. 
Participants will be assessed at the Follow-up Visit to determine if any new AEs have occurred. After this 
period, Investigators should report only SAEs that are considered to be related to study treatment. 
All Serious Adverse Events (SAEs) that occur following the participant's first does of study treatment 
through 100 days of discontinuation of dosing must be reported to according to section 7.3, whether 
related or not related to study drug. 
Following the participant's first dose of study treatment, all SAEs, whether related or not related to 
study drug, are collected, including those thought to be associated with protocol-specified procedures. 
The investigator should report any SAE occurring after these aforementioned time periods, which is 
believed to be related to study drug or protocol-specified procedure. 
7.1 Definition of AEs 
7.1.1 AEs 
An AE (also referred to as an adverse experience) is any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. An AE can therefore be any of the 
following: 
Any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a drug, whether or not considered related to the drug. 
Any new disease or exacerbation of an existing disease (a worsening in the character, frequency, or 
severity of a known condition). 
Recurrence of an intermittent medical condition (eg, headache) not present at baseline. 
 
Any deterioration in a laboratory value or other clinical test (eg, ECG, X-ray) that is associated with 
symptoms or leads to a change in study treatment or concomitant treatment or discontinuation from 
study treatment. 
AEs that are related to a protocol-mandated intervention, including those that occur prior to assignment 
of study treatment (eg, screening invasive procedures such as biopsies). 
An AE can arise from any use of the drugs (eg, off-label and in combination with another drug) and from 
any route of administration, formulation, or dose, including an overdose. 
7.1.2 Progression of Underlying Malignancy 
Progression of underlying malignancy should not be reported as an AE if it is clearly consistent with the 
suspected progression of the underlying cancer as defined by RECIST vl.1 (solid tumor) or RANO 


62
 
(glioma). Clinical symptoms of progression may be reported as AEs if the symptoms cannot be 
determined as exclusively due to the progression of the participant's underlying malignancy or does 
not fit the expected pattern of progression for the disease. 
If there is any uncertainty about an AE being due only to the disease under study, it should be reported 
as an AE or SAE. 
7.1.3 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization or prolonged hospitalization should be documented and reported 
as an SAE except as outlined below. 
The following hospitalization scenarios are not considered to be SAEs: 
 
• 
Hospitalization for respite care 
 
• 
Standard procedure for protocol therapy administration; however, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be reported 
as an SAE 
• 
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition 
• 
Administration of blood or platelet transfusion as routine treatment of studied indication; 
however, hospitalization or prolonged hospitalization for a complication of such transfusion 
remains a reportable SAE 
• 
A procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling); however, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable SAE 
• 
Hospitalization or prolongation of hospitalization for technical, practical, or social reasons, 
in absence of an AE. 
7.1.4 
Persistent or Recurrent AEs 
A persistent AE is one that extends continuously, without resolution, between participant evaluation 
time points. The initial severity of the event should be recorded, and the severity should be updated 
to reflect the most extreme severity any time the event worsens in intensity or grade. 
A procedure that is planned (i.e., planned prior to start of treatment on study); must be documented 
in the source document and the eCRF; hospitalization or prolonged hospitalization for a complication 
remains a reportable SAE 
An elective treatment of or an elective procedure for a pre-existing condition, unrelated to the studied 
indication, that has not worsened from baseline 
7.1.5 
Related AES 
A related AE is any AE for which there is a reasonable possibility that the drug(s) caused the AE. 
Assessment of Causality of AEs 
Investigators should use their knowledge of the participant, the circumstances surrounding the event, 
and an evaluation of any potential alternative causes to determine whether or not an AE is considered 


63
 
to be related to the study treatment, per Table 5 below. The following guidance should be taken into 
consideration: 
• 
Temporal relationship of event onset to the initiation of study treatment 
• 
Course of the event, considering especially the effects of dose reduction, discontinuation 
of study treatment, or reintroduction of study treatment (where applicable) 
• 
Known association of the event with the study treatment or with similar treatments 
• 
Known association of the event with the disease under study 
 
• 
Presence of risk factors in the participant or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 5: Causal Attribution Guidance 
 
• 
Is the adverse event suspected to be caused by the study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
Definitely 
related 
There is a reasonable causal relationship between the study drug and the AE. The event 
responds to withdrawal of investigational product (dechallenge), and recurs with 
rechallenge when clinically feasible. 
Probably 
related 
There is a reasonable causal relationship between the study drug and the AE. The event 
responds to dechallenge. 
Possibly 
related 
There is a reasonable possibility that the drug caused the adverse event. The investigator 
can provide a rationale or evidence to suggest a causal relationship between the study 
drug and the adverse event other than just a temporal relationship. 
Unlikely 
related 
There is only a temporal relationship to study drug, but not a reasonable causal 
relationship between the investigational product and the AE. 
Unrelated 
There is no temporal relationship to study drug; there is a reasonable causal relationship 
to another drug product, concurrent disease, or circumstance. 
 
 
7.1.6 Serious AEs (SAEs) 
An AE or suspected adverse reaction is considered a serious AE (SAE) if, in the view of either 
Investigator, it could result in any of the following outcomes: 
• 
Fatal (i.e., the AE actually causes or leads to death). 
 
• 
Life-threatening. Life-threatening means that the participant was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction that hypothetically might 
have caused death had it occurred in a more severe form. 


64
 
• 
In-patient hospitalization or prolongation of existing hospitalization. Hospitalization admissions 
and/or surgical operations scheduled to occur during the study period but planned prior to study 
entry are not considered AEs if the illness or disease existed before the participant was enrolled 
in the study, provided that it did not deteriorate in an unexpected manner during the study (eg, 
surgery performed earlier than planned}. 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother or father exposed 
to study treatment. 
• 
Important medical event. An important medical event is an event that may not result in death, 
be life- threatening, or require hospitalization but may be considered an SAE when, based upon 
appropriate medical judgment, it may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in the definitions for SAEs. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in in-patient 
hospitalization, or the development of drug dependency or drug abuse. 
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an AE (rated as 
mild, moderate, or severe, or according to NCI CTCAE criteria}; the event itself may be of relatively 
minor medical significance (such as severe headache without any further findings}. 
Severity and seriousness need to be independently assessed for each AE recorded on the eCRF. 
7.2 Procedures for Reporting AEs and SAEs 
 
7.2.1 Routine AE Reporting 
All AEs (serious and non-serious} spontaneously reported by the participant and/or in response to 
an open question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures will be recorded. The Investigator must determine the intensity of any 
adverse events according to the NCI CTCAE version 5 and their causal relationship to study 
treatment. Any clinically relevant deterioration in laboratory assessments or other clinical findings is 
considered an AE and must be recorded. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. 
7.2.2 SAE Reporting 
All events meeting the definition of a serious adverse events, which occur after the date of first dose of 
study treatment and within 100 days of the last dose of study treatment, should be reported according 
to the departmental SAE checklist and SAE form. The initial SAE form should be sent to the following 
within 1 business day of the Principal Investigator becoming aware: 
 
1. Sponsor-Investigator: Jason Luke, lukejj@upmc.edu 
2. crssafetysubmissions@upmc.edu 
3. Local Institutional Review Board when reporting requirements are met. 
4. BMS SAE Email Address: Worldwide.Safety@BMS.com or facsimile +1 609-818-3804 
5. Servier SAE Email Address:  pharmacovigilance-US@servier.com 


65
 
In addition to completing appropriate patient demographic and suspect medication information, the 
report should include as applicable the following information that is available at the time of report 
within the Sections Band C of the departmental SAE form: 
 
• 
CTCAE term(s) and grade(s) 
• 
current status of study drug 
• 
all interventions to address the AE (testing and result, treatment and response) 
• 
hospitalization and/or discharge dates 
• 
event relationship to study drug 
 
Pregnancies and overdoses must also be reported and submitted as instructed above. 
 
Follow-up reports: 
Additional information may be added to a previously submitted report by adding to the original 
departmental SAE form and submitting it as follow-up or creating supplemental summary information 
and submitting it as follow-up with the original departmental SAE form. All SAEs should be followed to 
resolution or stabilization. 
The Sponsor will reconcile the clinical database SAE cases (case level only) transmitted to BMS Global 
Pharmacovigilance (Worldwide.Safety@bms.com). Frequency of reconciliation should be every 3 
months and prior to the database lock or final data summary. BMS GPV&E will email, upon request from 
the Investigator, the GPV&E reconciliation report. Requests for reconciliation should be sent to 
aepbusinessprocess@bms.com. The data elements listed on the GPV&E reconciliation report will be 
used for case identification purposes. If the Investigator determines a case was not transmitted to BMS 
GPV&E, the case should be sent immediately to BMS. 
7.2.3 Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded rather than only individual signs and symptoms (eg, record only 
liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis or 
syndrome at the time of reporting, each individual event should be recorded. 
7.2.4 AEs Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) should be 
identified by their primary cause, with the exception of severe or serious secondary events. However, 
medically significant AEs occurring secondary to an initiating event that are separated in time should be 
recorded as independent events. 
 
7.2.4.1 QT Prolongation 
Prolongation of heart-rate corrected QT (QTc) interval has been observed in monkeys at relatively high 
doses of ivosidenib as well as in patients while receiving ivosidenib. Please refer to the current 
ivosidenib 1B for detailed information. 
Participants may be at increased risk for the development of QT prolongation when treated with 
ivosidenib in combination with fluoroquinolones, azole antifungal agents, or serotonin (S-HT3) 
antagonists. Investigators need to be vigilant regarding concomitant medications associated with QT 


66
 
prolongation, and if no other therapeutic options are available, monitor participants receiving AG-120 
with the combination of these drugs, and evaluate ECG and electrolytes (including potassium, 
magnesium, and calcium) particularly in participants presenting with nausea, vomiting, or diarrhea. 
Participants who experience prolongation of the heart-rate corrected QT interval, Fridericia's correction 
(QTcF) to> 480 ms (Grade 2) while treated with ivosidenib, should be promptly evaluated for causality 
of the QTc prolongation and managed according. For details, refer to the current Investigator brochure. 
Once the signs and symptoms resolve and the participant's clinical condition improves, ivosidenib may 
be reinitiated. 
 
7.2.4.2 Leukoencephalopathy 
Leukoencephalopathy is a potential risk associated with ivosidenib treatment based on clinical safety 
findings observed across the ivosidenib clinical development program. Progressive multifocal 
leukoencephalopathy (PML) and posterior reversible encephalopathy syndrome (PRES), both Grade 3 
SAEs, have each been reported in one participant. 
The signs and/or symptoms of PML may begin gradually, usually worsen rapidly, and vary depending on 
which part of the brain is infected. Signs and symptoms may include difficulty with walking and other 
movements, progressive weakness, decline in mental function, visual field deficits, and speech and 
language disturbances. Rarely, headaches and seizures occur. Participants should be monitored for 
onset of signs or symptoms suggestive of PML. Diagnostic evaluations may include consultation with a 
neurologist, MRI of the brain, lumbar puncture, and/or brain biopsy as clinically warranted. The 
Investigator should immediately contact the Study Medical Monitor when PML is a suspected or 
confirmed diagnosis. Treatment with ivosidenib should be suspended in the setting of suspected PML 
and permanently discontinued in participants with confirmed PML. 
PRES is a rare clinico-radiological neurological syndrome (Linda and von Heijne 2015). Clinical 
characteristics may include sub-acute onset of headache, hypertension, seizures, altered mental status, 
visual disturbances, and occasionally other focal neurological signs. Radiologically, signs of vasogenic 
edema are usually seen bilaterally in the white mater of the parieto-occipital lobes, but changes can also 
be seen in frontal and temporal lobes, brainstem, cerebellum, and in cortical as well as deep gray 
matter. Participants should be monitored for onset of neurological signs and/or symptoms that are 
clinically associated with PRES. Diagnostic evaluations may include consultation with a neurologist, MRI 
of the brain, and other recognized standard of care measures as clinically warranted. Additionally, the 
Investigator should consult with the Study Medical Monitor for management guidelines to be utilized in 
the setting of suspected or confirmed PRES. 
Refer to Section 6.5.8.1 (PML) and Section 6.5.8.2 (PRES) in the AG-120 IB for further details on these 
events. 
 
7.2.4.3 Sensorimotor Neuropathy/Polyneuropathy 
Sensorimotor neuropathy/polyneuropathy is a potential risk associated with ivosidenib treatment 
based on safety findings observed across the ivosidenib clinical development program. Guillain-Barre 
syndrome (Grade 2 SAE in one participant; Grade 3 SAE in one participant) and lumbosacral plexopathy 
(Grade 2 SAE in one participant) are rare, serious syndromes that affect the central and peripheral 
nervous systems. 
Participants should be monitored for onset of new signs or symptoms or motor and/or sensory 


67
 
neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. If a participant 
experiences signs or symptoms suggestive of sensorimotor neuropathy, Guillain-Barre syndrome, or 
lumbosacral plexopathy, diagnostic evaluation may include a consultation with a neurologist, lumbar 
puncture, and electromyography. The Investigator should immediately contain the Study Medical 
Monitor when Guillain-Barre syndrome is a suspected or confirmed diagnosis. lvosidenib should be 
permanently discontinued in participants with a confirmed diagnosis of Guillain-Barre syndrome. 
Refer to Section 7.2.4.3 (Sensorimotor Neuropathy/Polyneuropathy) in the AG-120 1B for further 
details on these events. 
7.2.5 Overdose or Incorrect Administration 
Study treatment overdose is the accidental or intentional use of the drug in an amount higher than the 
dose being studied. An overdose or incorrect administration of study treatment is not an AE unless it 
results in untoward medical effects. If the associated AE fulfills serious criteria, the event should be 
reported to the Lead Investigator within 1 business day after learning of the event. All occurrences of 
overdose of nivolumab must be reported as an SAE to Agios and BMS World Wide Safety. 
7.2.6 Review of Safety Information: Sponsor Responsibilities 
The sponsor must promptly review all information relevant to the safety of the drug obtained or 
otherwise received by the sponsor from foreign or domestic sources, including information derived 
from any clinical or epidemiological investigations, animal or in vitro studies, reports in the scientific 
literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities and 
reports of foreign commercial marketing experience for drugs that are not marketed in the United 
States. 
7.2.7 IND Safety Reports 
The sponsor must notify FDA and all participating investigators (i.e., all investigators to whom the 
sponsor is providing drug under its INDs or under any investigator's IND} in an IND safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting under 
Sections 7.2.10.1 to 7.2.10.4 below. In each IND safety report, the sponsor must identify all IND safety 
reports previously submitted to FDA concerning a similar suspected adverse reaction and must analyze 
the significance of the suspected adverse reaction in light of previous, similar reports or any other 
relevant information. 
 
7.2.7.1 Serious and unexpected suspected adverse reaction 
The sponsor must report any suspected adverse reaction that is both serious and unexpected. The 
sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to 
suggest a causal relationship between the drug and the adverse event, such as: 
 
• 
A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome); 
• 
One or more occurrences of an event that is not commonly associated with drug exposure, but 
is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture); 
• 
An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events that 
commonly occur in the study population independent of drug therapy) that indicates those 


68
 
events occur more frequently in the drug treatment group than in a concurrent or historical 
control group. 
 
7.2.7.2 Findings from other studies 
The sponsor must report any findings from epidemiological studies, pooled analysis of multiple 
studies, or clinical studies (other than those reported under section 1.5.1), whether or not conducted 
under an IND, and whether or not conducted by the sponsor, that suggest a significant risk in humans 
exposed to the drug. Ordinarily, such a finding would result in a safety-related change in the protocol, 
informed consent, investigator brochure (excluding routine updates of these documents), or other 
aspects of the overall conduct of the clinical investigation. 
 
7.2.7.3 Findings from animal or in vitro testing 
The sponsor must report any findings from animal or in vitro testing, whether or not conducted by the 
sponsor, that suggest a significant risk in humans exposed to the drug, such as reports of mutagenicity, 
teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the expected 
human exposure. Ordinarily, any such findings would result in a safety-related change in the protocol, 
informed consent, investigator brochure (excluding routine updates of these documents), or other 
aspects of the overall conduct of the clinical investigation. 
 
7.2.7.4 Increased rate of occurrence of serious suspected adverse reactions 
The sponsor must report any clinically important increase in the rate of a serious suspected adverse 
reaction over that listed in the protocol or investigator brochure. 
7.2.8 Submission of IND safety reports 
The sponsor must submit each IND safety report in a narrative format or on Form FDA 3500A or in an 
electronic format that FDA can process, review, and archive. FDA will periodically issue guidance on 
how to provide the electronic submission (e.g., method of transmission, media, file formats, 
preparation and organization of files). The sponsor may submit foreign suspected adverse reactions on 
a Council for International Organizations of Medical Sciences (CIOMS) I Form instead of a Form FDA 
3500A. Reports of overall findings or pooled analyses from published and unpublished in vitro, animal, 
epidemiological, or clinical studies must be submitted in a narrative format. Each notification to FDA 
must bear prominent identification of its contents, i.e., "IND Safety Report," and must be transmitted 
to the review division in the Center for Drug Evaluation and Research or in the Center for Biologics 
Evaluation and Research that has responsibility for review of the IND. Upon request from FDA, the 
sponsor must submit to FDA any additional data or information that the agency deems necessary, as 
soon as possible, but in no case later than 15 calendar days after receiving the request. 
7.2.8.1 Unexpected fatal or life-threatening suspected adverse reaction reports 
The sponsor must also notify FDA of any unexpected fatal or life-threatening suspected adverse 
reaction as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt 
of the information. 
 
7.2.8.2 Reporting format or frequency 
 
FDA may require a sponsor to submit IND safety reports in a format or at a frequency different than 
that required under this paragraph. The sponsor may also propose and adopt a different reporting 


69
 
format or frequency if the change is agreed to in advance by the director of the FDA review division 
that has responsibility for review of the IND. 
 
7.2.8.3 Investigations of marketed drugs 
A sponsor of a clinical study of a drug marketed or approved in the United States that is conducted 
under an IND is required to submit IND safety reports for suspected adverse reactions that are 
observed in the clinical study, at domestic or foreign study sites. The sponsor must also submit safety 
information from the clinical study as prescribed by the post marketing safety reporting requirements. 
 
7.2.8.4 Reporting study endpoints 
Study endpoints (e.g., mortality or major morbidity) must be reported to FDA by the sponsor as 
described in the protocol and ordinarily would not be reported under Section 1.7 third bullet of this 
section. However, if a serious and unexpected adverse event occurs for which there is evidence 
suggesting a causal relationship between the drug and the event (e.g., death from anaphylaxis), the 
event must be reported under Serious and unexpected suspected adverse reaction as a serious and 
unexpected suspected adverse reaction even if it is a component of the study endpoint (e.g., all-cause 
mortality). 
7.2.9 Follow-up 
• 
The sponsor must promptly investigate all safety information it receives. 
• 
Relevant follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such, i.e., "Follow-up IND Safety Report." 
• 
If the results of a sponsor's investigation show that an adverse event not initially determined 
to be reportable under section IND safety reports of this section is so reportable, the sponsor 
must report such suspected adverse reaction in an IND safety report as soon as possible, but in 
no case later than 15 calendar days after the determination is made. 
 
 
7.2.10 
Disclaimer 
A safety report or other information submitted by a sponsor under this part (and any release by FDA of 
that report or information) does not necessarily reflect a conclusion by the sponsor or FDA that the 
report or information constitutes an admission that the drug caused or contributed to an adverse 
event. A sponsor need not admit, and may deny, that the report or information submitted by the 
sponsor constitutes an admission that the drug caused or contributed to an adverse event. 
 
The principal investigator must promptly review all information relevant to the safety of the drug 
obtained or otherwise received from foreign or domestic sources, including information derived from 
any clinical or epidemiological investigations, animal or in vitro studies, reports in the scientific 
literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities and 
reports of foreign commercial marketing experience for drugs that are not marketed in the United 
States. The study sponsor must notify all participating investigators of potential serious risks, from 
clinical trials or any other source, as soon as possible. 
 
 
7.2.11 
Reporting adverse events to the responsible IRB 
In accordance with applicable policies of the University of Pittsburgh Institutional Review Board (IRB), 
the Sponsor-Investigator will report, to the IRB, any observed or volunteered adverse event that is 


70
 
determined to be 1) associated with the investigational drug or study treatment(s); 2) serious; and 3) 
unexpected. Adverse event reports will be submitted to the IRB in accordance with the respective IRB 
procedures. 
 
Applicable adverse events will be reported to the IRB as soon as possible and, in no event, later than 
10 calendar days following the sponsor-investigator's receipt of the respective information. Adverse 
events which are 1) associated with the investigational drug or study treatment(s); 2) fatal or life- 
threatening; and 3) unexpected will be reported to the IRB within 24 hours of the Sponsor- 
Investigator's receipt of the respective information. 
 
Follow-up information to a reported adverse event will be submitted to the IRB as soon as the relevant 
information is available. If the results of the Sponsor-Investigator's follow-up investigation show that 
an adverse event that was initially determined to not require reporting to the IRB does, in fact, meet 
the requirements for reporting; the Sponsor-Investigator will report the adverse event to the IRB as 
soon as possible, but in no event later than 10 calendar days, after the determination was made. 
7.3 Pregnancy Reporting 
Pregnancy is neither an AE nor an SAE, unless a complication relating to the pregnancy occurs 
(e.g., spontaneous abortion, which may qualify as an SAE). 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or disease 
state) of a female participant or partner of a male participant occurring while the participant is on study 
treatment, within 28 days or during at least 5 ti12 after product administration of the participant's last 
dose of study treatment, are considered immediately reportable events. If a female partner of a male 
participant taking investigational product becomes pregnant, the male participant taking study 
treatment should notify the Investigator, and the pregnant female partner should be advised to call her 
healthcare provider immediately. In pregnant female participants, study treatment is to be discontinued 
immediately and the participant instructed to return any unused study drug to the Investigator. The 
pregnancy, suspected pregnancy, or positive pregnancy test must be reported immediately to the Lead 
Pl. The Investigator must follow-up and document the course and outcome of all pregnancies even if the 
participant was discontinued from the study or if the study has finished. The female participant or 
partner of a male participant should receive any necessary counseling regarding the risks of continuing 
the pregnancy and the possible effects on the fetus. Monitoring should continue until conclusion of the 
pregnancy. 
All outcomes of pregnancy (from a female participant or the sexual partner of a male participant) must 
be reported by the Investigator to the Lead Pl as an SAE within 28 days after he/she has gained 
knowledge of the delivery or elective abortion. 
Any SAE that occurs during pregnancy must be recorded on the SAE report form (eg, maternal serious 
complications, spontaneous or therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, 
congenital anomaly, or birth defect) and reported within 24 h in accordance with the procedure for 
reporting SAEs. 
 
Females of reproductive potential must have a negative serum pregnancy test prior to the start of 
therapy, or a confirmation from an obstetrician in case of equivocal serum pregnancy results. Women of 
reproductive potential, as well as fertile men and their partners who are female with reproductive 


71
 
potential, must agree to use two effective forms of contraception (including at least one barrier form) 
from the time of giving informed consent throughout the study and 7 months (both females and males) 
following the last dose of study drug. Women of reproductive potential are defined as sexually mature 
women who have not undergone a hysterectomy or bilateral oophorectomy or who have not been 
naturally postmenopausal (ie, who have not menstruated at all) for at least 24 consecutive months 
(ie, has had menses at any time in the preceding 24 consecutive months). 
Men with partners who are women with reproductive potential must agree that they or their partners 
will use two effective forms of contraception (including at least one barrier form) when engaging in 
reproductive sexual activity throughout the study and will avoid conceiving 7 months after the last dose 
of study treatment. 
Effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, 
intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal ligation, condoms with 
spermicide, or male partner sterilization. 
7.3.1 Specific BMS Pregnancy Reporting 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 ti12 after product administration, the investigational product will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for participant). 
The investigator must immediately notify Worldwide.Safety@bms.com of this event in accordance with 
SAE reporting procedures. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome 
and, where applicable, offspring information must be reported. 
Any pregnancy that occurs in a female study participant or a female partner of a male study participant 
should be reported to BMS. Information on this pregnancy will be collected. The female participant or 
female partner must sign an informed consent form for disclosure of this information. 
7.4 Follow-up of Participants after AEs 
 
7.4.1 Investigator Follow-Up 
The Investigator should follow each AE until the event has resolved to baseline grade or better, the event 
is assessed as stable by the Investigator, the participant is lost to follow-up, or the participant withdraws 
consent. Every effort should be made to follow all SAEs considered related to study treatment or trial- 
related procedures until a final outcome can be reported. 
7.4.2 Post-study Adverse Events 
At the treatment discontinuation visit, the Investigator should instruct each participant to report to the 
Investigator any subsequent AEs that the participant's personal physician believes could be related to 
prior study treatment or study procedures. 
The Investigator should notify the Sponsor of any death, SAE, or other AE of concern occurring at any 
time after a participant has discontinued study participation if the event is believed to be related to 
prior study treatment or study procedures. The Sponsor should also be notified if the Investigator 


72
 
becomes aware of the development of cancer or a congenital anomaly/birth defect in a subsequently 
conceived offspring of a participant that participated in this study. 
7.5 Definition of DLT 
AEs will be graded according to the NCI CTCAE version 5.0. 
A DLT is defined as any AE (except clearly attributable to an extraneous cause, such as disease 
progression) occurring in Cycle 1 (only) that satisfies at least one of the following criteria: 
Non-hematologic AEs: 
 
• 
Grade 3 or 4 nausea or vomiting: 
o 
If no anti-emetic prophylaxis was administered, Grade 3 or 4 nausea or vomiting is 
considered a DLT only if lasting> 3 days despite maximum supportive care. 
o 
Grade 3 or 4 nausea or vomiting despite anti-emetic prophylaxis of any duration will be 
considered a DLT. 
• 
Grade 3 or 4 diarrhea: 
o 
If no anti-diarrheals were administered, Grade 3 or 4 diarrhea is considered a DLT only if 
lasting> 3 days despite maximum supportive care. 
o 
Grade 3 or 4 diarrhea despite the administration of anti-diarrheals of any duration will 
be considered a DLT. 
• 
Any other Grade 3 or 4 non-hematological AE, with the exception of asymptomatic 
amylase/lipase or other biochemical marker that does not resolve with adequate treatment 
and/or within a week. 
Hematologic AEs: 
 
• 
Absolute neutrophil count (ANC) < 500/mm3 for more than 7 days 
 
• 
Febrile neutropenia (a disorder characterized by an ANC < 1,000/mm3 and single temperature 2: 
38.3 °C or sustained temperature of 2: 38.0 °C for more than 1 h) 
 
• 
Platelets < 25,000/mm3 
 
• 
Hemoglobin< 8.0 g/dL 
 
• 
Grade 3 hemorrhage associated with thrombocytopenia less than Grade 4 (ie, grade 3 
hemorrhage with platelets> 25,000/mm3). 
General: 
 
• 
Interruption of ivosidenib dosing for more than a total of 2 weeks (not necessarily consecutive) 
during Cycle 1, if due to AEs related to ivosidenib. 
• 
Delay of starting Cycle 2 for> 2 weeks, if due to AEs related to ivosidenib. 
All safety data in Cycle 1 and subsequent cycles will be monitored on an ongoing basis. 
A patient who experiences a DLT at any dose level will receive appropriate treatment and supportive 


73
 
care as necessary and will be monitored closely until resolution of the AE to Grade Oto 1 severity or 
Baseline severity, whichever is more abnormal, or until the AE is stabilized at any acceptable grade. 
Patients who experience a DLT but who, in the opinion of the Investigator, are deriving clinical benefit 
will be permitted to continue treatment with ivosidenib at a lower dose that has been demonstrated to 
be well tolerated upon reasonable resolution of the DLT. 
AEs will be tabulated by type, severity, and attribution. Immune responses, as assessed at baseline, post 
ivosidenib lead in, and week 9 (first restaging) will be analyzed by mixed effects regression for 
longitudinal data. Baseline and post-treatment values will also be compared between responders and 
non-responders. 
 
8.0 Statistical Analysis Plan and Sample Size Justification 
The primary and secondary objectives and endpoints are in Section 2. The accrual goal for this trial is 35 
participants evaluable for both safety and efficacy. 
8.1 Evaluability 
 
8.1.1 Evaluability for Safety 
Participants will be evaluable for safety if they receive a minimum of 75% of the first cycle of ivosidenib 
and have received one dose of nivolumab, unless they experience a DLT. The DLTwindow will be 
defined as from first dose through completion of the first 28-day cycle. 
8.1.2 Evaluability for Efficacy 
Patients will be evaluable for the co-primary efficacy objectives of response and PFS at the time of first 
radiographic assessment at week 12 of the study. Patients must receive a minimum of 75% of the first 
cycle of ivosidenib and have received one dose of nivolumab to be considered evaluable. Any patient 
having taken 75% of ivosidenib with clear clinical progression prior to first restaging at will also be 
evaluable for this objective. 
8.2 Statistical Analysis Plan 
 
8.2.1 Primary Objective: Efficacy 
Given that the response rate would be expected to be< 10% and PFS < 3.5 months in this patient 
population of IDHl mutant advanced solid tumors or gliomas, we will consider a participant to have had 
a positive outcome if they have a positive PFS6 (PFS6 is scored as either No or Yes) and they have had at 
least a partial response (evaluated by RANO in glioma patients and RECIST in patients with solid tumors) 
at the 12 week scan. 
An Optimal Simon two-stage design is employed, where a probability of positive outcome less than 0.1 
would not be promising and a probability of positive outcome 0.3 would warrant further interest. In 
the first stage, 18 participants will be accrued. If three or more participants have positive outcomes, 17 
more participants will be accrued. If 7 or more out of the 35 participants have positive outcomes, the 
null hypothesis p<0.l will be rejected at a=0.05. This design has 90% power if p > 0.3. 
For all tumor types, six-month progression-free survival (PFS6) is defined as survival to six months 
after the initiation of treatment without objective tumor progression 
The probability of positive outcome and 95% confidence interval will be estimated using the method of 
Koyama and Chen (Koyama and Chen 2008). 


74
 
8.2.2 Secondary Objective: Safety 
Summary tables and listings for adverse events will include treatment-emergent adverse events (AEs), 
where AE is defined as any AE that occurred between the first dose of any study drug and 28 days 
following the last dose of any study drug. The incidence of AEs (new or worsening from baseline) will be 
summarized according to the Medical Dictionary for Regulatory Activities (MedDRA) by system organ 
class and/or preferred term, severity (based on NCI CTCAE vS.0 grading as assessed by the Investigator), 
seriousness, and relation to study treatment. All tabulations will be accompanied by probability of 
events and exact (Clopper-Pearson) 95% confidence intervals. The following summaries will be 
produced: 
• 
All AEs 
• 
AEs leading to dose modifications 
• 
Treatment-related AEs 
• 
Grade 3 or higher AEs 
• 
Grade 3 or higher treatment-related AEs 
• 
The most commonly reported AEs (ie, those events reported by 10% of all participants) 
• 
SAEs 
• 
Discontinuations due to AEs 
By- participant listings will be provided for on-treatment deaths (on-treatment is defined as the period 
starting from the first dose to 100 days after the last dose), AEs, SAEs, and AEs leading to 
discontinuation of treatment. 
8.2.2.1 Laboratory Abnormalities 
For laboratory tests included in the NCI CTCAE version 5.0, laboratory data will be graded accordingly; a 
Grade 0 will be assigned for all non-missing values not graded as 1 or higher. For laboratory tests where 
grades are not defined by NCI CTCAE, results will be graded by the low/normal/high classifications based 
on laboratory normal ranges. 
The following summaries will be generated separately for hematology, serum chemistry and coagulation 
studies, and urinalysis laboratory tests: 
• 
Descriptive statistics for the actual values and/or change from baseline of clinical laboratory 
parameters over time. 
• 
Shift tables using NCI CTCAE grades to compare baseline to the worst on-treatment value (for 
laboratory tests where NCI CTCAE grades are not defined, shift tables using the 
low/normal/high/[low and high] classification to compare baseline to the worst on-treatment 
may be generated). 
• 
Listing of all laboratory data with values flagged to show the corresponding NCI CTCAE grades 
and the classifications relative to the laboratory normal ranges. 
 
8.2.2.2 Other Safety Data 
• 
Descriptive statistics for the actual values and/or the changes from baseline of vital signs 
(including systolic and diastolic blood pressure, heart rate, respiratory rate, and 
temperature) over time will be summarized. 
• 
Descriptive statistics of ECOG PS over time will be summarized by frequency. Shift tables 


75
 
may be provided for ECOG PS from baseline to worst value of post-baseline 
assessments. 
• 
Categorical analysis of QTcF intervals may be performed. Maximum QTcF intervals and 
maximum changes from baseline may also be summarized similarly in a separate display. 
ECG abnormalities if collected will be presented in a data listing. 
• 
Additional safety analyses may be performed if deemed necessary. 
8.2.3 Secondary Objective: Longitudinal Clinical Outcomes 
The distribution of adverse events over time (during and after Cycle 1) will be tabulated and described 
graphically. Surviving participants without progression will be censored as of the date of the last 
negative examination. Progression-free survival, defined from the beginning of treatment as survival 
without objective tumor progression, up until 18 months after the last efficacy-evaluable participant 
has initiated treatment will be characterized by the product-limit (Ka-plan-Meier} method with a 95 
confidence region. 
8.2.4 Exploratory Objective: Biomarkers and Response to Treatment 
DLT (defined in Section 7.5} will be monitored throughout the trial and a stopping rule will be 
evaluated after every five participants have started Cycle 1. If the number of participants experiencing 
DLT equals or exceeds the number specified in the following table, the trial will be paused and the 
dosing reconsidered: 
 
# Participants 
# DLTs 
5 
3 
10 
5 
15 
7 
20 
8 
25 
10 
30 
12 
 
8.3 Justification of Design 
This trial employs an optimal Simon two-stage design with a= 0.05, assuming that the treatment is not 
worthy of further consideration if the probability of patients achieving a positive outcome (at least partial 
response and PFS 6 months} is less than 0.1. The design has 90% power if the true probability of positive 
outcome is 0.3 or greater. The stopping rule is designed to pause the trial if P(P[DLT > 0.3] > 0.7}, using a 
beta-binomial model with a=l and =4; that is, our prior expectation based on information equivalent to 
a total of five patients is that the P(DLT} = 0.2. The operating characteristics of the stopping rule, derived 
from a Monte Carlo simulation, are presented in the figure, where it is seen that, for instance, if the true 
probability of DLT is 0.3, the probability that the trial pauses is 0.4 and the expected number of 
participants accrued is 12. 


76
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 
 
"a.' 
c75 
- 
ro 
CL 
0.0 
0.1 
0.2 
0.3 
0.4 
0.5 
True P (DLT) 
 
 
 
9.0 Study Management, Agreement, and Ethical Considerations 
9.1 IRB Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance with federally 
mandated regulations. The IRB should approve the consent form and protocol. 
In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s) and should adhere to Good Clinical Practice (GCP) and to ethical principles 
that have their origin in the Declaration of Helsinki. 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of the 
study and will be given the opportunity to review the consent form. Each consent form must include all 
the relevant elements currently required by the FDA Regulations and local or state regulations. Once this 
essential information has been provided to the patient and the investigator is assured that the patient 
understands the implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form. 
Prior to a patient's participation in the trial, the written informed consent form should be signed and 
personally dated by the patient and by the person who conducted the informed consent discussion. 
9.2 FDA Approval 
This study will be conducted under an IND held by Dr. Jason Luke at the UPMC Hillman Cancer Center, 
which will be responsible for facilitating all communications with the FDA on behalf of the IND holder. 
9.3 Required Documentation 
Prior to the commencement the study the UPMC Hillman Cancer Center audit and trial oversight 
processes must be reviewed and approved by the Protocol Review and Monitoring System or Protocol 
Review Committee (PRMS/PRC). 
Before the study can be initiated, the following documentation must be provided to PRMS/PRC at the 
UPMC Hillman Cancer Center: 
• 
A copy of the official IRB approval letter for the protocol and informed consent 
• 
IRB membership list 
• 
CVs and medical licensure for the Pl and any sub-investigators who will be involved in the 
-
cu
 


77
 
study. 
• 
Form FDA 1572 appropriately filled out and signed with appropriate documentation 
• 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
• 
Financial disclosure forms for the Pl and any sub-investigators who will be involved in the 
study 
• 
lnvestigational drug accountability standard operating procedures 
Additionally, before the study can be initiated, the required executed research 
contract/subcontract must be on file with the UPMC Hillman Cancer Center. Once all required 
documents are received, reviewed and approved by the Coordinating Center's designated 
representative(s), a patient may be enrolled. 
9.4 Data and Safety Monitoring Plan 
Investigators, Sub-investigators and clinical research staff meet regularly in disease center Data 
Safety Monitoring Boards (DSMB) to review and discuss study data to include, but not limited to, 
the following: 
• 
Serious adverse events 
• 
Subject safety issues 
• 
Recruitment issues 
• 
Accrual 
• 
Protocol deviations 
• 
Unanticipated Problems 
• 
Breaches of confidentiality 
Minutes from the disease center DSMB meetings are available to those who are unable to attend in 
person or participate via teleconference. 
All toxicities encountered during the study will be evaluated on an ongoing basis according to the NCI 
Common Toxicity Criteria Version 5.0. All study treatment associated adverse events that are serious, 
at least possibly related and unexpected will be reported to the IRB. Any modifications necessary to 
ensure subject safety and decisions to continue or close the trial to accrual are also discussed during 
these meetings. If any literature becomes available which changes the risk/benefit ratio or suggests 
that conducting the trial is no longer ethical, the IRB will be notified in the form of an Unanticipated 
Problem submission and the study may be terminated. 
All study data reviewed and discussed during these meetings will be kept confidential. Any breach in 
subject confidentiality will be reported to the IRB in the form of an Unanticipated Problem 
submission. The summaries of these meetings are forwarded to the UPMC Hillman Cancer Center 
DSMC which also meets monthly following a designated format. 
For all research protocols, there will be a commitment to comply with the IRB's policies for reporting 
unanticipated problems involving risk to subjects or others (including adverse events). DSMC progress 
reports, to include a summary of all serious adverse events and modifications, and approval will be 
submitted to the IRB at the time of renewal. 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will be 


78
 
reviewed bi-annually. 
 
Both the UPMC Hillman Cancer Center DSMC as well as the individual disease center DSMB have the 
authority to suspend accrual or further investigate treatment on any trial based on information 
discussed at these meetings. 
All records related to this research study will be stored in a locked environment. Only the researchers 
affiliated with the research study and their staff will have access to the research records. 
9.5 Amendments to the Protocol 
All modifications to the protocol, consent form, or questionnaires will be submitted to the University of 
Pittsburgh IRB (Pitt IRB) for review and approval. A list of the proposed modifications or amendments to 
the protocol and/or an explanation of the need of these modifications will be submitted, along with a 
revised protocol incorporating the modifications. Only the Study Lead Pl can authorize any modifications, 
amendments, or termination of the protocol. Once a protocol amendment has been approved by the Pitt 
IRB, the Regulatory Specialist will send the amended protocol and consent form (if applicable) to the 
affiliate institutions electronically. Upon receipt of the packet the affiliate institution is expected to do the 
following: 
• 
The affiliate must reply to the email from the Regulatory Specialist indicating that the amendment 
was received by the institution and that it will be submitted to the local IRB. 
• 
The amendment should be submitted to the affiliate institution's IRB as soon as possible after 
receipt. The amendment must be IRB approved by the institution within 3 months from the date 
that it was received. 
• 
The UPMC Hillman Cancer Center version date, amendment number, or both must appear on the 
affiliate consent form and the affiliate IRB approval letter. The version dates can be found on the 
footer of every page of the protocol and consent form. The amendment number can be found on the 
University of Pittsburgh IRB (Pitt IRB) amendment approval letter that is sent with the 
protocol/amendment mailing. 
 
The IRB approval for the amendment and the amended consent form (if amended consent is necessary) 
for the affiliate institution must be sent to the designated CRS Regulatory Specialist as soon as it is 
received. 
9.6 Annual IRB Renewals, Continuing Review, and Final Reports 
A continuing review of the protocol will be completed by the Pitt IRB and the participating institutions' 
IRBs at least once a year for the duration of the study. The annual IRB renewal approvals for 
participating institutions should be forwarded promptly to the Regulatory Specialist. If the institution's 
IRB requires a new version of the consent form with the annual renewal, the consent form should be 
included with the renewal letter. 
9.7 Record Retention 
Study documentation includes all CRFs, data correction forms or queries, source documents, Sponsor- 
Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary for the evaluation and reconstruction of the clinical research study. 


79
 
Government agency regulations and directives require that all study documentation pertaining to the 
conduct of a clinical trial must be retained by the study investigator. In the case of a study with a drug 
seeking regulatory approval and marketing, these documents shall be retained for at least two years 
after the last approval of marketing application in an International Conference on Harmonization (ICH) 
region. In all other cases, study documents should be kept on file until three years after the completion 
and final study report of this investigational study. 
9.8 Obligations of Study Site Investigators 
The Pl is responsible for the conduct of the clinical trial in accordance with Title 21 of the Code of 
Federal Regulations and/or the Declaration of Helsinki. The Study Pl is responsible for personally 
overseeing the treatment of all study patients. He/she must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol and all 
FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and after study completion. 
The Study Site Pl will be responsible for assuring that all the required data will be collected and entered 
into the CRFs. Periodically, monitoring visits or audits will be conducted and he/she must provide access 
to original records to permit verification of proper entry of data. 
 
10.0 References 
Amary, M. F., K. Bacsi, F. Maggiani, S. Damato, D. Halai, F. Berisha, R. Pollock, P. O'Donnell, A. 
Grigoriadis, T. Diss, M. Eskandarpour, N. Presneau, P. C. Hogendoorn, A. Futreal, R. Tirabosco and A. M. 
Flanagan (2011). "IDHl and IDH2 mutations are frequent events in central chondrosarcoma and central 
and periosteal chondromas but not in other mesenchymal tumours." J Pathol 224(3): 334-343. 
 
Ayers, M., J. Lunceford, M. Nebozhyn, E. Murphy, A. Loboda, D. R. Kaufman, A. Albright, J. D. Cheng, S. P. 
Kang, V. Shankaran, S. A. Piha-Paul, J. Yearley, T. V. Seiwert, A. Ribas and T. K. Mcclanahan (2017). "IFN- 
gamma-related mRNA profile predicts clinical response to PD-1 blockade." J Clin Invest 127(8): 2930- 
2940. 


80
 
Borger, D.R., K. K. Tanabe, K. C. Fan, H. U. Lopez, V. R. Fantin, K. S. Straley, D. P. Schenkein, A. F. Hezel, 
M. Ancukiewicz, H. M. Liebman, E. L. Kwak, J. W. Clark, D. P. Ryan, V. Deshpande, D. Dias-Santagata, L. 
W. Ellisen, A. X. Zhu and A. J. Iafrate (2012). "Frequent mutation of isocitrate dehydrogenase (IDH)l and 
IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping." Oncologist 17(1): 72-79. 
 
Brieau, B., L. Dahan, Y. De Rycke, T. Boussaha, P. Vasseur, D. Tougeron, T. Lecomte, R. Coriat, J. B. 
Bachet, P. Claudez, A. Zaanan, P. Soibinet, J. Desrame, A. Thirot-Bidault, I. Trouilloud, F. Mary, L. 
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11.0 Appendix 
11.1 Eastern Cooperative Oncology Group Performance Status Scoring 
 
Grade 
Symptomatology 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Source: (Oken, Creech et al. 1982) 
 
 
 
11.2 Prohibited Concomitant Medications 
Prohibited medications and certain foods are not allowed in this study while participants are 
receiving study drug. 
Strong CYP3A Inducers 
CVP3A Substrates with a Narrow Therapeutic Window 
Avasimibe, carbamazepine, phenytoin, 
rifampin, rifabutin, St. John's wort 
Alfentanil, astemizole1, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, everolimus, 
sirolimus, tacrolimus, terfenadine1 
Sensitive P-gp Substrates with a Narrow Therapeutic 
Window 
Aliskiren, ambrisentan, colchicine, dabigatran etexilate, 
digoxin, everolimus, fexofenadine, imatinib, maraviroc, 
ranolazine, sirolimus talinolol, tolvaptan, topotecan 
Note that this is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DruglnteractionsL 
abeling/ucm080499.htm 
CYP or P-gp substrates with a narrow therapeutic window refers to drugs whose exposure-response 
relationship indicates that small increases in their exposure levels by the concomitant use of CYP 
inhibitors may lead to serious safety concerns (eg, Torsades de Pointes). 1 Withdrawn from the US 
market because of safety reasons. 


86
 
11.3 New York Heart Association Classification 
 
Class 
Symptomatology 
 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginaI pain. 
II 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Ill 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms at rest. If any 
physical activity is undertaken, discomfort is increased. 
Source: The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 
1994:253-256. 
 
 
11.4 Fridericia's Formula 
QTcF=QT/RR113 
 
11.5 Medications Known to Prolong the QT Interval 
 
amiodarone 
citalopram 
Escitalopram 
methadone 
sevoflurane 
astemizole 
clarithromycin 
Flecainide 
moxifloxacin 
sotalol 
azithromycin 
disopyramide 
Halofantrine 
pentamidine 
sparfloxacin 
bepridil 
dofetilide 
Haloperidol 
pimozide 
terfenadine 
chloroquine 
domperidone 
lbutilide 
probucol 
thioridazine 
chlorpromazine 
droperidol 
Levomethadyl 
procainamide 
 
cisapride 
erythromycin 
Mesoridazine 
quinidine 
 
 
 
Please note that this is not an exhaustive list. For an updated list, see the following link: 
http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm 
 
 
11.6 Representative Examples of Low-Fat and High-Fat, High-CalorieMeals 
Low-fat breakfast: 
A} 2 slices of white bread toast, 1 tablespoon light fat margarine, 1 tablespoon of jelly, and 8 ounces of 
skim milk (319 calories and 8.2 grams of fat}. 


87
 
B) 1 cup of cereal, 1 slice of toast with jam, 8 ounces of skim milk, and 1 cup of decaffeinated coffee or 
tea (520 calories and 2 grams of fat). 
A high-fat breakfast consists of the following and may be adapted to the local regional preference: 2 
eggs fried in butter, 2 strips of bacon, 2 slices of white bread with butter, 1 croissant with 1 slice of 
cheese, and 8 ounces of whole milk. This representative high-fat breakfast contains approximately 1000 
calories and 58 grams of fat. 
11.7 National Cancer Institute Common Terminology Criteria for Adverse Events 
The NCI CTCAE, version 5.0, can be accessed using the following link: 
http://evs.nci.nih.gov/ftpl/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.Sx11.pdf 
11.8 RECIST vl.1 
Tumor lesions are to be categorized as measurable versus non-measurable and target versus non-target 
based on RECIST vl.1 (Eisenhauer, Therasse et al. 2009). 
Measurable Lesions: 
 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable). 
20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must 
be 15mm on the short axis when assessed by CT scan. 
Non-measurable Lesions: 
 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with 
10 to <15 mm short axis) as well as truly non-measurable lesions, including leptomeningeal disease, 
ascites, pleural or pericardia! effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
 
Target Lesions: 
When more than 1 measurable lesion is present at baseline all lesions up to a maximum of 5 total (and a 
maximum of 2 lesions per organ) representative of all involved organs should be identified as target 
lesions and measured at baseline. 


88
 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. 
Pathological lymph nodes that are defined as measurable and identified as target lesions must have a 
short axis of 15 mm by CT scan. Only the short axis of these nodes contributes to the baseline sum. 
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. The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable dimension of the 
disease. 
Non-target Lesions: 
 
All other lesions (or sites of disease) including 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 'unequivocal progression.' 
The following criteria outlined in Table 6 will be used to assess response to treatment. 
 
Table 6: 
Disease Response Criteria for Target and Non-target Lesions 
 
 
 
I 
 
Response Criteria 
Category 
I
Target Lesions 
Non-Target Lesions/Tumor Markers 
Complete Response 
(CR) 
Disappearance of all target lesions. Any 
pathological lymph nodes (whether 
target or non-target) must have 
reduction in short axis to <10 mm 
Disappearance of all non-target 
lesions, and normalization of tumor 
marker level 
All lymph nodes must be non- 
pathological in size (<10 mm short 
axis). 
Partial Response 
(PR) 
A 30% decrease in the sum of the 
diameter of target lesions, taking as 
reference the baseline sum diameter 
N/A 
Stable Disease (SD)/ 
Incomplete 
Response 
Neither sufficient shrinkage to qualify 
for partial response nor sufficient 
increase to qualify for progressive 
disease, taking as reference the 
smallest sum diameter since the 
treatment started 
Persistence of 1 or more non-target 
lesion(s) and/or 
Maintenance of tumor marker levels 
above the normal limits 


89
 
Progressive Disease 
A 20% increase in the sum of the 
diameter of target lesions, taking as 
reference the smallest sum diameter 
recorded since the treatment started. 
In addition to the relative increase of 
20%, the sum must also demonstrate 
an absolute increase of at least 5 mm, 
or 
The appearance of 1 or more new 
lesions 
Appearance of 1 or more new 
lesions, and/or 
Unequivocal progression of existing 
non-target lesions 
 
 
Table 7: 
Overall Disease Response Criteria 
 
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Incomplete response/Non- 
Progressive disease 
No 
PR 
SD 
Incomplete response/Non- 
Progressive disease 
No 
SD 
Progressive disease 
Any 
Yes or no 
Progressive disease 
Any 
Progressive disease 
Yes or no 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
 
Abbreviations: CR= complete response; PR= partial response; SD= stable disease. 


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11.9 RANO Criteria 
Table 11.9.1: RANO Criteria for Response Assessment Incorporating MRI and Clinical Factors 
 
Response 
Criteriaa 
 
 
Complete response 
Requires all of tbe following: complete disappearance of all enhancing measurable and 
nonmeasurable disease sustained for at least 4 weeks; no new lesions; stable or improved 
nonenhancing (Tl/FLAIR) lesions; subjects must be off corticosteroids (or on physiologic 
replacement doses only)· and stable or improved clinically. ote: subjects with 
nonmeasurable disease only cannot have a complete response; the best response possible 
is stable disease. 
 
 
 
 
Partial response 
Requires all of the following: 2:'. 50% decrease compared with baseline in the sum of 
products of perpendicular diameters of all measurable enhancing lesions sustained for at 
least 4 weeks; no progression of non measurable dis ase· no new lesions; stable or 
.improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan; the corticosteroid dose at the time of the scan evaluation 
should be no greater than the dose at time of baseline scan; and stable or improved 
clinically. Note: Subjects with nonmeasurable d.isease only cannot have a partial response; 
the best response possible is stable disease. 
 
 
Stable disease 
Requir s a!] of the following: does not qualify for complete response, partial response, or 
progression; stab.le nonenhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan. In the event that the corticosteroid dose was 
increased for new symptoms and signs without confirmation of disease progression on 
neuroi.maging, aud subsequent follow-up imaging shows that thi increase in 
corticosteroids was required because of disease progression, the last scan considered to 
 
 
show stable disease will be the scan obtained when the corticosteroid dose was equivalent 
to the baseline dose. 
 
 
 
 
 
Progression 
Defined by any of the following: ;:,: 25% increase in sum of the products of perµ nd..icular 
diameters of enhancing lesions compared with the smallest tumor measurement obtained 
either at baseline (if no decrease) or best response, on stable or increasing doses of 
corticosteroids•; significant increase in T2/FLAIR nonenhancing lesions on stable or 
increasing doses of corticosteroids compared with baseline scan or best response after 
initiation oftberapy' not cause by comorbid events (eg, radiation therapy, demyelination, 
ischernic injury, infection, seizures, post-operative changes, or other treatment effects); 
any new lesion; clear clinical deterioration not attributable to other causes apart from the 
tumor eg, seizures, medication adverse effects, complications of therapy, cerebrovascular 
events, infection, and so on) or changes in corticosteroid dose; failure to return for 
evaluation as a result of death or deteriorating condition; or clear progression of 
nonmeasurable disease. 
NOTE: Radiologic interpretation guidelines, definitions and rumor measurement instructions will be provided 
separately in a separate imaging manual. All measurable and nonmeasurable lesions must be assessed using the 
same techniques as at baseline. 
Abbreviations: MRI, magnetic resonance imaging· FLAIR, fluid-attenuated inversion r covery 
* Stable doses of corticosteroids include subjects not 011 corticosteroids 
a From: Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorenson AG, Galanis E, et al. Updated Response 
Assessment Criteria for High-Grade Gbomas: Response Assessment in euro-Oncology Working Group; J Clin 
Oncol. 2010 Apr IO; 28(11):1963-72. 


91
 
Table 8: Assessment of Best Overall Response 
 
Best Overall Response 
Criteria 
Complete Response (CR) 
Partial Response (PR) 
 
Stable Disease (SD/ 
 
Not valuable ( 
) 
Progressive Disease (PD) 
CR observed in consecutive assessments 2'. 4 weeks apart per RANO 
PR observed in consecutive assessments 2'. 4 weeks apart per .RA 0 
SD observed and does uot qualify for CR or PR 
or Suspected PD followed with histologic results not confinning PD, and no 
CR, PR or SD observed 
Insufficient data to detennine disease progression or response 
No CR, PR, or SD prior to PD 
a  To qualify for SD there must be a minimum on-treatment period of 10 weeks. 


 
 
11.10 Patient Pill Diary 
Study name: Testing AG-120 in Combination 
with lmmunotherapy 
Please carefully read and follow these instructions: 
 
• 
Bring this Pill Diary and any remaining AG-120 pills to clinic visits 
so your doctor can make sure that you are taking the pills correctly. 
• 
Store the pills at room temperature at 20°C to 25°C (68°F to 77°F). 
• 
Each dose is 
 pills. Take each dose by mouth at the same time every day 
with one glass of water. Tablets should be swallowed whole. You can toke 
the pills with or without meals. 
If you miss taking a pill on time (a dose is missed) or you vomit 
after taking the pill, please do not repeat the dose. 
A dose is missed when more than 2 hours from the normal scheduled dosing 
time has elapsed. 
• 
In the boxes below, note the date and time each day you take the AG-120 
study drug pills: 
Patient Initials (FML):
 
 
Cycle Number 
Dose  
Research Assistant Signature: 
 
 
 


 
 
 
 
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