A Phase 1/2, Safety Lead-in and Dose Expansion, Open-label, Multicenter Trial Investigating the Safety, Tolerability, and Preliminary Activity of Ivosidenib in Combination With Nivolumab and Ipilimumab in Previously Treated Subjects With Nonresectable or Metastatic Cholangiocarcinoma With an IDH1 Mutation
Phase: PHASE1
Conditions: IDH1-mutant Cholangiocarcinoma
Sponsor: Servier Bio-Innovation LLC

 
Document title 
AMENDED CLINICAL STUDY PROTOCOL 
Study official title 
A Phase 1/2, Safety Lead-in and Dose Expansion, 
Open-label, Multicenter Trial Investigating the Safety, 
Tolerability, and Preliminary Activity of Ivosidenib in 
Combination with Nivolumab and Ipilimumab in 
Previously Treated Subjects with Nonresectable or 
Metastatic Cholangiocarcinoma with an IDH1 Mutation  
Study brief title 
Ivosidenib, Nivolumab, and Ipilimumab Combination in 
Previously Treated Subjects with Nonresectable or 
Metastatic IDH1-Mutant Cholangiocarcinoma  
Study public title 
A Phase 1/2, Safety Lead-in and Dose Expansion, Open-
label, Multicenter Trial Investigating the Safety, 
Tolerability, and Preliminary Activity of Ivosidenib in 
Combination with Nivolumab and Ipilimumab in 
Previously Treated Subjects with Nonresectable or 
Metastatic Cholangiocarcinoma with an IDH1 Mutation 
Test drug code 
S95031 (formerly identified as AG-120) 
Indication(s) 
Second- or third-line treatment of IDH1-mutant 
cholangiocarcinoma 
Development phase 
Phase 1/2 
Protocol code 
CL1-95031-006 
EU Trial Number 
2023-503236-41-00 
Universal Trial Number 
Not applicable 
Other register number 
(ISRCTN, CT. gov…) 
NCT05921760 
Investigational New Drug 
Application Number 
166683 
Sponsor 
Institut de Recherches Internationales Servier (I.R.I.S.) 
International Coordinator 
Robin K. (“Katie”) Kelley, MD 
Professor of Clinical Medicine 
Helen Diller Family Comprehensive Cancer Center 
Division of Hematology/Oncology 
University of California, San Francisco  
Date of the document 
06 May 2024 
Version of the document 
Final Version 
Version number 
5.0 
Substantial Amendment(s) 
integrated 
1.0 
 

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SYNOPSIS 
Name of the Sponsor: 
Institut de Recherches Internationales Servier (I.R.I.S.) 
Name of Finished Product: 
Ivosidenib  
Nivolumab 
Ipilimumab 
Name of Active Ingredient: 
S95031 (ivosidenib) 
Title of Study:  
A Phase 1/2, Safety Lead-in and Dose Expansion, Open-label, Multicenter Trial Investigating the Safety, 
Tolerability, and Preliminary Activity of Ivosidenib in Combination with Nivolumab and Ipilimumab in 
Previously Treated Subjects with Nonresectable or Metastatic Cholangiocarcinoma with an IDH1 Mutation 
Study Brief Title:  
Ivosidenib, Nivolumab, and Ipilimumab Combination in Previously Treated Subjects with Nonresectable or 
Metastatic IDH1-Mutant Cholangiocarcinoma 
Study Public Title:  
A Phase 1/2, Safety Lead-in and Dose Expansion, Open-label, Multicenter Trial Investigating the Safety, 
Tolerability, and Preliminary Activity of Ivosidenib in Combination with Nivolumab and Ipilimumab in 
Previously Treated Subjects with Nonresectable or Metastatic Cholangiocarcinoma with an IDH1 Mutation 
Coordinator(s) or Investigator or Steering Committee Chairman 
National coordinators and Investigators: listed in a separate document 
Study Center(s): 
This is an international multicenter study to be conducted in centers in the United States (US), Europe (EU), 
and United Kingdom. 
For the Safety Lead-in phase, approximately 10 sites will be opened. 
For the Expansion phase, additional countries and sites will be included and activated. 
Study Period: 
Study duration for the participants: including treatment period until progression 
of disease, unacceptable toxicity, or Investigator’s or subject’s decision to 
discontinue and additional follow-up for progression-free survival (PFS), safety, 
or overall survival (OS). 
­ Target study initiation: June 2023 
­ Target study completion: Estimated 2026 
Study Development Phase: 
Phase 1/2 
Objective(s), Endpoints(s), and Estimand(s):  
Objectives and Endpoints of the Safety Lead-in Phase 
 
Objectives 
Endpoints  
Primary 
To evaluate the safety and 
tolerability of ivosidenib in 
combination with nivolumab and 
ipilimumab and determine the 
recommended combination dose 
(RCD) of ivosidenib, nivolumab, 
and ipilimumab 
• 
Dose limiting toxicities (DLTs) associated with 
ivosidenib in combination with nivolumab and 
ipilimumab during the first 2 cycles of treatment 
• 
Adverse events (AEs), adverse events of special 
interest (AESIs), and serious adverse events 
(SAEs)  
Secondary 
To 
evaluate 
the 
pharmacokinetics 
(PK) 
of 
ivosidenib 
when 
given 
in 
combination with nivolumab and 
ipilimumab  
Plasma concentrations and PK parameters including, but 
not limited to, area under the concentration-vs-time 
curve (AUC) from 0 to time of last measurable 
concentration (AUC0-t), AUC over 1 dosing interval at 
steady state (AUCtau,ss), time to maximum concentration 
(Tmax), 
maximum 
concentration 
(Cmax), 
trough 
concentration (Ctrough), apparent volume of distribution 
(Vd/F), and apparent clearance (CL/F) 

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To 
evaluate 
the 
pharmacodynamic (PD) effects 
of ivosidenib when given in 
combination with nivolumab and 
ipilimumab 
Plasma 2-hydroxygluturate (2-HG) concentration 
Exploratory 
To evaluate ivosidenib exposure 
in tumor tissue  
Tumor tissue concentrations of ivosidenib  
To evaluate the PK of nivolumab 
and ipilimumab when given in 
combination with ivosidenib 
Serum concentrations of nivolumab and ipilimumab 
To evaluate immunogenicity of 
nivolumab and ipilimumab when 
given 
in 
combination 
with 
ivosidenib 
Measurement 
of 
anti-drug 
antibody 
(ADA) 
to 
nivolumab and ipilimumab  
To evaluate the PD effects of 
ivosidenib 
when 
given 
in 
combination with nivolumab and 
ipilimumab 
Tumor tissue 2-HG concentration  
 
To 
identify 
molecular 
and 
cellular biomarkers that may be 
indicative 
of 
clinical 
response/resistance, PD activity, 
and the mechanism of action 
• 
Associations of pre-treatment molecular and 
cellular markers with patient outcome  
• 
Differences in molecular and cellular markers 
between on-treatment and/or pre-treatment samples 
 
Objectives, Endpoints, and Estimands of the Expansion Phase 
 
Objectives 
Endpoints 
Other Estimand 
Attributes 
Primary 
To assess the clinical activity 
of ivosidenib in combination 
nivolumab and ipilimumab 
using Response Evaluation 
Criteria in Solid Tumors 
(RECIST) v1.1 
Objective response (confirmed 
complete response [CR] or 
confirmed 
partial 
response 
[PR]) of anti-tumor activity 
using RECIST v1.1) 
The primary estimand of 
interest is the objective 
response rate (ORR). The 
attributes of the primary 
estimand are defined as 
follows:  
• Treatment: ivosidenib 
plus nivolumab and 
ipilimumab 
• Population: 
Safety 
Analysis Set  
• Summary 
measure: 
objective 
response 
(Yes, No) 
• Intercurrent 
events 
(IE): 
1. Early 
treatment 
discontinuation 
2. Administration of 
further anti-cancer 
therapy 
Secondary 
To confirm the safety and 
tolerability 
of 
the 
recommended 
combination 
dose (RCD) of ivosidenib, 
nivolumab, and ipilimumab 
Adverse events (AEs), adverse 
events 
of 
special 
interest 
(AESIs), and serious adverse 
events (SAEs) 
Not applicable 

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To 
evaluate 
additional 
efficacy parameters to assess 
anti-tumor 
activity 
of 
ivosidenib in combination 
with 
nivolumab 
and 
ipilimumab 
 
Duration of response (DOR), 
progression-free 
survival 
(PFS) and disease control (CR, 
PR, or stable disease [SD] 
maintained for at least 5 
months), time to response 
(TTR) according to RECIST 
v1.1 
 
Overall survival (OS) 
Not applicable 
To 
evaluate 
the 
pharmacokinetics 
(PK) of 
ivosidenib when given in 
combination with nivolumab 
and ipilimumab 
Plasma concentrations and PK 
parameters including, but not 
limited to, area under the 
concentration-vs-time 
curve 
(AUC) from 0 to time of last 
measurable 
concentration 
(AUC0-t), AUC over 1 dosing 
interval 
at 
steady 
state 
(AUCtau,ss), time to maximum 
concentration 
(Tmax), 
maximum 
concentration 
(Cmax), trough concentration 
(Ctrough), apparent volume of 
distribution 
(Vd/F), 
and 
apparent clearance (CL/F) 
Not applicable 
To 
evaluate 
the 
pharmacodynamic 
(PD) 
effects of ivosidenib when 
given in combination with 
nivolumab and ipilimumab 
Plasma 2-hydroxyglutarate (2-
HG) concentration 
Not applicable 
Exploratory 
To 
evaluate 
ivosidenib 
exposure in tumor tissue 
Tumor tissue concentrations of 
ivosidenib 
Not applicable 
To evaluate the PK of 
nivolumab and ipilimumab 
when given in combination 
with ivosidenib 
Serum 
concentrations 
of 
nivolumab and ipilimumab  
Not applicable 
To evaluate immunogenicity 
of nivolumab and ipilimumab 
when given in combination 
with ivosidenib 
Measurement 
of 
anti-drug 
antibody (ADA) to nivolumab 
and ipilimumab 
Not applicable 
To evaluate the PD effects of 
ivosidenib when given in 
combination with nivolumab 
and ipilimumab 
Tumor 
tissue 
2-HG 
concentrations 
Not applicable 
To identify molecular and 
cellular biomarkers that may 
be 
indicative 
of 
clinical 
response/resistance, 
PD 
activity, and the mechanism 
of action 
Associations of pre-treatment 
molecular and cellular markers 
with patient outcome 
 
Differences in molecular and 
cellular markers between on-
treatment and/or pre-treatment 
samples 
Not applicable 
Methodology:  
This is a Phase 1/2, non-comparative, multicenter, open-label study of ivosidenib, an oral mutant isocitrate 
dehydrogenase-1 (IDH1) inhibitor, administered in combination with nivolumab and ipilimumab. Subjects are 
required to have a histologically confirmed diagnosis of cholangiocarcinoma (CCA), a local molecular IDH1 
gene-mutation and not eligible for curative resection, transplantation, or ablative therapies. The study will be 
conducted in adult subjects with nonresectable or metastatic CCA. Subjects must have progression of disease 
or treatment intolerance and have received at least 1 but not more than 2 prior treatment regimens for advanced 

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disease (nonresectable or metastatic). All subjects must have received either a gemcitabine- or a 5-fluorouracil 
(5-FU)–based chemotherapy regimen.  
Radiological tumor assessments will be based on Investigator assessments according to RECIST v1.1. These 
assessments will be conducted at Screening (Day -21 to Day -1), every 6 weeks beginning at C1D1 (± 7 days) 
for the first 2 assessments (i.e., through Week 12), and then every 8 weeks (± 7 days) thereafter independent of 
dose delays and/or dose interruptions, and/or at any time when progression of disease is suspected; tumor 
assessment frequency may be reduced to every 12 weeks after two years of study treatment initiation.   
The study will consist of 2 phases: 
Safety Lead-in Phase 
The Safety Lead-in phase will evaluate the safety and tolerability of ivosidenib in combination with nivolumab 
and ipilimumab in order to determine the RCD. This phase will enroll approximately 6-12 DLT-evaluable 
subjects with nonresectable or metastatic CCA with an IDH1 mutation. 
The first 6 subjects enrolled will receive a dose of 500 mg once daily (QD) of ivosidenib in combination with 
nivolumab 3 mg/kg IV infusion and ipilimumab 1 mg/kg IV infusion concurrently once every 3 weeks (Q3W) 
for 4 doses followed by nivolumab at 480 mg IV once every 4 weeks (Q4W) until progression or unacceptable 
toxicity (up to a maximum of 24 months of nivolumab). DLTs will be evaluated through Cycle 2 (i.e., during 
the first 42 days, 21 days/cycle). Based on the DLT evaluation of 500 mg QD, an additional 6 subjects may be 
enrolled to test an alternative dose of 250 mg QD. DLT evaluability is determined by subjects who have received 
the combination therapy and experienced a DLT through Cycle 2 or who have received at least 2 doses of 
nivolumab and ipilimumab, respectively, and at least 75% of ivosidenib at the assigned dose through Cycle 2 
without experiencing a DLT through Cycle 2. There will be no intra-subject dose escalations or reductions of 
nivolumab or ipilimumab allowed. Subjects must be dosed with nivolumab and/or ipilimumab no fewer than 
19 days from the previous dose for the first 4 cycles and no fewer than 25 days from the last dose in Cycle 5 
and beyond. A minimum of 6 DLT-evaluable subjects will be required to evaluate the safety and tolerability of 
the combination. Subjects who are not DLT evaluable will be replaced. A data review team (DRT) composed 
of Sponsor medical, safety, and statistical representatives, together with Principal Investigator(s), will review 
the available safety data when at least 6 DLT-evaluable subjects have completed at least 2 cycles of treatment 
or experienced a DLT within the first 2 cycles. 
Dose Stopping Criteria and De-escalation 
At the end of Cycle 2, if ≥ 33% of DLT-evaluable subjects have experienced a DLT, further dosing in that cohort 
will be halted and the dose of ivosidenib will be reduced to 250 mg for all subjects in that cohort. The DRT may 
recommend enrolling up to an additional 6 subjects to receive ivosidenib at a 250 mg QD dose level, and the 
same dose stopping rules will be applied after review of the safety data through Day 42 (through Cycle 2). The 
DRT may decide to cease enrollment in a dosing cohort if fewer than 2 subjects experience DLTs, but the nature 
of the event(s) is deemed a significant risk to subjects at that dose level. Because the immune-modulating 
regimen of nivolumab and ipilimumab itself may give rise to Grade 3 or 4 toxicity, the DRT will also consider 
the aggregate treatment-emergent data in relation to the known toxicity profile of nivolumab and ipilimumab 
and determine the acceptability of the safety profile of the combination. If 0 or 1 of the 6 evaluable subjects 
experience DLTs during the first 2 cycles at the 500 mg or the 250 mg QD dose levels, the study may proceed 
to the Expansion phase.  
Expansion Phase 
Once the RCD of ivosidenib in combination with nivolumab and ipilimumab has been determined, the 
Expansion phase of the study will begin. This phase will evaluate the clinical activity of ivosidenib in 
combination nivolumab and ipilimumab in this disease. Safety and tolerability data of ivosidenib in combination 
with nivolumab and ipilimumab will be reviewed on an ongoing basis during the study. 
This part will be conducted in 2 IDH1-mutated (IDH1m) CCA subpopulations:  
• Cohort 1: anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1)–naïve subpopulation: This 
subpopulation will include up to approximately 40 participants with nonresectable or metastatic CCA who 
have not received any anti-PD‑1/L1 therapy. 
• Cohort 2: anti-PD-1/L1 previously treated subpopulation: This subpopulation will include up to 
approximately 40 participants with nonresectable or metastatic CCA who have received anti-PD‑1/L1 
therapy. 

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abstinent. Sperm donation from male subjects will not be allowed during the study and for 3 months 
after the last dose of study treatment. 
Please refer to Appendix 7 for further contraception considerations. 
Informed Consent 
5. Obtained prior to any study-specific procedure as described in Section 13.3 of the protocol. 
Medical and Therapeutic Criteria  
6. Have a histopathological diagnosis consistent with nonresectable or metastatic cholangiocarcinoma and are 
not eligible for curative resection, transplantation or ablative therapies. 
7. Have documented IDH1 gene-mutated disease based on local testing procedure (R132C/L/G/H/S mutations 
variants tested). Preferably using a tumor biopsy sample collected within the last 3 years. 
8a.  Have disease progression or treatment intolerance following at least 1 and no more than 2 prior systemic 
regimens for advanced disease (nonresectable or metastatic) including the following:  
i. 
For Cohort 1: subjects who have not received any prior immune checkpoint inhibitor therapy but 
received at least 1 gemcitabine- or 5-FU-containg regimen for advanced cholangiocarcinoma.  
ii. 
For Cohort 2: subjects must have received at least two doses of anti-PD1/L1 therapy in first or second 
line, which may include combination with chemotherapy which should include at least 1 gemcitabine- 
or 5-FU-containg regimen for advanced cholangiocarcinoma. Combination therapy with other 
checkpoint inhibitors or investigational agents must be excluded.  
iii. 
Safety Lead-in phase: subjects eligible for either Cohort 1 or Cohort 2. 
Prior capecitabine or gemcitabine containing adjuvant chemotherapy will be considered a line of 
treatment if there is documented disease progression during or within 12 months of completing the 
therapy.  
9. 
Participants must have at least one measurable lesion, as defined by RECIST v1.1. Subjects who have 
received prior local therapy (including but not limited to embolization, chemoembolization, 
radiofrequency ablation, or radiation therapy) are eligible provided measurable disease falls outside of 
the treatment field or if within the field but has shown ≥ 20% growth in size post-treatment assessment. 
10. Adequate hematological function, defined as:  
i. 
WBC ≥ 2 x 109/L. 
ii. 
Absolute neutrophil count ≥ 1.5 x 109/L. 
iii. 
Hemoglobin ≥ 9 g/dL. In case of blood transfusion, the hemoglobin assessment must be performed 
2 weeks or more after the transfusion.  
iv. 
Platelet count ≥ 100 x 109/L.  
11. Adequate coagulation function as defined by International Normalization Ratio (INR), or Prothrombin 
Time (PT) or Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 upper limit of normal (ULN); Any 
subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout the 
study. Subjects receiving a factor Xa inhibitor who have abnormal PT/ partial thromboplastin time (PTT) 
may be eligible after discussion with the Sponsor. 
12. Adequate renal function defined as: calculated creatinine clearance ≥ 50 mL/min using the Cockcroft-Gault 
formula: 
(140 − Age) × (weight in kg) × (0.85 if female)/72 × serum creatinine 
13. Adequate hepatic function, defined as:  
i. 
Total serum bilirubin and direct bilirubin ≤ 1.5 x ULN (total serum bilirubin ≤ 3.0 x ULN for 
confirmed Gilbert disease). 
ii(a) Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 × ULN, exception to this range will 
need to be discussed and approved by the study medical monitor. 
iii. 
Serum albumin ≥ 2.8 g/dL. 
Exclusion Criteria: 
Subjects meeting any of the following criteria may not be enrolled in the study: 
General Criteria 
14. Inability to swallow oral medication.  
15. Pregnant and lactating women. 
16. WOCBP who tested positive in a serum pregnancy test within 24 hours prior to the first day of IMP 
administration, unless hCG has been determined to be elevated due to tumor production only with no 

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evidence of pregnancy by ultrasound and/or gynecologic evaluation. An extension up to 72 hours prior to 
the start of study treatment is permissible in situations where the results cannot be obtained within the 
standard 24-hour window. 
17. Unlikely to cooperate in the study. 
18. Participation in another interventional study at the same time or within 2 weeks prior to the first IMP 
administration. Participation in non-interventional registries or epidemiological studies is allowed. In 
addition, the first dose of ivosidenib should not occur before a period greater than or equal to 5 half-lives 
or 28 days, whichever is shorter, of the last dose of the investigational product. 
Medical and Therapeutic Criteria 
19. Subjects who received prior treatment with an IDH inhibitor or prior treatment with an immune checkpoint 
inhibitor other than anti-PD1/L1. 
20. Have a history of another primary cancer, with the exception of: a) curatively resected nonmelanoma skin 
cancer; b) curatively treated cervical carcinoma in situ; or c) other primary solid or liquid tumor within 
2 years prior (i.e., participants with a history of prior malignancy are eligible if treatment was completed at 
least 2 years before and the subject has no evidence of disease), with no known active disease present that, 
in the opinion of the Investigator, will not affect subject outcome in the setting of current 
cholangiocarcinoma diagnosis.   
21. Subjects with prior Grade ≥ 3 immune-related AE resulting from immune checkpoint inhibitors (ICI) 
therapy or have history of life-threatening toxicity related to prior immune therapy (ICI or any other 
antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those 
that are unlikely to re-occur with standard countermeasures (e.g., hypothyroidism).  
22. Subjects with active autoimmune disease or any condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily of prednisone equivalents) or other immunosuppressive medications within 
14 days of study treatment. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily 
prednisone equivalents are permitted in the absence of active autoimmune disease. 
23. Known prior severe hypersensitivity to investigational products or any component in their formulations. 
24. Participants who have not recovered from toxicity of previous anti-cancer therapy, including Grade ≥ 1 
non-hematologic toxicity, according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events v5.0, prior to the first IMP administration. Residual Grade ≤ 2 toxicity from chemotherapy 
(e.g., alopecia, neuropathy) may be allowed. 
25. Major surgery within 4 weeks prior to the first IMP administration or participants who have not recovered 
from side effects of the surgery. 
26. Have left ventricular ejection fraction (echocardiogram, multiple gated acquisition scan, or by other method 
according to institutional practice) < 40% by ECHO scan (or by other methods according to institutional 
practice) obtained within 28 days prior to the start of study treatment. 
27. Subjects who have heart rate-corrected QT interval using Fridericia’s formula (QTcF) of ≥ 450 msec or 
with other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, 
hypokalemia, family history of long QT interval syndrome). Subjects with bundle branch block and 
prolonged QTcF should be reviewed by the Sponsor for potential inclusion. 
28. History of motor neuropathy considered to be of autoimmune origin (e.g., Guillain-Barre syndrome, 
myasthenia gravis). 
29. Known immunodeficiency or HIV, hepatitis B, or hepatitis C infection. Antibody to hepatitis B or C without 
evidence of active infection may be allowed. Subjects with chronic hepatitis B virus that is adequately 
controlled per institutional guideline will be permitted.  
30. Severe or uncontrolled active acute or chronic infection. 
31. Have known symptomatic brain metastases requiring steroids. Subjects 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 4 weeks, and have radiographically stable disease for at least 3 months prior to study 
entry. Note: Up to 10 mg per day of prednisone equivalent will be allowed. 
32. Subjects who have received systemic anti-cancer treatment or palliative radiotherapy to bone metastases or 
other non-liver lesions less than 2 weeks before the first dose of ivosidenib. Arterial therapies and radiation 
to liver lesions less than 4 weeks before the first dose of ivosidenib. 
33. Treatment with a live/attenuated vaccine withing 30 days of first study treatment. 
34. History of non-infectious pneumonitis that required steroids, current pneumonitis, or history of interstitial 
lung disease. 
35. Subjects who discontinued prior treatment with ICIs for toxicity, irrespective of the grade of the event that 
triggered discontinuation. 

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36. Any clinically significant medical condition (e.g., organ dysfunction) or laboratory abnormality likely to 
jeopardize the participant’s safety or to interfere with the conduct of the study, in the Investigator’s opinion. 
37. Any contraindication to the use of nivolumab or ipilimumab as per standard labelling and local guidance. 
38. Are taking known strong cytochrome P450 (CYP) 3A4 inducers or sensitive CYP3A4 substrate medications 
with a narrow therapeutic window, unless they can be transferred to other medications within ≥ 5 half-lives 
prior to dosing. 
Note: Please refer to Appendix 10, Table 2 and Table 5, for further drug-drug interaction considerations.  
Test Drug: 
Ivosidenib (test drug), combined with nivolumab and ipilimumab. 
 
Ivosidenib 
Ivosidenib will be supplied as 250 mg strength tablets to be administered orally QD for a 21-day cycle. After 
the first 4 cycles, the cycle length will increase to 28 days. 
In the Safety Lead-In phase, ivosidenib will be administered orally at a starting dose of 500 mg QD. Depending 
on the DLT evaluation by the DRT, an alternative dose of 250 mg QD may be evaluated.  
 
Subjects enrolled in the Expansion phase will receive ivosidenib at the RCD in combination with nivolumab 
(3 mg/kg) and ipilimumab (1 mg/kg) concurrently Q3W for 4 doses followed by nivolumab (480 mg) Q4W 
until progression (up to a maximum of 24 months from date of first dose). 
 
In both phases, subjects will receive ivosidenib at the assigned dose on Days 1 through 21 in 21-day cycles for 
first 4 cycles followed by 28-day cycles starting with Cycle 5. Dosing is continuous, there are no planned rest 
periods. On days when subjects are receiving nivolumab and ipilimumab, ivosidenib should be administered 
approximately 30 minutes before the start of the infusion. It is recommended that each dose should be taken 
with or without food. Subjects taking ivosidenib with food should be advised to avoid grapefruit or grapefruit 
products and avoid consuming a high-fat meal (Please refer to examples of low-fat and high-fat meals in 
Appendix 11).  
No premedication is required prior to subjects receiving the first dose of ivosidenib. 
 
Nivolumab 
Nivolumab will be administered as an approximately 30-minute infusion at 3 mg/kg IV Q3W for the first 4 doses 
followed by 480 mg Q4W until progression and for up to a maximum of 24 months. Nivolumab infusion is to 
be administered prior to ipilimumab.  
Infusion duration: Nivolumab is to be infused over an approximately 30-minute (-5/+10 minutes) period. 
Subjects should be monitored for infusion reactions for 30 to 60 minutes after completing the nivolumab 
infusion. If a subject has an infusion reaction, a follow-up call approximately 24 hours after completion of 
infusion is recommended to ensure that the event is resolved. Premedications are not recommended for the first 
dose of nivolumab. 
 
Ipilimumab 
Ipilimumab will be administered as an approximately 30-minute infusion at 1 mg/kg IV Q3W for 4 total doses.  
Infusion duration: Ipilimumab is to be infused within 30 minutes after the end of nivolumab infusion over an 
approximately 30-minute (-5/+10 minutes) period. The time in between nivolumab and ipilimumab infusions is 
expected to be within approximately 30-minutes. 
Subjects should be monitored for infusion reactions for 30 to 60 minutes after completing the ipilimumab 
infusion. If a subject has an infusion reaction, a follow-up call approximately 24 hours after completion of 
infusion is recommended to ensure that the event is resolved.  
Duration of Treatment: 
Active treatment period: The planned duration of treatment is until disease progression. Subjects may be 
discontinued from treatment earlier due to unacceptable toxicity or other discontinuation criteria are met. End 
of Treatment (EOT) evaluations will be performed at the time of decision to discontinue treatment (or as close 
to the decision day as possible). Subjects may continue to receive up to a maximum of 24 months of nivolumab. 
Subjects who are still deriving clinical benefit after 24 months may continue to receive ivosidenib monotherapy 
until disease progression, unacceptable toxicity, or other discontinuation criteria are met.  
 

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Safety Follow-up period: Following discontinuation from study treatment, all subjects will have a 30-day Safety 
Follow-up visit. During the 30 (+5)-day Safety Follow-up period, all AEs and new medications (including new 
anti-cancer therapy) will be reported. Following the 30 (+5)-day Safety Follow-up period, subjects will be 
followed for safety for an additional 100 (+5) days after their last dose of immunotherapy or until they begin 
any other anti-cancer therapy, whichever is earlier.  
 
Overall Survival (OS) Follow-up period: Subjects will be followed for OS. Subjects will be contacted every 
12 weeks (±2 weeks) beginning at the EOT visit for up to 2 years after the last subject has been enrolled, or until 
death, lost to follow-up, withdrawal of consent from overall study participation, or Sponsor ending study, 
whichever occurs first.  
Data Review Team: A DRT composed of Sponsor medical, safety, and statistical representatives and study 
Investigator(s) will review the available safety data in all subjects enrolled in the 500 mg QD dose cohort of the 
Safety Lead-in phase in order to determine whether 500 mg QD is the ivosidenib RCD or whether the 250 mg 
QD dose level will be tested. If the 250 mg QD dose cohort is opened, the DRT will review the safety data in 
order to determine whether 250 mg QD is the RCD for the Expansion phase. 
 

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Table of contents 
1. ADMINISTRATIVE STRUCTURE OF THE STUDY ................................................. 23 
2. BACKGROUND INFORMATION ................................................................................. 23 
3. STUDY OBJECTIVES, ENDPOINTS AND ESTIMANDS ......................................... 31 
4. STUDY DESIGN ............................................................................................................... 33 
5. STUDY POPULATION AND WITHDRAWAL OF PARTICIPANTS ...................... 54 
6. TREATMENT OF PARTICIPANTS .............................................................................. 59 
7. ASSESSMENT OF EFFICACY ...................................................................................... 63 
8. ASSESSMENT OF SAFETY ........................................................................................... 65 
9. OTHER ASSESSMENTS NOT SPECIFICALLY RELATED TO EFFICACY 
OR SAFETY ...................................................................................................................... 80 
10. 
STATISTICS ................................................................................................................. 85 
11. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ........................................ 92 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 92 
13. 
ETHICS ......................................................................................................................... 95 
14. 
DATA HANDLING AND RECORD KEEPING ....................................................... 97 
15. 
INSURANCE ................................................................................................................. 98 
16. 
OWNERSHIP OF THE RESULTS – DATA SHARING POLICY AND 
PUBLICATION POLICY ................................................................................................ 99 
17. 
ADMINISTRATIVE CLAUSES ................................................................................. 99 
18. 
REFERENCES ............................................................................................................ 103 
19. 
APPENDICES ............................................................................................................. 106 
 

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List of tables 
Table (3) 1 - Study Objectives and Endpoints of the Safety Lead-in Phase ............................ 31 
Table (3) 2 - Study Objectives, Endpoints and Estimands of the Expansion Phase ................ 32 
Table (4.1.2) 1 - Schedule of Assessments for Subjects in the Safety Lead-in Phase and 
Expansion Phase ....................................................................................................................... 39 
Table (4.1.2) 2 - Pharmacokinetic and Pharmacodynamic Sampling for Subjects in the 
Safety Lead-in Phase: Ivosidenib in Combination with Nivolumab and Ipilimumab ............. 43 
Table (4.1.2) 3 - Pharmacokinetic and Pharmacodynamic Sampling for Subjects in the 
Expansion Phase: Ivosidenib in Combination with Nivolumab and Ipilimumab .................... 44 
Table (4.1.2) 4 - Mean Blood Volume for CL1-95031-006 ..................................................... 46 
Table (4.2) 1 - Description of the IMPs ................................................................................... 51 
Table (7.2) 1 - Imaging After First Radiological Evidence of Disease Progression ................ 64 
Table (8.12.1) 1 - Management of Ivosidenib related QT Prolongation and Adverse 
Events by NCI CTCAE Grade ................................................................................................. 77 
Table (10.2.2) 1 - Two-Sided 95% Exact Confidence Intervals for Various Observed 
Objective Response Rates (ORRs) (N = 40) ............................................................................ 90 
Table (19) 1 - Schedule of Assessments for Subjects in the Safety Lead-in Phase and 
Expansion Phase ..................................................................................................................... 148 
 

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List of figures 
Figure (4.1.1) 1 - Safety Lead-in Phase ................................................................................... 35 
Figure (4.1.1) 2 - Expansion Phase .......................................................................................... 35 
Figure (8.10.1) 1 - Rules for Adverse Event Reporting ........................................................... 72 
 

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List of appendices 
Appendix 1: World Medical Association Declaration of Helsinki ........................................ 107 
Appendix 2: Subject Registration Form Dose allocation - Subject Registration Form ......... 113 
Appendix 3: Subject Performance Status ............................................................................... 114 
Appendix 4: New Response Evaluation Criteria in Solid Tumors: Revised RECIST 
Guideline (Version 1.1), Eisenhauer, 2009 ............................................................................ 115 
Appendix 5: End of Cohort Meeting Minutes Template End of cohort meeting minutes ..... 124 
Appendix 6: Instructions to Investigator for Handling Data Rights Requests ....................... 125 
Appendix 7: Contraception Considerations ........................................................................... 127 
Appendix 8: Adverse Event Criteria for Delay, Resume, and Discontinue of Nivolumab 
and Ipilimumab ...................................................................................................................... 128 
Appendix 9: Management Algorithms for Studies Under CTCAE Version 5.0 .................... 133 
Appendix 10: ECOG Performance Status and Prohibited Concomitant Medications ........... 142 
Appendix 11: Examples of Low-Fat and High-Fat, High-Calorie Meals .............................. 144 
Appendix 12: National Cancer Institute Common Terminology Criteria for Adverse 
Events ..................................................................................................................................... 145 
Appendix 13: Local modification of the clinical study protocol (GBR)................................ 147 

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List of abbreviations 
Abbreviation 
Definition  
2-HG 
Plasma 2-hydroxygluturate 
5-FU 
5-fluorouracil based chemotherapy  
ADA 
Anti-Drug Antibody 
ADL 
Activities of daily living 
AE 
Adverse Events 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
AML 
Acute Myeloid Leukemia 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration 
AUC0-∞ 
Area under the concentration from 0 to infinity 
AUC0-t 
0 to time of last measurable concentration 
AUCtau,ss 
Area under the concentration over 1 dosing interval at steady state 
BOR 
Best overall response 
BTC 
Biliary tract cancer 
C1D1 
Cycle 1 Day 1 
CCA 
Cholangiocarcinoma 
CD 
Combination Dose 
cHL 
classical Hodgkin Lymphoma 
CI 
Confidence Interval 
CL 
Clearance 
CL/F 
Apparent Clearance 
Cmax 
Maximum Concentration 
CR 
Confirmed complete response 
CRC 
Colorectal Cancer 
CRO 
Contract research organizations 
CSR 
Clinical study report 
CT 
Cytotoxic T 
ctDNA 
Circulating tumor DNA 
CTLA4 
Cytotoxic T-lymphocyte associated protein 4 
Ctrough 
Trough concentration 
CV 
Curriculum vitae 
CYP 
Cytochrome p450 
DCR 
Disease control rate 
DLT 
Dose limiting toxicities 
DOR 
Duration of response 
DRT 
Data review team 
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEA 
European economic area 
EOT 
End of Treatment 
EU 
European union 

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FDA 
Food and drug administration 
FDG 
Fluorodeoxyglucose 
FGFR 
Fibroblast growth factor receptor 
FSP 
Full service provider 
GCP 
Good clinical practice 
GLP 
Good laboratory practice 
HCC 
Hepatocellular Carcinoma 
HPBL 
Human peripheral blood lymphocyte 
HR 
Hazard ratio 
IB 
Investigator brochure 
iCCA 
Intrahepatic 
ICF 
Informed consent form 
ICI 
Immune checkpoint inhibitors 
IDH1 
Isocitrate dehydrogenase 1 
IE 
Intercurrent events 
IEC 
Independent ethics committee 
Ig 
Immunoglobulin 
IMAE 
Immune-mediated adverse events 
IMP 
Investigational medicinal product 
INR 
International normalization ratio 
IO 
Immuno-oncology 
irAE 
Immune-related adverse events 
IRB 
Institutional review board 
IV 
Ivosidenib 
LEVF 
Left ventricular ejection fraction 
mAb 
Monoclonal antibody 
MedDRA 
Medical dictionary for regulatory activities 
MRI 
Magnetic resonance imaging 
MUGA 
Multiple gated acquisition 
NE 
Not evaluable 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PD 
Pharmacodynamic 
PD-L1 
Programmed death-ligand 1 
PD-L 
Programmed death 1 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PR 
Partial response 
PRES 
Posterior reversible encephalopathy syndrome 
PT 
Prothrombin time 
Q2W 
Once every 2 weeks 
Q3W 
Once every 3 weeks 
Q4W 
Once every 4 weeks 
QD 
Once daily 
QTcF 
QT interval using Fridericia’s formula 

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R/R 
Relapsed or refractory 
RCC 
Renal cell carcinoma 
RCD 
Recommended combination Dose 
RECIST 
Response evaluation criteria in solid tumors 
RTSM 
Randomization and trial supply management 
SAP 
Statistical analysis plan 
SAE 
Serious adverse events 
SCCHN 
Squamous cell carcinoma of head and neck 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
SmPC 
Summary of product characteristics 
T1/2 
Time required for drug concentration 
TEAE 
Treatment-emergent adverse events 
Tmax 
Time to maximum concentration 
TTR 
Time to response 
ULN 
Upper limit of normal 
US 
United States 
USPI 
US prescribing information 
Vd/F 
Apparent volume of distribution 
WMA 
World medical association 
WOCBP 
Women of childbearing potential 
WT 
Wild-type tumors 
 

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1. ADMINISTRATIVE STRUCTURE OF THE STUDY 
Non-Sponsor parties, Sponsor parties, and contract research organizations (CROs) responsible 
for local management of the study are described in a separate document entitled 
“Administrative Part of Clinical Study Protocol.” The list of Investigators is given in a separate 
document attached to the protocol and entitled “Investigators.” 
2. BACKGROUND INFORMATION 
2.1. Cholangiocarcinoma 
2.1.1. 
Overview of Cholangiocarcinoma 
Cholangiocarcinomas (CCAs) are rare cancers (accounting for 3% of all gastrointestinal 
malignancies) that arise from biliary epithelium and are typically diagnosed at advanced stages 
for which curative surgery is not feasible. The classification of CCAs is divided anatomically 
as extrahepatic, intrahepatic (iCCA), and perihilar (Saha et al, 2014; Van Dyke et al, 2019). 
The disease is often advanced and incurable at the time of diagnosis. Common presentation 
includes symptoms related to biliary tract obstruction including jaundice, abdominal pain, 
weight loss, fever, fatigue, and abnormal liver function tests. The prognosis for subjects with 
CCA is poor; regardless of stage at diagnosis, the 5-year survival rates associated with both 
intrahepatic (iCCA) and extrahepatic CCA are 9% to 10% and only 2% in subjects with distant 
metastases (ACS, 2021). CCA (intrahepatic and extrahepatic) affects approximately 
8,000 people in the US annually (ACS, 2019) and approximately 1.3 in 10,000 people in the 
EU (Agency, 2018). 
Isocitrate dehydrogenase-1 (IDH1) mutations occur globally in approximately 16%, and up to 
29% in some reports, of iCCAs and approximately 0% to 7% of extrahepatic CCAs. Using a 
maximum incidence of 14% (13% for intrahepatic + 1% for extrahepatic) for IDH1 mutations 
in CCA indicates an overall prevalence of 0.182 in 10,000 people (Kendre et al, 2022). Based 
on majority of available literature, IDH1 mutations do not have a prognostic impact on clinical 
outcomes including progression-free survival (PFS) and overall survival (OS) (Boscoe et al, 
2019). Therefore, outcomes in this biomarker-selected population can be compared to those 
reported among the general advanced, previously treated CCA population (Boscoe et al, 2019; 
Goyal et al, 2015). 
2.1.2. 
Current Treatment of Cholangiocarcinoma 
As early-stage disease is commonly asymptomatic, only a minority of CCA subjects are 
diagnosed with resectable disease, while most of the subjects present with locally nonresectable 
or metastatic disease (Rizzo et al, 2021). The first-line standard of care treatment for subjects 
with CCA, including subjects with IDH1 mutation-positive CCA, in a locally nonresectable or 
metastatic setting is a combination of durvalumab with gemcitabine/cisplatin and a 
combination of pembrolizumab with gemcitabine/cisplatin. Approval of durvalumab in 
combination with gemcitabine/cisplatin was granted starting in 2022 in the US, EU, UK and 
other parts of the world and was based on the Phase 3 TOPAZ-1 trial evaluating the durvalumab 
and gemcitabine/cisplatin combination vs. gemcitabine/cisplatin. The addition of durvalumab 
resulted in an improved OS of 12.8 months compared with a gemcitabine/cisplatin OS of 
11.5 months (hazard ratio [HR]: 0.80, confidence interval [CI]: 0.66-0.97, p = 0.021) (Oh et al, 
2022). Approval of pembrolizumab in combination with gemcitabine/cisplatin was granted in 

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2023 in the US and was based on the Phase 3 Keynote-966 trial evaluating pembrolizumab and 
gemcitabine/cisplatin combination vs. gemcitabine/cisplatin. The addition of pembrolizumab 
resulted in an improved OS of 12.7 months compared to a gemcitabine/cisplatin OS of 10.9 
months (HR: 0.83, CI: 0.72–0.95, p = 0.0034) (Kelley et al, 2023). 
Second-line chemotherapy regimens produce an incrementally smaller therapeutic benefit, 
with an average median PFS of 2 to 3 months (Brieau et al, 2015; Lamarca et al, 2021). Overall 
survival outcomes are also limited to approximately 6 months (Kim et al, 2017; Lamarca et al, 
2021; Matsuyama et al, 2018; Ying and Chen, 2019), demonstrating the need for novel 
treatment options in subjects with CCA. 
Recent years have seen the advent of novel treatments in the biliary tract cancer (BTC) 
landscape, including targeted therapies (ivosidenib, pemigatinib, infigratinib, and futibatinib) 
and immune checkpoint inhibitors (ICIs), as monotherapy or in combination (Rizzo et al, 
2021).  
Ivosidenib, a potent and selective inhibitor of the IDH1 mutant protein, is the only drug 
approved for the treatment of adult subjects with previously treated, locally nonresectable or 
metastatic CCA with an IDH1 mutation (approval granted in the US in 2021). Pemigatinib, 
infigratinib, and futibatinib, selective inhibitors of fibroblast growth factor receptor (FGFR), 
are approved for treatment of adult subjects with previously treated, locally nonresectable or 
metastatic CCA who have FGFR2 fusions or rearrangements (approved in the US in 2020, 
2021, and 2022, respectively). Pemigatinib is also approved in EU (approval granted in 2021). 
FGFR fusions are detected in 10% to 15% of subjects with iCCA (Saborowski et al, 2020), 
however they rarely co-occur (less than 1% of subjects) with mutations of IDH1 (Abou-Alfa 
et al, 2020). 
The activity of ICIs (programmed death-1 [PD-1], programmed death-ligand 1 [PD-L1]) in 
previously treated BTC has been tested with heterogenous results. Results with ICI 
monotherapy in unselected BTCs, including CCA, suggest limited activity in recurrent disease; 
the objective response rate (ORR) of single-agent anti-PD-1 is approximately 10% (Doki et al, 
2022; Kim et al, 2020; Klein et al, 2020; Piha-Paul et al, 2020). 
Two Phase 1/2 studies testing the combination of a PD-1 or PD-L1 inhibitor with an anti–
cytotoxic T-lymphocyte associated protein 4 (CTLA4) agent showed superior efficacy than 
any compound alone. Durvalumab (anti-PD-L1) in combination with tremelimumab (anti-
CTLA4) was tested in Asian subjects resulting in an ORR of 10.8% and a median OS of 
10.1 months (Doki et al, 2022). In the second trial, nivolumab (anti-PD-1) plus ipilimumab 
(anti-CTLA4) (Klein et al, 2020) was administrated to 39 Australian subjects (16 with iCCA) 
resulting in an ORR of 23% (31% iCCA), and median PFS and median OS of 2.9 and 
5.7 months, respectively. These preliminary results appear to suggest that combination of anti-
PD-1 with anti-CTLA4 has superior efficacy compared with anti-PD-1 monotherapy and 
warrants further investigation in larger clinical trials.  
2.2. Overview of Ivosidenib 
Ivosidenib (also known as S95031, AG-120, and AGI-16678) is a potent, selective, orally 
active small molecule inhibitor of mutated IDH1. The clinical development of ivosidenib is 
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and in combination with other standard chemotherapies, and on advanced solid tumor 
malignancies as a single agent.  
Ivosidenib (TIBSOVO) is an IDH1 inhibitor indicated for subjects with a susceptible IDH1 
mutation as detected by a US Food and Drug Administration (FDA)-approved test:  
­ In combination with azacitidine or as a monotherapy for the treatment of newly diagnosed 
acute myeloid leukemia (AML) in adults 75 years or older, or who have comorbidities that 
preclude use of intensive induction chemotherapy. 
­ For the treatment of adult subjects with relapsed or refractory (R/R) AML. 
­ For the treatment of adult patients with relapsed or refractory myelodysplastic syndromes. 
­ For the treatment of adult subjects with locally advanced or metastatic CCA who have been 
previously treated. 
TIBSOVO is also registered in the EU, in combination with azacitidine for the treatment of 
adult patients with newly diagnosed AML with an IDH1 mutation who are not eligible to 
receive standard induction chemotherapy, or as monotherapy for the treatment of adult subjects 
with locally advanced or metastatic CCA with an IDH1 mutation, who have been previously 
treated. 
Details about the indication-specific safety information are provided in Section 6.5 and 
Section 6.6 of the Investigator’s Brochure (IB). 
Two studies investigated ivosidenib as a single agent in subjects with IDH1-mutated CCA. The 
results from the Phase 3 ClarIDHy study (AG120-C-005) and the supportive Phase 1 AG120-
C-002 study demonstrate clinically meaningful and durable efficacy in subjects who received 
at least 1 prior line of chemotherapy. 
2.2.1. 
Description of the Investigational Medicinal Product Ivosidenib 
2.2.1.1. 
Nonclinical Data 
Details of the nonclinical development program for ivosidenib are provided in the IB. 
2.2.1.2. 
Toxicology Summary of Ivosidenib 
The toxicity profile of ivosidenib was evaluated in vitro in a Good Laboratory Practice (GLP) 
bacterial reverse mutation assay, a GLP human peripheral blood lymphocyte micronucleus 
assay, and a GLP BALB/c 3T3 mouse fibroblast phototoxicity assay. In vivo GLP toxicology 
studies included repeat-dose 28-day and 3-month Sprague Dawley rat and cynomolgus monkey 
studies, dose range–finding and definitive embryo-fetal development studies in Sprague 
Dawley rats and New Zealand white rabbits, and a micronucleus study in Sprague Dawley rats. 
Based on the results of the nonclinical toxicology program conducted to date, ivosidenib has 
an acceptable safety profile for continued use in humans. 
2.2.2. 
Clinical Pharmacokinetics and Pharmacodynamics 
A total of 12 clinical studies have contributed to the characterization of the pharmacokinetics 
(PK) and pharmacodynamics (PD) of ivosidenib. Five of these studies were conducted in 
healthy subjects (all single-dose studies), and 7 of these studies were conducted in subjects 
with advanced hematologic malignancies and solid tumor malignancies (single and multiple 
doses). Ivosidenib demonstrated good oral bioavailability, rapid absorption, and a long 

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elimination half-life (t½) in subjects with IDH1-mutated AML and solid tumor malignancies, 
supporting a once daily (QD) dosing regimen. The mean terminal t½ at steady state of 
ivosidenib in subjects with CCA is 129 hours (102%). After multiple doses of ivosidenib, 
steady state was reached within 14 days, with approximately 2-fold accumulation in plasma 
exposure. Plasma exposure of ivosidenib increased less than dose proportionally from 100 to 
1,200 mg. 
Results from studies in subjects with advanced hematologic malignancies (AG120-C-001, 
AG120-221-C-001, and AG221-AML-005) and solid tumor malignancies (AG120-C-002, 
AG120-881-C-001, and AG120-C-005) indicate that plasma 2-hydroxyglutarate (2-HG) levels 
were substantially reduced in subjects with an IDH1 mutation (achieving levels similar to those 
in healthy subjects) at doses ranging from 200 to 1,200 mg QD. Multiple doses of ivosidenib 
also decreased 2-HG levels in bone marrow (AML) and tumor biopsies (CCA and 
chondrosarcoma) at doses ranging from 200 to 1,200 mg QD. Maximal plasma inhibition of 
2‑HG occurred at 500 mg QD in most subjects, with no additional inhibition observed at higher 
doses. 
2.3. Overview of Nivolumab and Ipilimumab 
2.3.1. 
Nivolumab  
2.3.1.1. 
Mechanism of Action 
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human 
monoclonal antibody (mAb) (immunoglobulin [Ig]G4-S228P) that targets the PD-1 cluster of 
differentiation (CD)279 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-L1 
and PD-L2, results in the down-regulation 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. 
Nivolumab (marketed in the US and EU under the trade name Opdivo®) is approved for the 
treatment of several types of cancer in multiple regions including the US (December 2014), the 
EU (June 2015), and Japan (July 2014).  
2.3.1.2. 
Nivolumab Clinical Activity 
Nivolumab has demonstrated durable responses exceeding 6 months as monotherapy in several 
tumor types, including non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma 
(RCC), classical Hodgkin lymphoma (cHL), small cell lung cancer (SCLC), gastric cancer, 
squamous cell carcinoma of head and neck (SCCHN), urothelial cancer, hepatocellular 
carcinoma (HCC), and colorectal cancer (CRC). In confirmatory trials, nivolumab as 
monotherapy demonstrated a statistically significant improvement in OS as compared with the 
current standard of care in subjects with nonresectable or metastatic NSCLC, unresectable or 
metastatic melanoma, advanced RCC, or recurrent or metastatic SCCHN. Details of the clinical 
activity in these various malignancies are provided in the US Prescribing Information (USPI) 
and Summary of Product Characteristics (SmPC), see Section 2.4.2.  

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2.3.2. 
Ipilimumab 
2.3.2.1. 
Mechanism of Action 
Ipilimumab (BMS-734016, MDX010, MDX-CTLA4) is a fully human monoclonal IgG1 
kappa specific for human CTLA4 (CD152), which is expressed on a subset of activated T cells. 
CTLA4 is a negative regulator of T-cell activity. Ipilimumab is a mAb that binds to CTLA4 
and blocks the interaction of CTLA4 with its ligands, CD80/CD86. Blockade of CTLA4 has 
been shown to augment T-cell activation and proliferation, including the activation and 
proliferation of tumor-infiltrating T-effector cells. Inhibition of CTLA4 signaling can also 
reduce T-regulatory cell function, which may contribute to a general increase in T-cell 
responsiveness, including the anti-tumor response. 
2.3.2.2. 
Ipilimumab Clinical Activity 
Ipilimumab (marketed in the US and EU under the trade name Yervoy®) is a recombinant, fully 
human mAb that binds to CTLA4 and is approved as monotherapy and in combination with 
nivolumab for the treatment of subjects with unresectable or metastatic melanoma; for the 
treatment of subjects with intermediate/poor-risk, previously untreated advanced RCC; for the 
first-line treatment of subjects with metastatic or recurrent NSCLC with no epidermal growth 
factor receptor or ALK receptor tyrosine kinase genomic tumor aberrations; and for the first-
line treatment of subjects with unresectable malignant pleural mesothelioma. 
2.3.3. 
Nivolumab Combined with Ipilimumab Clinical Activity 
Multiple clinical studies have evaluated nivolumab combined with ipilimumab at different 
doses and schedules. Based on Phase 3 data showing improved survival over standard of care 
therapies, nivolumab combined with ipilimumab has been approved in multiple countries for 
the treatment of subjects with unresectable or metastatic melanoma, intermediate or poor risk, 
previously untreated advanced RCC, and microsatellite instability-high or mismatch repair 
deficient CRC. Details of the clinical activity in these various malignancies are provided in the 
USPI and SmPC. The combination has been studied in subjects with biliary tract cancers with 
activity and safety summarized in Sections 2.4.2 and 2.5. 
2.4. Rationale for the Combination of Ivosidenib with Nivolumab and Ipilimumab in 
Cholangiocarcinomas 
2.4.1. 
Nonclinical Data for Ivosidenib in Combination with Nivolumab and Ipilimumab 
Mutations in the metabolic enzyme IDH1 occur in approximately 14% of subjects with iCCA 
and result in overproduction of the oncometabolite 2-HG (Dang et al, 2009; Figueroa et al, 
2010). IDH1 mutations may play a role in the pathogenesis of the CCA by blocking the 
differentiation of liver progenitor cells, promoting cellular proliferation (Valle et al, 2010), and 
activating a dual immunoevasion program reducing T-cell recruitment and interferon γ 
expression and response (Notarangelo et al, 2022; Wu et al, 2022).  
Ivosidenib is a novel, first-in-class, small molecule targeted selectively to inhibit the mutated 
IDH1 enzyme and reduce the production of the oncogenic metabolite 2-HG. It inhibits 2-HG 
production by > 95% in nonclinical studies (in vitro and in vivo) and reduces plasma 2-HG up 
to 98% in clinical studies (see the IB). Recent studies suggest a role for high 2‑HG in repressing 
key immune-related genes and impairing lymphocyte infiltration both in glioma and CCA 
(Kohanbash et al, 2017; Notarangelo et al, 2022; Thorsson et al, 2018 ; Wu et al, 2022). 

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Mutant IDH1 CCA subject samples exhibit a T-cell-deficient tumor microenvironment 
compared with IDH1 wild-type (WT) tumors (Wu et al, 2022; Xiang et al, 2021). In pre-
treatment CCA biopsies obtained in the Phase 3 study testing ivosidenib versus placebo in 
subjects with previously treated advanced CCA with IDH1 mutations (NCT02989857), an 
artificial intelligence–based histological analysis showed less lymphocyte infiltration pattern 
in IDH1-mutated tissue sections compared with IDH1 WT samples. The pattern was more 
pronounced in subjects with higher 2‑HG, supporting a role for elevated 2‑HG in immune-
quiescence. 
Direct effects of 2-HG on T cells and combination benefit between ivosidenib and immune 
checkpoint inhibition have been demonstrated in mouse models. In a mouse model of IDH1-
mutated CCA, ivosidenib treatment stimulated T-cell recruitment and effector function in the 
tumor and was synergistic in combination with CTLA4 inhibition, with the combination 
resulting in complete tumor regression in the majority of animals receiving a 26-day treatment 
course (Wu et al, 2022). In a second study, 2-HG was shown to directly impact the metabolism 
of CD8 T cells resulting in impaired effector function, and this effect was recapitulated in 
clinical samples from subjects with IDH-mutant glioma (Notarangelo et al, 2022). 
2.4.2. 
Clinical Data for Ivosidenib in Combination with Nivolumab and Ipilimumab 
The activity of ICIs (PD-1, PD-L1) in metastatic and recurrent BTC has been tested with 
heterogenous results. Monotherapy in unselected BTCs, including CCA, has had disappointing 
results and limited activity in recurrent disease; the ORR of a single-agent anti-PD-1 is 
approximately 10% (Doki et al, 2022; Kim et al, 2020; Klein et al, 2020; Piha-Paul et al, 2020). 
Two Phase 1/2 studies testing the association of a PD-1 or PD-L1 inhibitor with an anti-CTLA4 
showed superior efficacy than any compound alone. Durvalumab (anti-PD-L1) plus 
tremelimumab (anti-CTLA4) was tested in Asian subjects resulting in an ORR of 10.8% and a 
median OS of 10.1 months (Doki et al, 2022). In the second trial, nivolumab (anti-PD-1) plus 
ipilimumab (anti-CTLA4) (Klein et al, 2020) was administrated to 39 Australian subjects (16 
with iCCA) obtaining an ORR of 23% (31% iCCA) and a median PFS and median OS of 2.9 
and 5.7 months, respectively. These preliminary results showed that combination of an anti-
CTLA4 and an anti-PD-1 seemed to have superior efficacy than anti-PD-1 monotherapy and 
warrants further investigation from larger clinical trials. 
Additionally, an Investigator-initiated trial of ivosidenib in combination with nivolumab in 
IDH1-mutated advanced solid tumors is active with ongoing subject accrual in the US 
(NCT04056910).  
2.5. Overall Benefit/Risk 
The safety profile for ivosidenib is manageable based on the cumulative safety data from 
approximately 13,812 subjects/patients who have been exposed to 1 or more doses of 
ivosidenib. Important identified risks associated with ivosidenib administration based on the 
current safety profile include Electrocardiogram QT prolonged (all subjects) and 
Differentiation syndrome (hematologic malignancies only).    
The primary endpoint in the ClarIDHy study, PFS by IRC demonstrated a highly statistically 
significant and clinically meaningful reduction in the risk of progression or death (HR, 
p-value). This benefit in PFS was also apparent at the 6 and 12-month timepoints. Additionally, 
the benefit of OS in the ivosidenib arm compares favorably with chemotherapy. 

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Two Investigator-initiated studies tested the combination of nivolumab and ipilimumab in 
advanced biliary cancers. Among the 39 subjects included in a Phase 2 clinical trial 
investigating ipilimumab 1 mg/kg and nivolumab 3 mg/kg once every 3 weeks (Q3W) for a 
maximum of 4 cycles followed by nivolumab 3 mg/kg once every 2 weeks and continued for 
up to 96 weeks, the ORR was 23% (n = 9) with a disease control rate of 44% (n = 17); all 
responders had received prior chemotherapy, and none had a microsatellite unstable tumor. 
Immune-related toxic events were reported in 49% of subjects (n = 19), with 15% (n = 6) 
experiencing Grade 3 or 4 events. The most common irAE was rash/pruritis (33%), Grade 3 or 
higher irAE is rare, thyroiditis 3%, hypophysitis 5%, hepatitis 3%, enterocolitis/diarrhea 3%, 
and gastritis 3%. A separate trial investigated combination of 240 mg nivolumab once every 
2 weeks and ipilimumab 1 mg/kg once every 6 weeks in advanced biliary cancer without prior 
systemic therapy (Sahai et al, 2022). Among 33 evaluable subjects, the 6‑month PFS rate was 
21.1% (95% CI, 9.4%-36.3%) and median OS was 8.2 months (95% CI, 5.8-16.9 months), 
while the ORR was 3.0% (95% CI, 0.1%-15.8%). The incidence of SAEs was 36.4%, with 
Grade ≥ 3 treatment-related AEs of fatigue (6.1%), aspartate aminotransferase (AST) 
increased, or alanine aminotransferase (ALT) increased (9.1% each), diarrhea (6.1%), and 
colitis (6.1%). There was no Grade 3 or higher hematologic AEs.  
In summary, CCA with an IDH1 mutation is a rare, aggressive, and life-threatening 
malignancy. Ivosidenib is the only approved therapy targeting IDH1-mutated CCA. However, 
novel scientifically rational combination approaches are needed for this subject population to 
improve clinical outcomes and emerging science suggests that combination of an IDH1 
inhibitor with immunotherapy, i.e., anti-CTLA4 and anti-PD-1 mAbs, may work 
synergistically to enhance anti-tumor response in previously treated CCA. Although previous 
or ongoing studies have tested one or more of these drugs in combination, this is the first study 
that will test a triple combination. Therefore, the study will first test the safety of the 
combination in a small number of subjects during a Safety Lead-in phase in order to evaluate 
for DLTs and identify the RCD (For more details, see Section 4.1.4).  
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
the ethical principles that have their origin in the Declaration of Helsinki and the applicable 
regulatory requirements. 

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3. STUDY OBJECTIVES, ENDPOINTS AND ESTIMANDS 
The study objectives and corresponding endpoints are summarized in Table (3) 1 and 
Table (3) 2 for the Safety Lead-in phase and Expansion phase, respectively. 
Table (3) 1 - Study Objectives and Endpoints of the Safety Lead-in Phase 
Objectives 
Endpoints 
Primary 
To evaluate the safety and tolerability of 
ivosidenib in combination with nivolumab and 
ipilimumab and determine the recommended 
combination dose (RCD) of ivosidenib, 
nivolumab, and ipilimumab 
• 
Dose limiting toxicities (DLTs) associated with 
ivosidenib in combination with nivolumab and 
ipilimumab during the first 2 cycles of treatment 
• 
Adverse events (AEs), adverse events of special 
interest (AESIs), and serious adverse events (SAEs)  
Secondary 
To evaluate the pharmacokinetics (PK) of 
ivosidenib when given in combination with 
nivolumab and ipilimumab 
Plasma concentrations and PK parameters including, but 
not limited to, area under the concentration-vs-time curve 
(AUC) from 0 to time of last measurable concentration 
(AUC0-t), AUC over 1 dosing interval at steady state 
(AUCtau,ss), time to maximum concentration (Tmax), 
maximum concentration (Cmax), trough concentration 
(Ctrough), apparent volume of distribution (Vd/F), and 
apparent clearance (CL/F)  
To evaluate the pharmacodynamic (PD) effects 
of ivosidenib when given in combination with 
nivolumab and ipilimumab 
Plasma 2-hydroxygluturate (2-HG) concentration 
Exploratory 
To evaluate ivosidenib exposure in tumor tissue 
Tumor tissue concentrations of ivosidenib  
To evaluate the PK of nivolumab and ipilimumab 
when given in combination with ivosidenib 
Serum concentrations of nivolumab and ipilimumab  
To evaluate immunogenicity of nivolumab and 
ipilimumab when given in combination with 
ivosidenib 
Measurement of anti-drug antibody (ADA) to nivolumab 
and ipilimumab  
To evaluate the PD effects of ivosidenib in tumor 
tissue 
when 
given 
in 
combination 
with 
nivolumab and ipilimumab 
Tumor tissue 2-HG concentration  
To identify molecular and cellular biomarkers 
that 
may 
be 
indicative 
of 
clinical 
response/resistance, 
PD 
activity, 
and 
the 
mechanism of action 
Associations of pre-treatment molecular and cellular 
markers with patient outcome 
Differences in molecular and cellular markers between on-
treatment and/or pre-treatment samples 
 
 

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Table (3) 2 - Study Objectives, Endpoints and Estimands of the Expansion Phase 
Objectives 
Endpoints 
Other Estimand Attributes 
Primary 
 
To assess the clinical activity of 
ivosidenib 
in 
combination 
with 
nivolumab and ipilimumab using 
Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 
Objective response (confirmed 
complete 
response 
[CR] 
or 
confirmed partial response [PR]) 
of 
anti-tumor 
activity 
(using 
RECIST v1.1) 
The primary estimand of interest 
is the objective response rate 
(ORR). The attributes of the 
primary estimand are defined as 
follows:  
• 
Treatment: ivosidenib plus 
nivolumab and ipilimumab 
• 
Population: Safety Analysis 
Set  
• 
Summary 
measure: 
objective response (Yes, 
No) 
• 
Intercurrent events (IE): 
1. Early 
treatment 
discontinuation 
2. Administration of further 
anti-cancer therapy 
Secondary 
To confirm the safety and tolerability 
of the recommended combination 
dose (RCD) of ivosidenib, nivolumab. 
and ipilimumab 
Adverse events (AEs), adverse 
events of special interest (AESIs), 
and serious adverse events (SAEs) 
Not applicable 
To 
evaluate 
additional 
efficacy 
parameters 
to 
assess 
anti-tumor 
activity of ivosidenib in combination 
with nivolumab and ipilimumab 
• 
Duration of response (DOR), 
progression-free 
survival 
(PFS) and disease control 
(CR, PR, or SD maintained 
for at least 5 months), time to 
response (TTR) according to 
RECIST v1.1 
• 
Overall survival (OS) 
Not applicable 
To evaluate the pharmacokinetics 
(PK) of ivosidenib when given in 
combination with nivolumab and 
ipilimumab 
Plasma concentrations and PK 
parameters including, but not 
limited 
to, 
area 
under 
the 
concentration-vs-time 
curve 
(AUC) from 0 to time of last 
measurable 
concentration 
(AUC0‑t), AUC over 1 dosing 
interval at steady state (AUCtau,ss), 
time to maximum concentration 
(Tmax), maximum concentration 
(Cmax), 
trough 
concentration 
(Ctrough), 
apparent 
volume 
of 
distribution (Vd/F), and apparent 
clearance (CL/F) 
Not applicable 
To evaluate the pharmacodynamic 
(PD) effects of ivosidenib when given 
in combination with nivolumab and 
ipilimumab 
Plasma 2-hydroxyglutarate (2-
HG) concentration 
Not applicable 

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Objectives 
Endpoints 
Other Estimand Attributes 
Exploratory 
To evaluate ivosidenib exposure in 
tumor tissue 
Tumor tissue concentrations of 
ivosidenib  
Not applicable 
To evaluate the PK of nivolumab and 
ipilimumab 
when 
given 
in 
combination with ivosidenib 
Serum 
concentrations 
of 
nivolumab and ipilimumab  
Not applicable 
To 
evaluate 
immunogenicity 
of 
nivolumab and ipilimumab when 
given in combination with ivosidenib 
Measurement 
of 
anti-drug 
antibody (ADA) to nivolumab and 
ipilimumab 
Not applicable 
To evaluate the PD effects of 
ivosidenib in tumor tissue when given 
in combination with nivolumab and 
ipilimumab 
Tumor tissue 2-HG concentrations 
Not applicable 
To identify molecular and cellular 
biomarkers that may be indicative of 
clinical 
response/resistance, 
PD 
activity, and the mechanism of action 
Associations 
of 
pre-treatment 
molecular and cellular markers 
with patient outcome 
Differences in molecular and 
cellular markers between on-
treatment and/or pre-treatment 
samples 
Not applicable 
4. STUDY DESIGN 
4.1. Investigational Plan 
4.1.1. 
Study Plan 
This is a Phase 1/2, non-comparative, multicenter, open-label study of ivosidenib, an oral 
mutant IDH1 inhibitor, administered in combination with nivolumab and ipilimumab. Subjects 
are required to have a histologically confirmed diagnosis of cholangiocarcinoma (CCA), a local 
molecular IDH1 gene-mutation CCA and not eligible for curative resection, transplantation, or 
ablative therapies. The study will be conducted in adult subjects with nonresectable or 
metastatic CCA. Subjects must have progression of disease or treatment intolerance and have 
received at least 1 but not more than 2 prior treatment regimens for advanced disease 
(nonresectable or metastatic). All subjects must have received either a gemcitabine- or a 
5-fluorouracil (5-FU)–based chemotherapy regimen.  
This study consists of a Safety Lead-in phase and an Expansion phase as shown in 
Figure (4.1.1) 1 and Figure (4.1.1) 2, respectively. 
The first phase will be the Safety Lead-in to evaluate the safety and tolerability of ivosidenib 
in combination with nivolumab and ipilimumab in order to determine the recommended 
combination dose (RCD). This phase will enroll up to approximately 6-12 DLT-evaluable 
subjects with nonresectable or metastatic CCA with an IDH1 mutation. 

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4.1.1.1. 
Study Periods 
The study will be divided into the following periods for each subject. 
4.1.1.2. 
Screening Period/Inclusion 
Following subject signature of the informed consent form (ICF) (the signing of the ICF 
indicates the start of the study), subject eligibility will be confirmed during a Screening period 
that will occur within 28 days prior to the first dose of investigational medicinal product (IMP) 
for subjects in the Safety Lead-in phase and Expansion phase. Subjects will be enrolled based 
on local IDH1 mutation results. All subjects will have a radiographic evaluation (computed 
tomography [CT] or magnetic resonance imaging [MRI]) at Screening to confirm the presence 
of measurable disease (at least one measurable lesion, as defined by RECIST v1.1) according 
to the site radiologist/Investigator. Additional screening procedures for all subjects include 
medical, surgical, and medication history; complete physical examination, height, and weight; 
vital signs; Eastern Cooperative Oncology Group (ECOG) performance status; 12-lead ECG; 
evaluation of left ventricular ejection fraction (LVEF) (echocardiogram [ECHO], multiple 
gated acquisition [MUGA] scan, or by other method according to institutional practice); and 
clinical laboratory assessments (hematology, chemistry, thyroid function tests, coagulation, 
and pregnancy test). A buccal swab for germ-line mutation analysis will also be obtained at 
Screening.  
In case of non-inclusion of a subject, it is the Investigator’s responsibility to ensure, in 
accordance with the local standards of care and medical practices, that:  
­ The reason of non-inclusion is explained to the subject.  
­ Any event associated with any procedure/condition required by the study protocol (e.g., an 
event occurring following the discontinuation of a forbidden treatment) is collected.  
­ Adequate alternative medical care is proposed to the subject.  
A non-inclusion visit is not mandatorily carried out, provided these requirements are met and 
documented in the medical file of the subject. 
4.1.1.3. 
Treatment Period 
The study will include 2 separate phases, the Safety Lead-in phase and the Expansion phase. 
Eligible subjects can participate in one of the 2 phases only. Subjects enrolled in Safety Lead-
in phase will not participate in the Expansion phase. 
Safety Lead-In Phase 
Following the Screening period, the first 6 subjects enrolled will receive a dose of 500 mg QD 
of ivosidenib in combination with nivolumab  mg/kg and ipilimumab  mg/kg 
 
 followed by nivolumab 
 mg 
 (up to 24 total doses of nivolumab). 
Based on the DLT evaluation of 500 mg QD, an additional 6 subjects could be enrolled to test 
an alternative dose of 250 mg QD. DLTs will be evaluated through Cycle 2 (i.e., during the 
first 42 days, 21 days/cycle). Subjects may receive up to a maximum of 24 months of 
nivolumab. Subjects who are still deriving clinical benefit after 24 months may continue to 
receive ivosidenib monotherapy until disease progression, unacceptable toxicity, or other 
discontinuation criteria are met (see Section 4.3).  
Starting from Cycle 5, subjects in the Safety Lead-in phase who discontinue one IMP for a 
reason other than disease progression may continue to receive the other IMP with Sponsor 
CCI
CCI
CCI
CCI
CCI

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approval until disease progression or other discontinuation criteria (including the criterion of 
having received a maximum of 24 months of nivolumab) are met. 
Expansion Phase 
Following the Screening period, subjects enrolled into the Expansion phase will receive 
ivosidenib at the RCD as determined by the Safety Lead-in phase in combination with 
nivolumab  mg/kg and ipilimumab
 mg/kg 
 followed by 
nivolumab at 
 mg 
. Subjects may receive up to a maximum of 24 months of nivolumab. 
Subjects who are still deriving clinical benefit after 24 months may continue to receive 
ivosidenib monotherapy until disease progression, unacceptable toxicity, or other 
discontinuation criteria are met (see Section 4.3).  
Starting from Cycle 5, subjects in the Expansion phase who discontinue one IMP for a reason 
other than disease progression may continue to receive the other IMP with Sponsor approval 
until disease progression or other discontinuation criteria (including the criterion of having 
received up to a maximum of 24 months of nivolumab) are met. 
All subjects will undergo safety assessments throughout the Safety Lead-in and Expansion 
phase treatment periods, which will include limited physical examination, vital signs including 
weight, ECOG performance status, ECG, and clinical laboratory assessments (hematology, 
chemistry, thyroid function tests, coagulation, and pregnancy testing). Serial blood samples 
will be drawn at specified time points from all subjects receiving ivosidenib in combination 
with nivolumab and ipilimumab to determine ivosidenib plasma concentration–time profiles 
and PK parameters, PD, nivolumab and ipilimumab serum concentrations, and anti-drug 
antibody (ADA) parameters. Archival tumor (collected on Cycle 1 Day 1 [C1D1] only), and 
buccal swab samples (collected at Screening) and blood samples will be collected for 
exploratory biomarker analysis. All subjects will undergo radiographic evaluations (MRI or 
CT) to assess the extent of their disease at Screening and at regular intervals while on-treatment 
and/or at any time when progression of disease is suspected. 
4.1.1.4. 
End of Treatment/Withdrawal Visit 
All subjects will undergo an End of Treatment (EOT) assessment within 7 days after the last 
dose of IMP (for combination, this is to occur after all 3 IMPs have been discontinued). 
However, when this is not possible (e.g., dose delay more than 7 days), EOT assessment can 
be performed at the 30-day safety follow-up visit. Every effort must be made to perform 
protocol-specified evaluations unless consent to participate in the study is withdrawn. 
4.1.1.5. 
Post-Withdrawal Follow-up and End of Study 
Safety Follow-up: Following discontinuation of study treatment, a post-treatment Safety 
Follow-up visit is to occur 30 (+5) days after the last dose of ivosidenib and immunotherapy. 
Subjects will be followed for an additional 100 (+5) days after the last dose of immunotherapy, 
unless they have started another anti-cancer therapy, whichever occurs earlier. Every effort 
must be made to perform protocol-specified evaluations unless consent to participate in the 
study is withdrawn.  
CCI
CCI
CCI
CCI
CCI

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PFS and Overall Survival Follow-up: Subjects who discontinue study treatment for reasons 
other than disease progression or withdrawal of consent from treatment and are alive by EOT 
will enter PFS follow-up with the same schedule of assessments as before study treatment 
discontinuation, until documented disease progression, death, the start of subsequent anti-
cancer therapy, withdrawal of consent, or the end of study/study termination. Following 
discontinuation of study treatment, all subjects will be followed for survival. Subjects will be 
contacted every 12 weeks (± 2 weeks) after the subject experiences documented disease 
progression or begins subsequent anti-cancer therapy. This contact will continue for up to 2 
years after the last subject has been enrolled, or until end of study, withdrawn consent, or are 
lost to follow-up, or the Sponsor has terminated the study, whichever occurs first.  
Each subject will have an End of Study visit defined as the time at which the subject has 
permanently discontinued treatment and has completed the Safety Follow-up visit and survival 
follow-up period, or has died, been lost to follow-up, or withdrawn consent from the study or 
the Sponsor has terminated the study, whichever occurs first. 
4.1.1.6. 
End of Trial 
End of trial is defined as the date of the last visit/follow-up of the last subject (including visit 
or remote contact), or the date of the last contact attempt if the last subject is declared lost to 
follow-up. 
4.1.2. 
Investigation Schedule 
Assessments for subjects in the Safety Lead-in and Expansion phases are in Table (4.1.2) 1. 
PK and PD blood sampling are described in Table (4.1.2) 2 and Table (4.1.2) 3 for the Safety 
Lead-in phase and Expansion phase, respectively. 

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Table (4.1.2) 1 - Schedule of Assessments for Subjects in the Safety Lead-in Phase and Expansion Phase 
Visit/Cycle 
Screening1 
Cycle 1 (21 Days) 
Cycle 2 
(21 Days) 
Cycles 3 
and 4 
(21 Days) 
Cycle 5 and 
Beyond 
(28 Days 
Each Cycle) 
End of 
Treatment
2 
Safety Follow-up2 
PFS 
Follow
-up3 
Survival 
Follow-
up 
Study Day 
D-28 to  
D-1 
D1 
D8 
D15 
(± 2 
Days) 
D1 
(± 2 
Days) 
D15 
(± 2 
Days) 
D1 
(± 2 Days) 
D1 
(± 2 Days) 
Within 7 
Days After 
Last Dose 
30 (+5) 
Days 
After 
Last 
Dose 
100 (+5) 
Days After 
Last 
Nivolumab 
Dose 
 
Every 
12 
weeks 
(± 2 
weeks) 
Allocation to IMP4 
 
X 
 
 
X 
 
X 
X 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Exam  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Exam  
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Height and Weight5 
X 
X 
 
 
X 
 
X 
X 
 
 
 
 
 
ECOG Performance Status 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
 
Vital Signs6 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
12-lead ECG7,8 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
LVEF (ECHO, MUGA scan, or 
by other method according to 
institutional practice) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology9  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Serum Chemistry10 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Coagulation Studies11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test12 
X12 
X12 
 
 
X12 
 
X12 
X12 
X12 
 
 
 
 
Thyroid Function Tests13 
X 
X 
 
 
 
 
X (only at 
C3D1) 
X (every 
other cycle) 
X 
 
 
 
 
Radiographic Evaluation of 
Disease14 
X (D-21 to 
D-1)  
 
 
 
 
 
X (only 
C3D1)15 
X15 (every 
other cycle) 
X15,16 
 
 
X 
 
Ivosidenib Administration17 
 
 
X 
 
 
 
 
 

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Visit/Cycle 
Screening1 
Cycle 1 (21 Days) 
Cycle 2 
(21 Days) 
Cycles 3 
and 4 
(21 Days) 
Cycle 5 and 
Beyond 
(28 Days 
Each Cycle) 
End of 
Treatment
2 
Safety Follow-up2 
PFS 
Follow
-up3 
Survival 
Follow-
up 
Study Day 
D-28 to  
D-1 
D1 
D8 
D15 
(± 2 
Days) 
D1 
(± 2 
Days) 
D15 
(± 2 
Days) 
D1 
(± 2 Days) 
D1 
(± 2 Days) 
Within 7 
Days After 
Last Dose 
30 (+5) 
Days 
After 
Last 
Dose 
100 (+5) 
Days After 
Last 
Nivolumab 
Dose 
 
Every 
12 
weeks 
(± 2 
weeks) 
Nivolumab Administration18 
 
X 
 
 
X 
 
X 
X (every 
cycle) 
 
 
 
 
 
Ipilimumab Administration19 
 
X 
 
 
X 
 
X  
 
 
 
 
 
 
IMP Compliance20 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
Tumor Biopsy21 
X 
 
 
 
 
 
X (± 7 
days for 
biopsy 
collection) 
 
X 
 
 
 
 
Buccal Swab for Germ-line 
Mutation Analyses22 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sampling for 
Exploratory Biomarkers23 
X 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
Adverse Events24 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Prior and Concomitant 
Medications/Procedures25 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Subsequent Anti-cancer 
Therapy 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Survival Status26 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations  AE = adverse event; C = Cycle; CFR = Code of Federal Regulations; CT = computed tomography; D = Day; ECG = electrocardiogram; ECHO = echocardiography; ECOG = Eastern Cooperative 
Oncology Group; eCRF = electronic case report form; EOT = End of Treatment; FFPE = formalin-fixed paraffin-embedded; GDPR = General Data Protection Regulation; HIPAA = Health Insurance Portability and 
Accountability Act; ICF = informed consent form; IDH1 = Isocitrate dehydrogenase-1; IMP = investigational medicinal product; IV = intravenous; LVEF = left ventricular ejection fraction; MRI = magnetic resonance 
imaging; MUGA = multiple gated acquisition; PFS = progression-free survival; Q3W = once every 3 weeks; Q4W = once every 4 weeks; QTcF = heart rate-corrected QT interval by Fridericia’s method; RTSM = 
Randomisation and Trial Supply Management; SAE = serious adverse event. 
Note  One, or two if required by local regulation, original information and consent form(s) must be completed, dated, and signed personally by the participant and by the person responsible for collecting the informed 
consent. According to each study participant’s own preference, the ICF could be made available both printed on paper or/and electronically through a HIPAA, 21 CFR Part 11, and GDPR compliant web-based platform. 
Local regulations permitting, the electronic signature for the ICF could be made available to interested study participants. Interested study participants will be offered the possibility to replace certain in-person visits to 
the research site by televisits. This means that some study visits could be conducted using a HIPAA, 21 CFR Part 11, and GDPR compliant web-based platform, as per each study participant’s own preference. Follow-
up (for survival status until the end of the study) can be done remotely by using various telecommunication technologies including but not limited to phone, web-based remote video-calling, and shared electronic medical 
records. 

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1. 
Day -28 is relative to first dose of IMP. 
2. 
All subjects will undergo an EOT assessment within 7 days after the last dose of IMP (for combination, this is to occur after all 3 IMPs have been discontinued). However, when this is not possible (e.g., dose delay 
more than 7 days), EOT assessment can be performed at the 30-day safety follow-up visit. A second Safety Follow-up will occur 100 (+5) days after last nivolumab dose or ipilimumab if no other anti-cancer therapy 
is initiated.  
3. 
Subjects who discontinue study treatment for reasons other than disease progression or withdrawal of consent and are alive by EOT will enter PFS follow-up with the same schedule of assessments as before study 
treatment discontinuation, until documented disease progression, death, start of subsequent anti-cancer therapy, withdrawal of consent, or the end of study/study termination. 
4. 
Allocation of IMP will occur via RTSM. 
5. 
Height is to be obtained only at Screening assessment. 
6. 
Systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature. Assessments should be conducted while the subject is seated or supine. 
7. 
Subjects with a QTcF of ≥ 450 msec at baseline will not be allowed to enroll in the study. Up to three 12 lead ECG tests under stable condition can be performed at each visit during screening and throughout 
treatment and study follow-up.  
8. 
ECG can be performed at any time during the study visit (on-site or at local clinic); however, it is required once weekly for the first 3 weeks of treatment, and then once every cycle for the duration of therapy.  
9. 
Hematocrit, hemoglobin, red blood cell count, white blood cell count with differential, and platelet count. Hemoglobin criteria of ≥ 9.0 g/dL or ≥ 5.6 mmol/L at Screening must be met without packed red blood cell 
transfusion within the prior 2 weeks. Subjects can be on stable dose of erythropoietin (≥ approximately 3 months). On C1D1, assessments should be conducted prior to IMP administration. 
10. Sodium, potassium, chloride, calcium, magnesium, phosphorus, carbon dioxide, albumin, glucose, blood urea nitrogen (BUN)/UREA, creatinine, alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, gamma glutamyl transferase, total bilirubin, direct bilirubin, and indirect bilirubin. On C1D1, assessments should be conducted prior to IMP administration.  
11. Activated partial thromboplastin time and either prothrombin time or international normalized ratio. 
12. For women of childbearing potential, a serum pregnancy test will be performed at Screening, and a urine pregnancy test will be conducted on the day of IMP administration and is to be confirmed negative prior to 
dosing. If the urine pregnancy test is positive and cannot be confirmed negative, a serum pregnancy test must be performed and shown to be negative within 24 hours prior to the first day of IMP administration. An 
extension up to 72 hours prior to the start of study treatment is permissible in situations where the results cannot be obtained within the standard 24-hour window.  
13. Thyroid function test includes triiodothyronine (T3) or free T3, free thyroxine, and thyroid stimulating hormone. Thyroid function tests are to be performed every 6 weeks for the first 4 cycles and then every 8 weeks 
starting from Cycle 5 and to be performed at EOT. On C1D1, assessments should be conducted prior to IMP administration. Thyroid function test results obtained after the visit are acceptable so long as the value at 
screening was normal or considered not clinically significant per investigator assessment. 
14. Tumor assessments will include all known or suspected disease sites. CT imaging of the chest, abdomen, and pelvis (torso) with triphasic IV contrast should be performed at baseline and on study. For subjects with 
allergy to IV iodine contrast, CT chest without IV contrast and MRI abdomen with IV contrast should be performed at baseline and on study. Brain scans with CT or MRI should be performed at baseline in subjects 
with known treated brain metastases and on study at the same imaging time points as torso imaging. Additional anatomy should be imaged based on the signs and symptoms of individual subjects at baseline and 
follow-up. Radiographic assessment (CT or MRI or other imaging modalities as appropriate per RECIST v1 1 Appendix 4) for evaluation of disease response to be conducted at Screening (Day -21 to Day -1), every 
6 weeks (±7 days) for the first 2 assessments (i.e., through Week 12), and then every 8 weeks (± 7 days) thereafter independent of dose delays and/or dose interruptions, and/or at any time when progression of 
disease is suspected. Tumor assessment frequency can be reduced to every 12 weeks after 2 years of treatment initiation. 
15. Response to treatment is to be assessed at this visit if the subject discontinues treatment for reasons other than disease progression or start of another anticancer therapy.  
16. If a subject goes off treatment for reasons other than disease progression or withdrawal of consent from treatment, response assessments will be conducted at the EOT visit  
17. Ivosidenib is to be taken daily. Subjects should be instructed to take their daily dose at approximately the same time each day. Each daily dose should be taken with or without food. Subjects taking ivosidenib with 
food should be advised to avoid grapefruit or grapefruit products and avoid consuming a high-fat meal. If the subject forgets to take the daily dose, then they should take ivosidenib within 12 hours after the missed 
dose. If more than 12 hours have elapsed, then that dose should be omitted, and the subject should resume treatment with the next scheduled dose. The dose on C1D1, C1D15, and Day 1 of each cycle thereafter is 
to occur in-clinic to allow for pre-treatment assessments and to accommodate PK sampling. In subjects receiving the combination, on days when nivolumab and ipilimumab are administered, ivosidenib should be 
administered approximately 30 minutes before the start of the nivolumab infusion. 
18. Nivolumab is to be administered over an approximately 30-minute IV infusion. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of 
infusion pumps from site to site, a window between -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes (-5 minutes/+10 minutes). When study treatments nivolumab and ipilimumab are to be 
administered on the same day, nivolumab is to be administered first. Nivolumab infusion must be promptly followed by a flush of diluent to clear the line of nivolumab before starting the ipilimumab infusion. The 
second infusion will always be the ipilimumab study treatment and will start after the infusion line has been flushed, filters changed, and subject has been observed to ensure that no infusion reaction has occurred. 
19. Ipilimumab is to be administered over an approximately 30-minute IV infusion. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of 
infusion pumps from site to site, a window between -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes (-5 minutes/+10 minutes). When study treatments nivolumab and ipilimumab are to be 
administered on the same day, nivolumab is to be administered first. Nivolumab infusion must be promptly followed by a flush of diluent to clear the line of nivolumab before starting the ipilimumab infusion. The 
second infusion will always be the ipilimumab study treatment and will start after the infusion line has been flushed, filters changed, and subject has been observed to ensure that no infusion reaction has occurred. 
The time in between nivolumab and ipilimumab infusions is expected to be within approximately 30-minutes. 
20. Treatment compliance for ivosidenib is to be assessed based on the drug diary and/or return of unused drug. 
21. Tumor tissue for retrospective central laboratory confirmation of IDH1 gene mutation status and exploratory biomarker analysis at Screening is requested. Subjects will have locally documented presence of the 
IDH1 gene mutation for inclusion. If a subject cannot undergo a biopsy at Screening, collection of archival tumor tissue from the most recent biopsy/resection of at least 20 freshly cut, unstained FFPE slides (4-

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5 µm each) plus 1 H&E slide will be submitted at a later time together with the pathology report upon sponsor’s request. Tumor biopsies are to be collected at baseline, C3D1, and EOT from similar anatomical 
locations for exploratory biomarker analyses including PK/PD. In case of limited tissue amounts, biopsy samples will be formalin fixed and paraffin embedded. Please refer to the laboratory manual for priorities in 
tissue processing. If a required tumor biopsy (any time point) cannot be performed due to concerns around subject safety, a discussion with the Sponsor is required and biopsy can be omitted. Further details on 
screening and on-treatment biopsy collections are provided in the laboratory manual. Additional unscheduled tumor biopsy collected as standard of care, if any, will be used for the optional analysis of biomarkers 
(including genomic biomarkers). 
22. A buccal swab for germ-line mutation analysis will be obtained at Screening. 
23. Blood samples for exploratory biomarker assessments, including plasma circulating tumor DNA, will be collected at Screening and Day 1 of every cycle through Cycle 6, followed by every 6 months thereafter, and 
at EOT. 
24. From the time of informed consent signing through the first dose of IMP, SAEs resulting from a study-related procedure and assessed as related to that procedure, as well as all fatal AEs whether or not related to 
research procedures, must be recorded. All AEs will be recorded from all subjects from the date of first dose through 30 days following the last dose of ivosidenib and/or nivolumab or ipilimumab, whichever occurs 
later. Following the 30-day Safety Follow-up period, any SAEs that occur within 100 days after last dose of immunotherapy are to be reported, or until the subject initiates another anti-cancer therapy, whichever is 
earlier. Only SAEs that are considered as related to either IMP by the Investigator are to be reported after the respective Safety Follow-up periods. Fatal events, related or not to the research, occurring after ICF 
signature and before first IMP administration, must be reported on an AE form.  
25. All concomitant medications/procedures within 21 days of the first dose of IMP through 30 days (+ 5 days) after the last dose of ivosidenib and/or immunotherapy and through 100 days after the last dose of 
immunotherapy (whichever is later) are to be reported on the eCRF. 
26. Subjects will be contacted every 12 weeks (± 2 weeks) after the subject experiences documented disease progression or begins subsequent anti-cancer therapy for up to 2 years after the last subject has been enrolled, 
or until death, lost to follow-up, withdrawal of consent from overall study participation, or Sponsor ending study, whichever occurs first. 

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Table (4.1.2) 2 - Pharmacokinetic and Pharmacodynamic Sampling for Subjects in the Safety Lead-in Phase: Ivosidenib in Combination with Nivolumab 
and Ipilimumab 
Visit/Cycle: 
Screening 
Cycle 1  
(21 Days) 
Cycle 2  
(21 Days) 
Cycle 3  
(21 Days) 
Cycle 4  
(21 Days Each 
Cycle) 
Cycle 5 and Beyond  
(28 Days Each Cycle) 
Study Day: 
D-28 to D-1 
D1 
D15 (± 2 Days) D1 (± 2 Days) 
D1 (± 2 Days) 
D1 (± 2 Days) 
D1 (± 2 Days) 
Blood Sample for Ivosidenib PK Pre-dose1,2,3 
 
X 
X 
X 
X 
X 
X3 
Blood Sample for PD (2-HG) Pre-dose1,2,3 
 
X 
X 
X 
X 
X 
X3 
Blood Sample for Nivolumab PK and Nivolumab 
ADA Pre-dose1,2,4 
 
X 
 
X 
X 
X 
X4 
Blood Sample for Ipilimumab PK and Ipilimumab 
ADA Pre-dose1,2,5 
 
X 
 
X 
X 
X 
 
Tumor Biopsy for Ivosidenib PK Pre-dose6,7 
X 
 
 
 
 
 
 
Tumor Biopsy for Ivosidenib PK Post-dose6 
 
 
 
 
X (± 7 days for 
biopsy collection) 
 
 
Tumor Biopsy for PD (2-HG) Pre-dose6,7 
X 
 
 
 
 
 
 
Tumor Biopsy for PD (2-HG) Post-dose6 
 
 
 
 
X (± 7 days for 
biopsy collection) 
 
 
Blood Sample for Nivolumab and Ipilimumab PK 
Post-dose8 
 
X (EOI) 
 
 
 
 
 
Blood Sample for Ivosidenib PK Post-dose8 
 
 2 Hours post-dose 
 
 
 
X 
 
 
 
 3 Hours post-dose 
 
 
 
X 
 
 
 
 4 Hours post-dose 
 
 
 
X 
 
 
 
 6 Hours post-dose 
 
 
 
X 
 
 
 
Abbreviations: 2-HG = 2-hydroxyglutarate; ADA = anti-drug antibody; D = Day; EOI = End of Infusion; PD = pharmacodynamic; PK = pharmacokinetic.  
1. On the days when pre-dose samples are to be collected, subjects should be instructed to not take that day’s dose of ivosidenib, nivolumab or ipilimumab dose until PK/PD samples have been collected (ivosidenib 
dose is to be administered in the clinic).  
2. Pre-dose blood samples for ivosidenib, nivolumab, and ipilimumab PK, ADA, and 2-HG are to be collected from all subjects within 30 minutes before ivosidenib, nivolumab, and ipilimumab dosing. All pre-dose 
samples may be collected in one blood draw. 
3. Pre-dose blood samples for ivosidenib PK and 2-HG are to be collected on C1D1, C1D15, C2D1, C3D1, C4D1, C5D1, and Day 1 of every cycle through Cycle 13, and Day 1 of every other cycle thereafter (e.g., 
Cycles 15, 17, etc.). 
4. Pre-dose blood samples for nivolumab PK and nivolumab ADA are to be collected on C1D1, C2D1, C3D1, C4D1, and Day 1 of every 4 cycles up to 2 years (e.g., C8D1, C12D1, etc.)  
5. Pre-dose blood samples for ipilimumab PK and ipilimumab ADA are to be collected on C1D1, C2D1, C3D1, and C4D1. 
6. 
 Refer to the lab manual for details on tumor biopsy collection.  
7.  If a subject cannot undergo a biopsy at Screening, archived fresh-frozen tumor biopsy, if available, can be used for the measurement of baseline 2-HG.  
8. 
 Post-dose blood samples to be collected within ± 10 minutes of the specified time. 

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Table (4.1.2) 3 - Pharmacokinetic and Pharmacodynamic Sampling for Subjects in the Expansion Phase: Ivosidenib in Combination with Nivolumab 
and Ipilimumab 
Visit/Cycle: 
Screening 
Cycle 1 
(21 Days) 
Cycle 2 
(21 Days) 
Cycle 3 
(21 Days) 
Cycle 4 
(21 Days) 
Cycle 5 and 
beyond (28 Days 
Each Cycle) 
Study Day: 
D-28 to D-1 
D1 
D15 (± 2 Days) D1 (± 3 Days) 
D1 (± 2 Days) 
D1 (± 2 Days) 
D1 (± 2 Days) 
Blood Sample for Ivosidenib PK Pre-dose1,2,3 
 
X 
X 
X 
X 
X 
X3 
Blood Sample for PD (2-HG) Pre-dose1,2,3 
 
X 
X 
X 
X 
X 
X3 
Blood Sample for Nivolumab PK and Nivolumab 
ADA Pre-dose1,2,4 
 
X 
 
X 
X 
X 
X4 
Blood Sample for Ipilimumab PK and Ipilimumab 
ADA Pre-dose1,2,5 
 
X 
 
X 
X 
X 
 
Tissue Biopsy for Ivosidenib PK Pre-dose6,7 
X 
 
 
 
 
 
 
Tissue Biopsy for Ivosidenib PK Post-dose6 
 
 
 
 
X (± 7 days for 
tissue sample only) 
 
 
Tissue Biopsy for PD (2-HG) Pre-dose6,7 
X 
 
 
 
 
 
 
Tissue Biopsy for PD (2-HG) Post-dose6 
 
 
 
 
X (± 7 days for 
tissue sample only) 
 
 
Blood Sample for Nivolumab and Ipilimumab PK 
Post-dose8 
 
X (EOI) 
 
 
 
 
 
Blood Sample for Ivosidenib PK Post-dose8 
 
 
 
 
 
 
 
 2 hr post-dose 
 
 
 
 
 
X 
 
 3 hr post-dose 
 
 
 
 
 
X 
 
 4 hr post-dose 
 
 
 
 
 
X 
 
 6 hr post-dose 
 
 
 
 
 
X 
 
Abbreviations: 2-HG = 2-hydroxyglutarate; ADA = anti-drug antibody; D = Day; EOI = End of Infusion; PD = pharmacodynamic; PK = pharmacokinetic.  
1.  On the days when pre-dose samples are to be collected, subjects should be instructed to not take that day’s dose of ivosidenib, nivolumab or ipilimumab dose, until PK/PD samples have been collected (ivosidenib 
dose is to be administered in the clinic). If it is known that a dose is going to be delayed, then collect the pre-dose samples just prior to the delayed dose. However, if a pre-dose sample is collected, but the dose 
is subsequently delayed, do not collect an additional pre-dose sample. 
2. Pre-dose blood samples for ivosidenib, nivolumab, and ipilimumab PK, ADA, and 2-HG are to be collected from all subjects within 30 minutes before ivosidenib, nivolumab, and ipilimumab dose. All pre-dose 
samples may be collected in one blood draw. 
3. Pre-dose blood samples for ivosidenib PK and 2-HG are to be collected on C1D1, C1D15, C2D1, C3D1, C4D1, C5D1, and Day 1 of every cycle through Cycle 13, and Day 1 of every other cycle thereafter (e.g., 
Cycles 15, 17, etc.). 
4. Pre-dose blood samples for nivolumab PK and nivolumab ADA are to be collected on C1D1, C2D1, C3D1, C4D1, and Day 1 of every 4 cycles up to 2 years (e.g., C8D1, C12D1, etc.)  
5. Pre-dose blood samples for ipilimumab PK and ipilimumab ADA are to be collected on C1D1, C2D1, C3D1, and C4D1. 
6.  Refer to the lab manual for details on tumor biopsy collection. 
7.  If a subject cannot undergo a biopsy at Screening, archived fresh-frozen tumor biopsy, if available, can be used for the measurement of baseline 2-HG. 

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8.  Post-dose blood samples to be collected within ±10 minutes of the specified time. 
 

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A mean volume of blood collected for all type of analyses is shown in Table (4.1.2) 4. 
Table (4.1.2) 4 - Mean Blood Volume for CL1-95031-006 
Visit/Cycle 
Total volume/visit (mL) 
Total volume/cycle (mL) 
Screening 
39.7 
39.7 
C1D1 
53 
67 
C1D15 
14 
C2D1 
60 
79 
C2D15 
19 
Cycle 3  
48 
48 
Cycle 4  
48 
48 
Cycle 5  
41 
41 
Cycle 6  
30 
30 
ODD cycles (C7, C9, C1, etc.) 
9 
Even cycles (C8, C10, C12, etc.) 
from 3 to 27 mL depending on assessments, except for cycles 
Cycle 14 and Cycle 22 where no blood draws are planned 
EOT 
32 
32 
4.1.3. 
Dose Justification 
4.1.3.1. 
Dose Justification for Ivosidenib 
The selection of the 500 mg QD clinical dose of ivosidenib was based on PD (2-HG 
suppression), PK, safety, and efficacy data from the Phase 1 (AG120-C-002) and Phase 3 
(AG120-C-005) studies. The 500-mg dose level is also the approved dose for the US Marketing 
Authorization of ivosidenib for the CCA indication (TIBSOVO®, 2021). 
Plasma ivosidenib exposure increases in a less than dose-proportional manner from 200 mg to 
1,200 mg QD, with exposure plateauing at daily doses above 500 mg QD. Mean plasma 2-HG 
concentrations for subjects with CCA were elevated at baseline (ranging from 222 to 
5,220 ng/mL). After multiple doses of ivosidenib, plasma 2-HG levels were substantially 
reduced to concentrations similar to healthy subjects (
 ng/mL). No additional 2-HG 
suppression was observed at doses > 500 mg QD compared with 500 mg QD, while doses 
< 500 mg QD were associated with lower levels of suppression. In tumor biopsies of subjects 
with CCA, near maximal mean reduction in 2‑HG concentrations of 82.2% (coefficient of 
variation, 32.4%) was observed at the 500 mg QD dose. Analysis of the relationship between 
ivosidenib exposure and QT interval prolongation demonstrated that the risk of QT interval 
prolongation increases with increases in plasma Cmax and suggests that doses higher than 
500 mg QD may be associated with longer QT intervals.  
In Study AG120-C-002, there have been minimal dose interruptions, and no apparent dose 
relationship for any commonly reported TEAEs or Grade ≥ 3 TEAEs. No DLTs were reported 
in the study. The Phase 3 study, AG120-C-005, demonstrated that as a single agent in subjects 
with advanced CCA, ivosidenib was generally well tolerated with a manageable safety profile. 
The efficacy of ivosidenib at the recommended 500 mg QD dose was supported by the efficacy 
results from Study AG120-C-002. As of the 16 January 2019 cutoff date, the median OS was 
 at the 500 mg QD level.  
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The efficacy of ivosidenib at the recommended dose of 500 mg QD in subjects with CCA was 
established based upon the efficacy results of ivosidenib from Study AG120-C-005. 
Improvement in PFS by Independent Review Committee assessment was demonstrated for 
subjects randomized to treatment with ivosidenib compared with placebo (1-sided 
p-value < 0.0001; HR = 0.37; 95% CI: 0.25, 0.54). A benefit in OS was also observed in favor 
of ivosidenib.  
In summary, the PK and PD profiles along with the safety and efficacy results of ivosidenib in 
subjects with CCA support selection of the 500 mg QD dose.  
4.1.3.2. 
Dose Justification for Nivolumab and Ipilimumab Combination 
The nivolumab and ipilimumab combination is currently approved in the US and EU in multiple 
tumor types, including melanoma, NSCLC, RCC, and CRC using a regimen of either 
nivolumab  mg/kg and ipilimumab  mg/kg or nivolumab  mg/kg and ipilimumab  mg/kg. 
NIVO has a wide therapeutic index with no maximum tolerated dose identified at doses up to 
10 mg/kg Q2W. Nivolumab PK was assessed using a population PK approach for both single-
agent nivolumab and nivolumab with ipilimumab. When nivolumab  mg/kg was administered 
in combination with ipilimumab  mg/kg, the clearance (CL) of nivolumab was increased by 
29%, and the CL of ipilimumab was unchanged compared with nivolumab administered alone. 
When nivolumab  mg/kg was administered in combination with ipilimumab  mg/kg, the CL 
of nivolumab and ipilimumab were unchanged. Additionally, the presence of anti-nivolumab 
antibodies increased the CL of nivolumab. 
Subjects enrolled in this study will receive ivosidenib 500 mg QD in combination with 
nivolumab 
mg/kg and ipilimumab
 mg/kg concurrently 
. The dosing 
regimen for nivolumab 
 mg/kg and ipilimumab 
 mg/kg was selected based on the 
encouraging clinical activity observed in previously treated BTC (Klein et al, 2020) and the 
current approval for this dosing regimen in advanced RCC and metastatic CRC. Additionally, 
the lower dose of ipilimumab (  mg/kg) provides a more manageable safety profile for this 
subject population.  
4.1.3.3. 
Dose Justification for Nivolumab Flat Dose 
After initiation of treatment and completion of the first  doses of nivolumab and ipilimumab 
combination, subjects will receive a flat dose of nivolumab 
mg 
 for up to a maximum 
of 24 months. Relatively flat Exposure-Response (E–R) relationships were observed for safety 
across tumor types as monotherapy and in combination with ipilimumab which suggests that 
no additional washout is warranted before starting the NIVO 480 mg Q4W maintenance dose  
(Zhao et al, 2020).  
Nivolumab PK has been extensively studied in multiple tumor types, including melanoma, 
NSCLC, RCC, cHL, SCCHN, CRC, and urothelial carcinoma and has been safely administered 
at doses up to 10 mg/kg once every 2 weeks (Q2W). Nivolumab monotherapy was originally 
approved as a body-weight based dose of 3 mg/kg Q2W and was updated to 240 mg Q2W or 
480 mg Q4W in multiple indications (OPDIVO, 2020). The less frequent 480 mg Q4W dosing 
regimen can reduce the burden to subjects of frequent, lengthy intravenous (IV) treatments and 
allow combination of nivolumab with other agents using alternative dosing regimens. 
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CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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Any of the following will be considered as DLTs that may be applicable for immuno-oncology 
(IO) therapy and ivosidenib:  
­ Any Grade ≥ 4 irAE. 
­ Any Grade 3 irAE (excluding colitis, pneumonitis, or carditis) that does not improve 
to Grade 2 within 7 days after onset of the event despite optimal medical 
management including systemic corticosteroids or does not improve to Grade ≤ 1 or baseline 
within 14 days. 
­ Any Grade ≥ 3 colitis. 
­ Any Grade 3 non-infectious pneumonitis irrespective of duration. 
­ Any Grade ≥ 2 pneumonitis that does not resolve to Grade ≤ 1 within 7 days of the initiation 
of maximal supportive care. 
­ Any Grade ≥ 2 myocarditis. 
­ Any Grade ≥ 2 neurological toxicity including Guillain-Barre syndrome, myasthenia gravis, 
encephalitis, and myelitis. 
­ AST or ALT > 3 × the upper limit of normal (ULN) with concurrent increase in total bilirubin 
> 2 × ULN without evidence of cholestasis or alternative explanations, e.g., viral hepatitis, 
disease progression in the liver (Hy’s law). 
­ Any Grade ≥ 3 non-irAE, except for those listed below. 
­ Any death unless related to disease progression, intercurrent illness, concomitant 
medications, or extraneous causes. 
The DLT definition excludes the following conditions: 
­ Grade 3 QTc prolongation resolving to Grade 1 within 7 days. 
­ Grade 3 fatigue lasting ≤ 7 days. 
­ Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is managed 
with or without systemic corticosteroid therapy and/or hormone replacement therapy and the 
subject is asymptomatic. 
­ Grade 3 inflammatory reaction attributed to a local anti-tumor response (e.g., inflammatory 
reaction at sites of metastatic disease, lymph nodes). 
­ Concurrent vitiligo or alopecia of any CTCAE grade. 
­ Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that improves 
by at least 1 grade within 7 days. Grade 3 or Grade 4 febrile neutropenia will be a DLT 
regardless of duration or reversibility. 
­ Grade 3 or 4 lymphopenia. 
­ Isolated Grade 3 thrombocytopenia that is not associated with clinically significant bleeding 
and does not require medical intervention. 
­ Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 days. 
­ Isolated Grade 3 amylase or lipase abnormalities that are not associated with clinical 
signs/symptoms or findings on imaging consistent with pancreatitis. 
4.1.4.3. 
DLT Management 
Ivosidenib, nivolumab, and ipilimumab must be immediately interrupted for any subject who 
experiences a DLT. If a DLT occurs, the subject should be withdrawn from all 3 drugs unless 
in the opinions of the Investigator, the subject is deriving clinical benefit and the AE can be 
managed without recurrence, and with Sponsor approval. If ivosidenib is resumed following a 
DLT, it should be resumed at a reduced dose (250 mg) after the AE has resolved to Grade 1 or 

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4.2.1. 
IMP Management 
For further details regarding IMP temperature management, returns, destructions, complaints, 
and handling, please refer to the pharmacy manual. IMP receipt, dispensing according to the 
experimental design of the study (for the description of dispensing methods, refer to 
Section 6.2), accountability, and collection are the responsibility of the Investigator and/or 
pharmacist of the medical institution. All of these actions have to be done in the Randomization 
and Trial Supply Management (RTSM) system as explained in the training video embedded in 
RSTM, the user manual, and the pharmacy manual.  
The IMP should be stored in a secure area with restricted access. Specific storage conditions 
are mentioned on IMP labeling. IMP management will be verified on a regular basis by the 
study monitor. 
In case of temperature deviation, the Investigator/pharmacist should immediately: 
­ Block in RTSM the concerned boxes and place them in quarantine. 
­ Alert the monitor and forward all needed information and implement the instructions 
received. 
Furthermore, the Investigator/pharmacist must put in place an adequate corrective/preventive 
action once the first temperature deviation occurs in order to avoid recurrence. 
The Investigator and/or the pharmacist of the medical institution should only use the IMP 
provided for the participants involved in the study. 
The Investigator and/or the pharmacist of the medical institution and/or a designated person 
from their study team must enter and complete in real time the RTSM and all the documents 
provided by the Sponsor concerning IMP management (refer to the pharmacy manual). 
Destruction of the IMP is the responsibility of the Sponsor and/or the Investigator and/or the 
pharmacist of the medical institution.  
Remaining treatments (used and unused IMPs) will subsequently be collected and stored 
according to the local procedures and requirements, by the person responsible for the IMP 
management. 
Used 
IMPs 
will 
be 
collected 
by 
the 
center 
at 
the 
time 
of 
preparation/administration along with the other wastes to be destroyed according to local 
routines.  
A certificated destruction or equivalent will be performed according to standard modalities for 
that class of product and the attestation must be sent to the Sponsor. The practical procedures 
for destruction of unused IMP will be defined by the Sponsor and adapted to the center.  
Recovery and destruction will be tracked in RTSM before the shipment of IMP to destruction. 
Destruction of IMP may be possible (after drug accountability and Sponsor authorization) when 
the product has been used, has expired or after at least the last visit of the last treated subject.  
All defects or deterioration of IMPs or their packaging are to be reported to the study monitor. 
The Investigator will notify the monitor of all complaints set out by a subject/pharmacist 
(change of appearance, etc.). 

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In the event of anticipated return of IMPs to the Sponsor (batch recall), the Sponsor will prepare 
an information letter intended for the Investigator and/or pharmacist of the medical institution. 
This letter will be sent by the person locally responsible for the study to each study center. On 
receipt of the letter, the Investigator and/or the pharmacist will identify the participants in 
possession of the IMP at the moment the incident becomes known, by using RTMS or an 
equivalent document and will contact them immediately. 
4.2.2. 
Management of Blinding Systems 
Not applicable. 
4.3. Discontinuation of the Study or Temporary Halt 
4.3.1. 
Premature Discontinuation of the Study or Temporary Halt 
After having informed the Investigator(s), this study may be temporarily halted or prematurely 
discontinued at any time for any sufficient reasonable cause by the Sponsor (or by the Sponsor 
further a request from a DRT or by the Institutional Review Board [IRB])/Independent Ethics 
Committee [IEC] or by the Competent Authorities).  
Two copies of the written confirmation will be dated and signed by the Investigator(s). The 
IRB/IECs and Competent Authorities will be informed according to local regulations. If the 
study is prematurely discontinued due to safety concerns, subjects on treatment should be 
discontinued from treatment and seen as soon as possible and the same assessments as described 
in Section 4.1.1.3 should be performed.  
If the study is prematurely discontinued for reasons other than safety, subjects who are receiving 
treatment at the time the study is discontinued may remain on IMP if they are clinically 
benefiting. Subjects may receive nivolumab up to a maximum of 24 months. Ivosidenib may 
be continued for as long as the subject is receiving clinical benefit. Under some circumstances, 
the Investigator may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the subject’s interests.  
In case of study temporary halt, the study may resume after concerns about safety, protocol 
compliance, and data quality are addressed and satisfy the Sponsor, following approval from 
the IRB/IEC and/or Competent Authorities, according to local regulations. 
4.3.2. 
Premature Discontinuation of the Study in an Investigator Site (Early Site 
Closure) 
The Sponsor reserves the right to close a study site at any time for any sufficient reasonable 
cause at the sole discretion of the Sponsor.  
The Investigator may also initiate study site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 

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Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
­ Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Competent Authorities, the Sponsor’s procedures, or GCP guidelines 
­ Inadequate recruitment of participants by the Investigator 
­ Discontinuation of further study intervention development 
The IRB/IEC(s) and Competent Authorities will be informed according to local regulations. 
4.3.3. 
Discontinuation of the Study in the Event of Objective Reached 
Not applicable. 
4.4. Source Data 
Source data and source documents of the center should be clearly identified in a specific, 
detailed, and signed document before the beginning of the study. Subject’s medical file (e.g., 
information regarding the subject’s medical history, ECG reports, clinical laboratory 
examination reports, imaging reports and all other subjects’ examination results, requisition 
forms and registration forms) and drug diary will be considered as source documents. 
5. STUDY POPULATION AND WITHDRAWAL OF PARTICIPANTS 
5.1. Inclusion Criteria 
Participants are eligible to be enrolled in the study only if all the all the following criteria apply: 
Demographic Characteristics 
1. Male or female participant age ≥ 18 years old. 
General Criteria  
2. Estimated life expectancy ≥ 12 weeks. 
3. ECOG performance status ≤ 1. 
Sex and Contraceptive/Barrier Requirements  
4. Women of childbearing potential (WOCBP) must agree to abstain from sexual 
intercourse or to use 2 highly effective (Appendix 7) forms of contraception, at least 
one of which must be a barrier method, from the time of giving informed consent 
throughout the study, and for 5 months after the last dose of study treatment. Ivosidenib, 
nivolumab, and ipilimumab may have adverse effects on a fetus in utero. Furthermore, 
it is not known if nivolumab and ipilimumab have transient adverse effects on the 
composition of sperm. Subjects should be informed that taking the study medication 
may involve unknown risks to the fetus (unborn baby) if pregnancy were to occur during 
the study. Egg donation (ova, oocytes), for the purpose of reproduction, will not be 
allowed during the study and for 5 months after the last dose of study treatment.  
• Male subjects with WOCBP partners must use a condom during the study and until at 
least 3 months after the last dose of study treatment. In addition, contraception should be 
considered for their female partners. Contraceptive measures do not apply if the subject 
is sterile, vasectomized, or sexually abstinent. Sperm donation from male subjects will 
not be allowed during the study and for 3 months after the last dose of study treatment. 
Note: Please refer to Appendix 7 for further contraception considerations. 

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Informed Consent 
5. Obtained prior to any study-specific procedure as described in Section 13.3 of the 
protocol. 
Medical and Therapeutic Criteria  
6. Have a histopathological diagnosis consistent with nonresectable or metastatic 
cholangiocarcinoma and are not eligible for curative resection, transplantation or 
ablative therapies.  
7. Have documented IDH1 gene-mutated disease based on local testing procedure 
(R132C/L/G/H/S mutations variants tested). Preferably using a tumor biopsy sample 
collected within the last 3 years.  
8a  Have disease progression or treatment intolerance following at least 1 and no more than 
2 prior systemic regimens for advanced disease (nonresectable or metastatic) including 
the following: 
i. 
For Cohort 1: subjects who have not received any prior immune checkpoint 
inhibitor therapy but received at least 1 gemcitabine- or 5-FU-containg regimen 
for advanced cholangiocarcinoma.  
ii. 
For Cohort 2: subjects must have received at least two doses of anti-PD1/L1 
therapy in first or second line, which may include combination with 
chemotherapy which should include at least 1 gemcitabine- or 5-FU-containg 
regimen for advanced cholangiocarcinoma. Combination therapy with other 
checkpoint inhibitors or investigational agents must be excluded. 
iii. 
Safety Lead-in phase: subjects eligible for either Cohort 1 or Cohort 2. 
 
Prior capecitabine or gemcitabine containing adjuvant chemotherapy will be 
considered a line of treatment if there is documented disease progression during or 
within 12 months of completing the therapy. 
9. Participants must have at least one measurable lesion, as defined by RECIST v1.1. 
Subjects who have received prior local therapy (including but not limited to 
embolization, chemoembolization, radiofrequency ablation, or radiation therapy) are 
eligible provided measurable disease falls outside of the treatment field or if within the 
field but has shown ≥ 20% growth in size post-treatment assessment. 
10. Adequate hematological function, defined as: 
i. WBC ≥ 2 x 109/L. 
ii. Absolute neutrophil count ≥ 1.5 x 109/L. 
iii. Hemoglobin ≥ 9 g/dL. In case of blood transfusion, the hemoglobin assessment must 
be performed 2 weeks or more after the transfusion. 
iv. Platelet count ≥ 100 x 109/L. 
11. Adequate coagulation function as defined by International Normalization Ratio (INR), 
or Prothrombin Time (PT) or Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 
ULN; Any subject receiving anticoagulant therapy should have coagulation factors 
monitored closely throughout the study. Subjects receiving a factor Xa inhibitor who 
have abnormal PT/ partial thromboplastin time (PTT) may be eligible after discussion 
with the Sponsor. 
12. Adequate renal function defined as: calculated creatinine clearance ≥ 50 mL/min using 
the Cockcroft-Gault formula: 
1. (140 − Age) × (weight in kg) × (0.85 if female)/72 × serum creatinine. 
13. Adequate hepatic function, defined as: 
i. 
Total serum bilirubin and direct bilirubin ≤ 1.5 x ULN (total serum bilirubin ≤ 3.0 
x ULN for confirmed Gilbert disease). 

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ii(a) Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN, exception to 
this range will need to be discussed and approved by the study medical monitor. 
iii. 
Serum albumin ≥ 2.8 g/dL. 
5.2. Exclusion Criteria 
Subjects meeting any of the following criteria may not be enrolled in the study: 
General Criteria 
14. Inability to swallow oral medication.  
15. Pregnant and lactating women. 
16. WOCBP who tested positive in a serum pregnancy test within 24 hours prior to the first 
day of IMP administration. An extension up to 72 hours prior to the start of study 
treatment is permissible in situations where the results cannot be obtained within the 
standard 24-hour window. 
17. Unlikely to cooperate in the study. 
18. Participation in another interventional study at the same time or within 2 weeks prior to 
the first IMP administration. Participation in non-interventional registries or 
epidemiological studies is allowed. In addition, the first dose of ivosidenib should not 
occur before a period greater than or equal to 5 half-lives or 28 days, whichever is 
shorter, of the last dose of the investigational molecule. 
Medical and Therapeutic Criteria 
19. Subjects who received prior treatment with an IDH inhibitor or prior treatment with an 
immune checkpoint inhibitor other than anti-PD1/L1. 
20. Have a history of another primary cancer, with the exception of: a) curatively resected 
nonmelanoma skin cancer; b) curatively treated cervical carcinoma in situ; or c) other 
primary solid or liquid tumor within 2 years prior (i.e., participants with a history of 
prior malignancy are eligible if treatment was completed at least 2 years before and the 
subject has no evidence of disease), with no known active disease present that, in the 
opinion of the Investigator, will not affect subject outcome in the setting of current 
cholangiocarcinoma diagnosis.   
21. Subjects with prior Grade ≥ 3 immune-related AE (irAE) resulting from ICI therapy or 
have history of life-threatening toxicity related to prior immune therapy (ICI or any 
other antibody or drug specifically targeting T-cell co-stimulation or immune 
checkpoint pathways) except those that are unlikely to re-occur with standard 
countermeasures (e.g., hypothyroidism).  
22. Subjects with active autoimmune disease or any condition requiring systemic treatment 
with either corticosteroids (> 10 mg daily of prednisone equivalents) or other immune-
suppressive medications within 14 days of study treatment. Inhaled or topical steroids 
and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in 
the absence of active autoimmune disease. 
23. Known prior severe hypersensitivity to investigational products or any component in 
their formulations. 
24. Participants who have not recovered from toxicity of previous anti-cancer therapy, 
including Grade ≥ 1 non-hematologic toxicity, according to the NCI CTCAE v5.0, prior 
to the first IMP administration. Residual Grade ≤ 2 toxicity from chemotherapy (e.g., 
alopecia, neuropathy) may be allowed. 
25. Major surgery within 4 weeks prior to the first IMP administration or participants who 
have not recovered from side effects of the surgery. 

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26. Have LVEF (ECHO, MUGA scan, or by other method according to institutional 
practice) < 40% by ECHO scan (or by other methods according to institutional practice) 
obtained within 28 days prior to the start of study treatment. 
27. Subjects who have heart rate-corrected QT interval using Fridericia’s formula (QTcF) 
of ≥ 450 msec or with other factors that increase the risk of QT prolongation or 
arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval 
syndrome). Subjects with bundle branch block and prolonged QTcF should be reviewed 
by the Sponsor for potential inclusion. 
28. History of motor neuropathy considered to be of autoimmune origin (e.g., Guillain-
Barre syndrome, myasthenia gravis). 
29. Known immunodeficiency or HIV, hepatitis B, or hepatitis C infection. Antibody to 
hepatitis B or C without evidence of active infection may be allowed. Subjects with 
chronic hepatitis B virus that is adequately controlled per institutional guideline will be 
permitted. 
30. Severe or uncontrolled active acute or chronic infection. 
31. Have known symptomatic brain metastases requiring steroids. Subjects 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 4 weeks, and 
have radiographically stable disease for at least 3 months prior to study entry. Note: Up 
to 10 mg per day of prednisone equivalent will be allowed. 
32. Subjects who have received systemic anti-cancer treatment or palliative radiotherapy to 
bone metastases or other non-liver lesions less than 2 weeks before the first dose of 
ivosidenib. Arterial therapies and radiation to liver lesions less than 4 weeks before the 
first dose of ivosidenib. 
33. Treatment with a live/attenuated vaccine withing 30 days of first study treatment. 
34. History of non-infectious pneumonitis that required steroids, current pneumonitis, or 
history of interstitial lung disease. 
35. Subjects who discontinued prior treatment with ICIs for toxicity, irrespective of the 
Grade of the event that triggered discontinuation. 
36. Any clinically significant medical condition (e.g., organ dysfunction) or laboratory 
abnormality likely to jeopardize the participant’s safety or to interfere with the conduct 
of the study, in the Investigator’s opinion. 
37. Any contraindication to the use of nivolumab or ipilimumab as per standard labelling 
and local guidance. 
38. Are taking known strong cytochrome P450 (CYP) 3A4 inducers or sensitive CYP3A4 
substrate medications with a narrow therapeutic window, unless they can be transferred 
to other medications within ≥ 5 half-lives prior to dosing. 
Note: Please refer to Appendix 10, Table 2 and Table 5, for further drug-drug interaction 
considerations.  
Prior/Concomitant Therapy  
For prior and forbidden concomitant medication, refer to Section 6.3. 
5.3. Retest Management During Screening Period 
A participant who has (a) laboratory result(s) that does not satisfy the entrance criteria may 
have the test(s) repeated providing that the Investigator judges it relevant according to the 
participant previous results, or medical history and if s/he considers laboratory abnormalities 
are likely to be transient. Results of the test(s) repeated should be obtained within the allowed 

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screening period. In this case the participant will not be required to sign another informed 
consent, and the original participant ID number assigned by the Investigator will be used. 
For ECGs, up to three 12 lead ECG tests under stable condition can be performed at each visit 
during screening and throughout treatment and study follow-up.  
In any case, the last result available for each parameter must be considered for the participant 
inclusion. 
5.4. Participant Withdrawal 
5.4.1. 
Withdrawal Criteria 
Premature discontinuation of IMP does not mean that the subject prematurely stops the 
participation in the study.  
Subjects discontinuing study treatment for reasons other than withdrawal of consent from 
overall study participation will be expected to continue in the study including Safety Follow-
up visits and be contacted for survival follow-up. Information to be collected during the last 
visit for these subjects is given in Section 5.4.3. 
The reasons for premature discontinuation of IMP are: 
­ AEs, according to the judgment of the Investigator, including no recovery in safety 
parameters. 
­ Disease progression as assessed by the Investigator/site radiologist according to RECIST 
v1.1 (Appendix 12). Clinically stable subjects may continue beyond confirmed disease 
progression if benefits are expected to outweigh risks in the opinion of the Investigator and 
in consultation with the Sponsor. 
­ Clinical disease progression manifested by symptomatic deterioration. 
­ Completion of a maximum of 24 months of nivolumab (note that subjects receiving 
combination may continue to receive ivosidenib monotherapy).  
­ Pregnancy (for reporting, see Section 8.10.2.3).  
­ Major protocol deviation if it interferes with the study evaluations and/or if it jeopardizes 
subject’s safety, e.g., any medical event requiring administration of an unauthorized 
concomitant treatment (see Section 6.3). 
­ Withdrawal of consent (only for IMP discontinuation): Subjects will be asked if they are 
willing to continue the safety and disease/survival follow-up. 
­ Physician decision (for reasons that cannot be included in any of the criteria listed above, for 
example, availability of a better therapeutic alternative for the subject). 
­ Study terminated by Sponsor. 
5.4.2. 
Criteria for Premature Study Discontinuation 
­ Withdrawal of consent: Subjects may leave the study at any time for any reason if they wish 
to do so, without consequence. If a subject withdraws consent from overall study 
participation (and not just study treatment), no further evaluations should be performed, and 
no attempts should be made to collect additional data.  
­ Death.  
­ Lost to follow-up.  

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­ Study terminated by Sponsor.  
5.4.3. 
Procedure 
Upon discontinuation of study treatment, the Investigator must: 
­ Notify the Sponsor immediately. 
­ Record this information in the eCRF, specifying the reason for the subject’s withdrawal. If 
there are several reasons, the Investigator must indicate the main reason. The Investigator 
should document the discontinuation in the corresponding medical file. 
An EOT visit should always be suggested to the subject and should take place within 7 days 
after the last IMP administration or at the 30-day safety follow-up visit if this is not possible, 
and prior to the start of a new anti-cancer therapy. 
In the case of premature study treatment discontinuation due to an AE, the Investigator must 
make every effort to collect the information relating to the outcome of the event. If necessary, 
the information will be collected afterward. This information is recorded in that part of the 
eCRF that concerns AEs. If the Investigator cannot collect the information from a visit, the 
Investigator must collect it from the doctor ensuring the follow-up of the participant. 
The dispositions to be taken after the IMP discontinuation are described in Section 6.5. 
5.4.4. 
Lost to Follow-up 
When the Investigator has no news of the participant, the Investigator must make every effort 
to contact the participant or a person around the participant (phone calls, letters including 
registered ones, etc.) to establish the reason for the discontinuation of IMP and to suggest that 
the participant attends a withdrawal visit. If after the Investigator has completed all due 
diligence and all attempts to contact the participant fail, the Investigator can then declare the 
participant “lost to follow-up”. The Investigator should document all contact attempts in the 
corresponding medical file. 
6. TREATMENT OF PARTICIPANTS 
IMP treatment of study subjects is outlined in the sections below. Complete details are provided 
in the pharmacy manual. 
6.1. IMPs Administered 
Product Description 
and Dosage Form 
Concentration 
Primary Packaging 
Secondary Packaging 
Ivosidenib / tablet 
Tablets of 250 mg 
One pillbox = 60 tablets of 
250 mg 
One box containing one 
pillbox of 60 tablets 
Nivolumab / solution 
for injection 
 mg/mL  
One vial = 
 mL 
 mg/mL  
One box containing one 
vial 
Ipilimumab / solution 
for injection 
mg/mL 
One vial = 
 mL vial at 
 mg/mL 
One box containing one 
vial 
It is recommended that each dose should be taken with or without food. Subjects taking 
ivosidenib with food should be advised to avoid grapefruit or grapefruit products and avoid 
CCI
CCI
CCI
CC
CCI
CCI

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consuming a high-fat meal (Please refer to examples of low-fat and high-fat meals in 
Appendix 12).  
For treatment dose modifications due to toxicities, please refer to Section 8.12. All the IMP 
tracking is managed in RTSM in real time. The procedures to be followed by the Investigator 
or authorized person are detailed in the training video embedded in RSTM or user manual. 
6.2. IMP Dispensing 
After completion of IRT, IMPs will be allocated, dispensed, and tracked via RTSM by the 
pharmacist/responsible individual of the healthcare establishment upon prescription of the 
Investigator only. The Investigator may only use the IMPs provided for the subjects involved 
in the study and treated under the Investigator’s responsibility. All dosages of nivolumab and 
ipilimumab are prescribed to the subject and all dose changes during the study must be done 
via RTSM and recorded in the eCRF. For doses of ivosidenib, should a subject be unable to 
receive or return to the site for dose administration, delivery of the dose to the subject’s home 
is permitted.  
One drug kit of ivosidenib will be dispensed to the subject at Day 1 of each cycle. Nivolumab 
will be infused to the subject at Day 1 of each cycle. The number of vials of nivolumab allocated 
and the volume to infuse will be calculated in RTSM based on subject weight (from Cycle 1 to 
Cycle 4) and will be the same (48 mL) beginning at Cycle 5. At Day 1 of the first 4 cycles 
(Cycle 1 to Cycle 4), ipilimumab will be infused to the subject. The number of vials of 
ipilimumab allocated and the volume to infuse will be calculated based on subject weight. 
The pharmacist/responsible individual of the healthcare establishment prepares the treatment in 
accordance with the Pharmacy Manual and documents it in the drug kit tracking file or 
equivalent validated tracking system. The individual then either sticks the drug kit label to the 
paper label collection form or assigns a drug kit number in the validated electronic tool based 
on site procedures, or scans the QR code in the validated electronic tool at the site level to log 
the dispensation. 
The drug kit will be identified by a 6-digit number for identification, tracking, and stock 
management purposes.  
6.3. Previous and Concomitant Treatments 
6.3.1. 
Prior Medications and Procedures 
All medications administered and procedures conducted within 4 weeks (28 days) prior to the 
first day of study drug administration (C1D1) are to be recorded in the eCRF.  
As available, transfusion history, including red blood cell and platelet transfusion, for 56 days 
prior to C1D1 should be recorded at the Screening visit. This documentation should include 
dates of each transfusion and units administered. 
6.3.2. 
Concomitant Medications and Procedures 
All medications (other than IMPs) and significant non-drug therapies (including physical 
therapy, IV medications and fluids, herbal/natural medications, over-the-counter medications, 
and blood transfusions) administered during the study must be listed in the eCRF. If changes 

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occur during the study period, documentation of drug dosage, frequency, route, and date should 
also be included on the eCRF. The Investigator should instruct the subject not to take any 
additional medications (including over-the-counter products) during the study without prior 
consultation with the Investigator. In general, the use of any concomitant medication deemed 
necessary for the care of the subject is permitted in this study, except as specifically prohibited 
in Section 6.3.2.1. Information on prior anti-neoplastic treatment received for the primary 
diagnosis including prior radiation therapy will be collected.  
A list of prohibited and unauthorized treatments by drug class can be consulted in the eCRF. 
6.3.2.1. 
Prohibited Concomitant Therapies 
The following concomitant therapies are prohibited for participants receiving treatment with 
ivosidenib in combination with nivolumab and ipilimumab. 
­ Strong inducers of CYP3A4 (Table 2, Appendix 10): Ivosidenib is mainly metabolized by 
CYP3A4; therefore, subjects should not use strong CYP3A4 inducers during treatment with 
ivosidenib. 
­ Sensitive CYP3A4 substrates with a narrow therapeutic window: Ivosidenib is an inducer of 
human CYP3A4/5; therefore, medications of sensitive CYP3A4 substrates with a narrow 
therapeutic window (Table 2, Appendix 10) should be avoided unless the subject can be 
transferred to other medications prior to enrolling. 
­ Immunosuppressive agents. 
­ Immunosuppressive doses of systemic corticosteroids. Participants are permitted the use of 
topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal 
systemic absorption). Adrenal replacement steroid doses > 10 mg daily prednisone are 
permitted. A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g., contrast 
dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type 
hypersensitivity reaction caused by a contact allergen) is permitted. 
­ Any live/attenuated vaccine (e.g., varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella) during treatment and until 100 days post last dose. 
­ Any COVID-19 vaccine that cannot be rescheduled within 14 days prior to first dose of 
study drug or cannot be rescheduled during the DLT period. 
­ Any complementary medications (e.g., herbal supplements or traditional Chinese medicines) 
intended to treat the disease under study. Such medications are permitted if they are used as 
supportive care. 
­ Any concurrent systemic anti-neoplastic therapy (i.e., chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents for treatment of CCA). If alternative 
therapy is required for treatment of the subject’s disease, the subject should be discontinued 
from the study treatment. 
­ Any non-palliative radiation therapy. Localize radiation therapy administered with palliative 
intent is permitted for subjects who continue to receive ivosidenib following documented 
disease progression and must be documented on the CRF. 
6.3.2.2. 
Concomitant Therapies Requiring Careful Monitoring (Use with Caution) 
Based on the results of in vitro and in vivo studies, the following therapies should be avoided 
and replaced with alternative treatments. If this is not possible, participants receiving these 
drugs should be carefully monitored. 
­ Concomitant use of drugs with a potential for QT prolongation should be avoided and 
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should be adequately monitored by ECG controls, drug concentration (where applicable), 
and serum electrolytes (i.e., potassium and magnesium).  
These medications include but are not limited to: 
 Fluoroquinolones such as, ciprofloxacin and moxifloxacin. 
 Azole antifungals such as fluconazole and posaconazole. 
 Serotonin (5-HT3) antagonists such as granisetron and ondansetron. See Appendix 10, 
Table 4 for a complete list of medications known to prolong the QT interval. 
­ Moderate or strong inhibitors of CYP3A4: Ivosidenib clinical trials and physiologically 
based pharmacokinetic simulations have shown that ivosidenib plasma concentrations 
increase with co-administration of a strong or moderate CYP3A4 inhibitor, and increased 
ivosidenib plasma concentrations may increase the risk of QTc prolongation. Therefore, 
alternative therapies that are not moderate or strong CYP3A4 inhibitors should be considered 
during treatment with ivosidenib. If concomitant use of moderate CYP3A4 inhibitors is 
unavoidable, subjects should be monitored for increased risk of QTc prolongation. If a strong 
CYP3A4 inhibitor must be co-administered, reduce the ivosidenib dose to 250 mg QD. If 
the strong inhibitor is discontinued, increase the ivosidenib dose (after at least 5 half-lives 
of the strong CYP3A4 inhibitor) to the recommended dose of 500 mg QD (see Table 5 in 
Appendix 10). 
­ Sensitive substrates of CYP2C9: Ivosidenib may also induce CYP2B6, CYP2C8, and 
CYP2C9. Consider alternative therapies that are not sensitive substrates of CYP2C9 (e.g., 
phenytoin, warfarin). Monitor INR levels more frequently in subjects receiving warfarin (a 
CYP2C9 substrate) during initiation or discontinuation of ivosidenib. 
­ Coadministration of ivosidenib may decrease the concentrations of hormonal contraceptives. 
Consider alternative methods of contraception in subjects receiving ivosidenib as described 
Appendix 7. 
6.4. IMP Compliance 
For ivosidenib, subjects will be dispensed the appropriate number of Sponsor-packaged and 
labeled bottles to allow for 21 ± 2 days of dosing for the first 4 cycles then for 28 ± 2 days of 
dosing from the Cycle 5. Alternatively, they may be dispensed appropriate bottle(s) until the 
next scheduled visit. The number of pill bottles dispensed and the number of tablets returned 
by the subject are to be counted by the Investigator or delegate and recorded. For the infusion 
therapies, the number of vials dispensed will be counted by the Investigator or designee and 
recorded in the eCRF and RTSM or an equivalent document. 
Subjects will receive instructions for home administration of IMP along with a diary to record 
the date and time of each dose, as well as the number and strength (mg) of tablets taken.  
Treatment compliance will be assessed using the drug diary and/or return of unused drug. 
Accountability for the IMP at the study site is the responsibility of the Investigator. The 
Investigator will ensure that the IMP 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 subject, and return to Sponsor or its designee (or disposal of the drug, if approved 
by Sponsor). These records will adequately document that the subjects were provided the doses 
as specified in the protocol and should reconcile all IMP received from Sponsor.  

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Accountability records will include dates, quantities, batch/serial numbers, expiration dates, 
and subject numbers. The Sponsor or designee will review drug accountability at the site on an 
ongoing basis during monitoring visits. IMP must not be used for any purpose other than the 
present study. IMP that has been dispensed to a subject and returned unused must not be 
redispensed to a different subject. All unused and used IMP should be retained at the site until 
inventoried by the study monitor. All used, unused, or expired IMP, disposed of at the study 
site per the site’s standard operating procedures and documented via a destruction certificate, 
or drug kits can be recovered from the site and, after Sponsor approval, sent to a destruction 
body who will destroy and provide a destruction certificate for documentation. 
6.5. Discontinuation of the IMP 
After the discontinuation of the IMP, the participant’s treatment is left to the physician’s 
discretion. 
7. ASSESSMENT OF EFFICACY 
7.1. Efficacy Measurements 
Efficacy measurements performed during the study are indicated in Table (4.1.2) 1. 
Standard response criteria will be applied for disease assessments and response evaluations 
(RECIST v1.1 [Table (4.1.2) 1]). Assessments should be performed at the intervals specified in 
the investigation schedules and in the event of suspected disease progression. 
The same method(s) of disease evaluation and the same techniques should be used throughout 
the study as the baseline.  
7.2. Methods and Measurement Times 
Response will be assessed by the Investigator or qualified designee and will be noted at each 
evaluation point as complete response (CR), partial response (PR), SD, progressive disease, or 
not evaluable (NE) (Table (7.2) 1). 
Radiographic assessments (CT or MRI) for evaluation of disease response are to be conducted 
at Screening (Day -21 to to Day -1), every 6 weeks (± 7 days) for the first 2 assessments (i.e., 
through Week 12), and then every 8 weeks (± 7 days) thereafter, independent of dose delays 
and/or dose interruptions, and/or at any time when progression of disease is suspected. Tumor 
assessment frequency may be reduced to every 12 weeks 2 years after treatment initiation. 
Per RECIST v1.1, response should be confirmed by repeat imaging assessment not less than 
4 weeks from the date the response was first documented. The scan for confirmation of the 
response may be performed at the earliest 4 weeks after the first documentation of response or 
at the next scheduled scan (approximately 6 to 8-week interval from last scan), whichever is 
clinically indicated. 
The Investigator should consider all lesions (target and non-target) in assessing the tumor 
burden at repeat imaging prior to making a decision for continuation of treatment. 

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Table (7.2) 1 - Imaging After First Radiological Evidence of Disease Progression 
Scenario 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiological 
evidence of disease 
progression 
Repeat imaging at 
≥ 4 weeks to 
confirm disease 
status 
May continue study 
treatment per 
Investigator 
discretion while 
waiting 
confirmation scan 
Repeat imaging at 
≥ 4 weeks to 
confirm disease 
progression per 
Investigator 
discretion only 
Discontinue 
treatment 
Repeat scan 
confirms disease 
progression 
No additional 
imaging required 
Discontinue 
treatment 
(exception upon 
consultation with 
the Sponsor) 
No additional 
imaging required 
NA 
Repeat scan shows 
SD, PR, or CR 
Continue tumor 
imaging assessment 
at scheduled 
intervals 
Continue study 
treatment per 
Investigator 
discretion 
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment if 
condition has 
improved and/or is 
clinically stable as 
per Investigator 
discretion 
Abbreviations  CR = complete response; NA = not applicable; PR = partial response; SD = stable disease. 
Note: if a subject has confirmed radiological disease progression but the subject is achieving a 
clinically meaningful benefit, an exception to continue treatment may be considered after 
consultation with the Sponsor. In this case, the subject must have absence of symptoms and 
signs of progression of disease, absence of decline in ECOG performance status, and absence 
of tumor progression at critical anatomic sites. In such cases, subject should be followed for 
tumor assessment and safety per protocol required schedule of assessment.  
7.3. Central Imaging Facility 
During the Expansion phase, a central imaging facility may evaluate imaging studies and 
supportive clinical data in a central and independent fashion, from subjects enrolled in Safety 
Lead-In phase and the Expansion phase. The facility will not perform independent clinical 
evaluations. The central imaging facility may be chartered to establish radiographic progression 
and may consider selected clinical data solely to aid in the interpretation of radiographic images. 
A detailed site-specific Imaging Core Manual will be made available regarding scan acquisition 
requirements. All radiological scans acquired at all scheduled time points and any additional 
(unscheduled) radiological images acquired to evaluate for potential metastatic disease also 
may be sent to the central imaging facility. In addition, the most recent pre-treatment scans (i.e., 
prior to screening) may also be requested, if available, from subjects in the dose escalation 
phase of the study. These scans will be collected and sent to a central imaging facility as detailed 
in the site-specific Imaging Core Manual. 
The site is expected to maintain a copy of digital data for the retention period applicable to the 
protocol, GCP, and federal, international and/or state legal and medical requirements. The 
Sponsor and/or designee may retain the media until or beyond study completion. 

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7.4. Continuation of Treatment Beyond Radiographic Progression 
In the event of radiographic progression per RECIST v1.1 but in the absence of clinical 
deterioration, worsening ECOG performance status, or disease progression that may 
compromise organ function, the subject may continue to receive study treatment with 
ivosidenib, nivolumab, and/or ipilimumab at the discretion of the treating physician in 
consultation with the Sponsor. Nivolumab will be permitted for up to a maximum of 24 months 
from date of first dose. If there is clinical deterioration or continued radiographic progression 
documented on subsequent imaging, treatment with either ivosidenib, nivolumab, or both will 
be discontinued, and the subject will complete the EOT and Safety Follow-up visits and enter 
Survival Follow-up. 
All other elements of the main consent including description of reasonably foreseeable risks or 
discomforts, or other alternative treatment options, will still apply. Treatment beyond 
progression may be administered during or after localized interventions (surgery/radiation 
therapy). 
8. ASSESSMENT OF SAFETY 
All AEs and other situations relevant to the safety of the participants must be followed up and 
fully and precisely documented to ensure that the Sponsor has the necessary information to 
continuously assess the benefit-risk balance of the clinical trial. 
8.1. Specification of Safety Parameters 
Safety measurements, including a limited physical examination and vital signs including 
weight, performed during the study are indicated in Table (4.1.2) 1. 
8.2. Methods and Measurement Times 
Safety measurements will include ECOG performance status, ECG, and clinical laboratory 
assessments (hematology, chemistry, thyroid function tests, coagulation, and pregnancy testing) 
and be performed locally per the schedule outlined in Table (4.1.2) 1. 
Clinical laboratory assessment details for assessments performed centrally are described in the 
study lab manual.  
8.3. Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a subject participating in a clinical 
study, whether or not there is a causal relationship with the IMP and/or experimental 
procedures, occurring or detected from the date the participant signs the information and 
consent form, irrespective of the period of the study (periods without administration of the IMP 
(e.g., run-in period) are also concerned). 

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An AE can therefore be: 
­ Any unfavorable and unintended sign (including an abnormal finding from an additional 
examination such as lab tests, X-rays, and ECG) that is deemed clinically relevant by the 
Investigator. 
­ Any symptom or disease. 
­ Any worsening during the study of a symptom or a disease already present when the 
participant entered the study (increase in frequency and/or intensity). 
Fatal studied disease progression, detected during a study visit or at an additional examination 
or occurred since the previous study visit. An AE can arise from any use of the drug (e.g., off-
label use, use in combination with another drug) and from any route of administration, 
formulation, or dose, including an overdose. 
Of note: 
­ Any hospitalization for administration of anti-tumoral treatment and/or associated protocol 
(during or after the study) or other care measures for cancer (e.g., overnight hospital stay to 
receive a blood or platelets transfusion), for social reasons, educational purpose (e.g., 
learning of diabetes management by the participant) or routine check-up should not be 
considered as an AE and should not be reported in the eCRF. 
­ Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments, which are associated with the studied disease should not be considered as an 
AE unless judged by the Investigator to be more severe than expected for the participant’s 
condition. 
­ Non-fatal studied disease progression should not be considered as an AE.  
­ The following procedures, whether planned before the study or not, whether leading to a 
hospitalization or not, should not be reported in the eCRF and should be kept in the 
source data (or participant file):  
 therapeutic procedures related to a non-aggravated medical history (e.g., cataract 
extraction not due to an aggravation of the cataract during the study, haemodialysis 
sessions related to a renal insufficiency not aggravated during the study), 
 prophylactic procedures (e.g., sterilization, wisdom teeth removal), 
 comfort procedures (e.g., cosmetic surgery), 
 control procedures of a pre-existing condition without aggravation (e.g., colonoscopy to 
control the remission of colon cancer). 
8.4. Definition of Serious Adverse Events 
An SAE is any AE that, at any dose: 
­ results in death, 
­ is life-threatening(1), 
­ requires insubject hospitalization or prolongation of existing hospitalization, 
­ is medically significant(2), 
­ results in persistent or significant disability/incapacity(3), 
­ is a congenital anomaly/birth defect(4). 
(1) Life-threatening in this context refers to an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe.  

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(2) Any event that might not be immediately life-threatening or result in death or hospitalization, but 
might jeopardize the participant or might require intervention to prevent one of these outcomes (for 
example: oedema or allergic bronchospasm that required intensive treatment at home, blood dyscrasia, 
convulsions that do not result in hospitalization, or development of drug dependence or drug abuse). 
The Investigator should exercise his/her scientific and medical judgement to decide whether or not such 
an event requires expedited reporting to Sponsor. 
(3) Disability/incapacity in this context refers to any event that seriously disrupts the ability of the 
participant to lead a normal life, in other words leads to a persistent or permanent significant change, 
deterioration, injury or perturbation of the participant’s body functions or structure, physical activity 
and/or quality of life. 
(4) Congenital anomaly or birth defect refers to the exposure to the IMP before conception (in men or 
women) or during pregnancy that resulted in an adverse outcome in the child. 
It is under Investigator’s responsibility to evaluate the AE seriousness according to international 
guidance (see ICH Topic E2A and EU DIRECTIVE 2001/20/EC of 4 April 2001 or further 
regulation (EU) No 536/2014). The Sponsor will review the AE seriousness. The seriousness 
may be upgraded (but never downgraded). 
8.5. Definition of Overdose 
This refers to any intake of a quantity of IMP that is above the maximum dose recommended 
in the study protocol, independent of the occurrence of any AE. 
The quantity should be considered per administration or cumulatively regarding the maximum 
dose recommended in the study protocol.  
8.5.1. 
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. Any study treatment overdose or incorrect 
administration of study treatment should be noted on the Study Drug Administration eCRF. 
All AEs associated with an overdose or incorrect administration of study treatment should be 
recorded on the Adverse Event eCRF. If the associated AE fulfills serious criteria, the event 
should be reported to the Sponsor by the Investigator within 24 hours after learning of the event. 
8.6. Definition of Adverse Event of Special Interest 
An adverse event of special interest (AESI) is one of scientific and medical interest or concern 
regarding the IMP for which recording rules, special documentation such as hospital records 
and/or adjudication committee could be appropriate. It may be a serious or non-serious AE that 
may require further investigation in order to be characterized and understood. 

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8.6.1. 
QT Prolongation 
Any QT prolongation event assessed as Grade ≥ 2 (i.e., QTcF interval longer than 480 msec or 
≥ 60 msec change from baseline with Torsade de pointes or polymorphic ventricular 
tachycardia or signs/symptoms of serious arrhythmia), irrespective of the seriousness, should 
be reported as an AESI to the Sponsor within 24 hours. See Section 8.6.1.1 for further details 
on managing subjects with QT prolongation. Heart rate-corrected QT interval will be calculated 
using Fridericia’s formula (QTcF = QT/RR1/3). 
8.6.1.1. 
Management of QT Prolongation 
Events of QT prolongation (i.e., QTcF Grade ≥ 3) should be reported as AESIs to the Sponsor 
within 24 hours, according to expedited reporting procedures (see Section 8.3). 
Subjects 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) 
antagonists. Investigators must be vigilant; refrain from administering concomitant medications 
associated with QT prolongation and if no other therapeutic options are available, monitor 
subjects receiving study treatment with the combination of these drugs and evaluate ECG and 
electrolytes (including potassium, magnesium, and calcium), particularly in subjects presenting 
with nausea, vomiting, or diarrhea. Systemic administration of a moderate or strong CYP3A4 
inhibitor requires careful monitoring of QTcF. 
Subjects who experience QT prolongation (i.e., QTcF > 480 msec; NCI CTCAE Grade ≥ 2) 
while receiving study treatment should be promptly evaluated for causality of the QT 
prolongation and managed according to the following guidelines.  
­ 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 Investigator believes it is appropriate, particularly if 
QTcF remains elevated (after the 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 QT prolongation event was first observed or more 
frequently as clinically indicated.  
Please refer to Table (8.12.1) 1 for the management of QT prolongation by NCI CTACE 
grade. 
8.7. Immune-Related Adverse Events 
Immune-mediated AEs are AEs consistent with an immune-mediated mechanism or immune-
mediated component for which non-inflammatory etiologies (e.g., infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology that 
were exacerbated by the induction of autoimmunity. Information supporting the assessment 
will be collected on the participant’s case report form. 
Every AE must be assessed by the Investigator with regard to whether it is considered immune 
mediated. For events which are potentially immune mediated, additional information will be 
collected on the participant’s case report form. 

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AEs associated with nivolumab and ipilimumab exposure may represent an immunologic 
etiology. These irAEs may occur shortly after the first dose or several months after the last dose 
of nivolumab and/or ipilimumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of nivolumab and/or ipilimumab, administration of corticosteroids 
and/or other supportive care.  For suspected irAEs, ensure adequate evaluation to confirm 
etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of 
irAEs, withhold or permanently discontinue nivolumab and/or ipilimumab and administer 
corticosteroids. Dose modification and toxicity management guidelines for irAEs associated 
with nivolumab and/or ipilimumab are provided in Appendix 8 and Appendix 10. 
8.8. Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject 
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. 
When an AE becomes serious (regardless of changes in grade or severity), the eCRF should be 
updated to reflect this. As such, a new AE (serious event with onset date for when AE became 
serious) should be added to the eCRF. 
However, the same does not hold true for AEs that change from serious to non-serious events. 
When an AE does not resolve but is downgraded from a serious to a non-serious event, a new 
AE is not required to be captured on the eCRF. A resolution date is required to be entered on 
the SAE form once an AE changes from a serious to non-serious event since this would result 
in the SAE resolving. 
A recurrent AE is 1 that resolves between subject evaluation time points and subsequently 
recurs. Each recurrence of an AE should be recorded separately on the Adverse Event eCRF. 
8.8.1. 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE. A laboratory test result should be reported 
as an AE if it meets any of the following criteria: 
a. Accompanied by clinical symptoms. 
b. Results in a change in study treatment (e.g., dosage modification, treatment interruption, or 
treatment discontinuation). 
c. Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a 
change in concomitant therapy. 
d. Clinically significant in the Investigator’s judgment. 
It is the Investigator’s responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 × ULN associated with cholecystitis), only the diagnosis (i.e., 
cholecystitis) should be recorded on the Adverse Event eCRF. 

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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the Adverse Event eCRF, along with a descriptor 
indicating if the test result is above or below the normal range. Where possible, please enter a 
condition (e.g., neutropenia) rather than the lab finding (e.g., decreased neutrophils). 
8.9. Classification of an Adverse Event (Seriousness, Severity, Causality, Expectedness) 
It is important that the Investigator gives their own opinion regarding the seriousness, the 
intensity of the event, as well as the cause-effect relationship between an AE and the research 
or disease progression. This evaluation must be assessed by the Investigator and reported in the 
AE form. In addition, the Sponsor will be responsible for the evaluation of the expectedness of 
the event (see Section 8.10.3). 
The seriousness should be evaluated according to international guidance (see definition 
Section 8.4, It is under Investigator’s responsibility to evaluate the AE seriousness according 
to international guidance (see ICH Topic E2A and EU DIRECTIVE 2001/20/EC of 4 April 
2001 or further regulation (EU) No 536/2014). The Sponsor will review the AE seriousness. 
The seriousness may be upgraded (but never downgraded). 
The severity of all AEs will be graded according to the NCI CTCAE version 5.0 on a 5-point 
scale (Grade 1 to 5): 
­ Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
­ Grade 2: moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)1. 
­ Grade 3: severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL2. 
­ Grade 4: life-threatening consequences; urgent intervention indicated. 
­ Grade 5: death related to AE. 
The cause-effect relationship: The Investigator must make an assessment in the AE form 
whether the AE is related or not to the research, meaning:  
­ a procedure scheduled in the study protocol (e.g., exercise test, MRI), or  
­ a change or withdrawal of previous/concomitant treatment related to the conditions of the 
protocol. 
Moreover, the Investigator has to assess if the AE is related to disease progression. Cases ticked 
“related” by the Investigator or judged by the Sponsor as having a reasonable suspected causal 
relationship to the IMP (AE linked to the mechanism of action of the IMP), will be considered 
as suspected adverse drug reactions. In general, if a relationship between AE and IMP is at least 
reasonably possible (i.e., the relationship cannot be ruled out) it is to be considered as “related”. 
 
1 Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
2 Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden”. 

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8.10. Reporting Procedures 
8.10.1. Time Frame for AE Reporting 
Any event meeting the above-mentioned definitions (see Section 8.3; Figure (8.10.1) 1) must 
be reported to the Sponsor on an AE form if it occurs:  
­ Before the first administration of IMP, for fatal events and events related to the research.  
­ At any time after the first administration of IMP.  
­ Up to 30 calendar days after the subject’s last administration for all AEs and AESIs 
(including overdose). 
­ Up to 90 calendar days after the subject’s last administration for all SAEs, or until the subject 
initiates new anti-cancer therapy, whichever is earlier.  
­ Up to 180 calendar days after the subject’s last administration for all pregnancies and 
exposures during breastfeeding, or until the subject initiates new anti-cancer therapy, 
whichever is earlier.  
­ Irrespective of the time of onset in case of SAEs assessed as related to the research. 
Of note, non-fatal events occurring between the signature of the ICF and the first administration 
of the IMP for which the Investigator does not consider an association with the research must 
be reported as medical history or as signs or symptoms related to the studied disease in the 
dedicated form of the eCRF.  
Fatal events, related or not to the research, occurring after ICF signature and before first IMP 
administration, must be reported on the AE form.

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8.10.2. Responsibilities of the Investigator 
For any AE or special situation mentioned above, the Investigator must: 
­ Note in the participant’s medical file the date on which the Investigator learned of the 
event (at a follow-up visit or a telephone contact with the participant or a third person, etc.) 
and any other relevant information that the Investigator has learned of the event. 
­ Assess the event in terms of seriousness, severity, and causality. 
­ Report the event to the Sponsor using the AE form. 
­ Document the event with additional useful information. 
­ Ensure the follow-up of the event. 
­ Fulfil Investigator regulatory obligations to the Competent Authorities and/or to the 
IRB/IEC, in accordance with local regulations. 
­ Demonstrate oversight of data reported and ensure the whole content’s accuracy, 
completeness, and legibility in accordance with the GCP (see Section 14.1). 
Moreover, the Investigator must report to the Sponsor and/or to the IRB/IEC and/or to the 
Competent Authorities in accordance with the local regulation, any new information that might 
materially influence the benefit-risk assessment of the test drug or that would be sufficient to 
consider changes in the test drug administration or in the overall conduct of the clinical 
investigation. 
8.10.2.1. Documentation of the Event 
The Investigator must ensure that all events are well documented and provide the Sponsor, on 
request, with anonymized copies of relevant documents (e.g., autopsy report and terminal 
medical reports [ICH E6 (R2)]). 
8.10.2.2. Follow-up of Adverse Events 
The Investigator must ensure that follow-up of the participant is appropriate to the nature of the 
event, and that it continues until resolution if deemed necessary. 
Any change in terms of diagnosis, severity (improvement), seriousness, measures taken, 
causality, or outcome regarding an AE already reported must be written up in a new complete 
evaluation of the event documented on the Adverse Event form previously created for the event. 
In case of worsening of severity, a new complete evaluation of the event must be documented 
on a new Adverse Event form. If the AE has not resolved at the participant’s final visit in the 
study, the participant must be followed up suitably and any information on the outcome of the 
event noted on the Adverse Event form previously created for the event. 
If the follow-up of the participant is not done by the Investigator (e.g., hospitalization, followed 
by a specialist or the participant’s general practitioner), the Investigator will do everything 
possible to establish/maintain contact with the person/department in charge of follow-up of the 
participant. 
 
 
 

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8.10.2.3. Special Situations (Pregnancy, Overdoses, Intake of IMPby a Person Around 
the Participant) 
Pregnancy 
If a female participant in the study becomes pregnant, the Investigator must: 
­ Stop immediately the test drug (if the pregnancy is a non-inclusion/exclusion criterion). 
­ Report it on the specific eCRF Pregnancy form and notify the Sponsor immediately (i.e., 
without delay and within 24 hours of awareness at the latest). 
­ Pregnancy should not be reported as an AE except in the following circumstances: 
 If it is associated with an AE. This consequence itself should be reported as an AE. 
 While pregnancy itself is not considered to be an AE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
­ Contribute to the follow-up of this pregnancy and provide the Sponsor with information 
concerning this follow-up (notably using the second page of the specific paper Pregnancy 
form). 
If the partner of a participant becomes pregnant during the study, the pregnancy should not be 
reported in the eCRF. The Investigator should immediately contact the Sponsor (contact details 
provided in the Investigator’s study file) who will determine the procedure to be followed.  
Overdose of IMP 
­ In case of overdose, the Investigator should report it on the IMP administration page. 
Overdose should not be reported as an AE except in the following circumstances: 
 The overdose is associated with an AE. This consequence itself should be reported as an 
AE. 
 The overdose is intentional with possible suicidal/self-harming intent should be reported 
as an AE regardless of sequelae. 
­ Overdose should be followed up to ensure that the information is as complete as possible 
with regard to:  
 Dose details (number of units, duration, etc.) and, if multiple overdoses, details regarding 
other medicinal products or substance, context of occurrence (i.e., intentional [suicide 
attempt, other reason] or accidental [error in prescription, administration, dispensing, 
dosage]), related signs and symptoms (“No related adverse events” to be reported 
otherwise), and outcome. 
­ Insofar as possible, a blood sample should be collected for assay of the IMP taken.  
Intake of IMP or Occupational Exposure by a Person Around the Participant 
This event should not be reported in the eCRF. The Investigator should immediately (i.e., 
without delay and within 24 hours of awareness at the latest) contact the Sponsor (contact 
details provided in the Investigator’s study file) who will determine the procedure to be 
followed. 

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8.10.2.4. Recording Methods in the eCRF 
Adverse events must be documented on the Adverse Event form of the eCRF. 
In case of chronic disease: 
­ If the disease is known when the participant enters in the study, only worsening (increased 
frequency and/or intensity of the episodes/attacks), this will be documented as an AE.  
­ If a disease is detected during the study and if repeated episodes enable diagnosis of a chronic 
disease, the episodes will be grouped on the Adverse Event form previously created for the 
event, which will clearly describe the diagnosis. 
8.10.2.5. Procedure for an Event Requiring an Immediate Notification 
In case of an event requiring an immediate notification, the Investigator must: 
­ Immediately after being informed of this event, fill in the participant’s medical file as well 
as the Adverse Event form of the eCRF (for SAEs and AESIs if applicable) according to 
the general instructions available in the eCRF, without waiting for the results of the clinical 
outcome or of additional investigations. When data will be submitted into the eCRF an email 
will be immediately and automatically sent to the Sponsor. However, for special situations 
requiring an immediate notification (as defined in Section 8.10.2.3) the completion of the 
Adverse Event form should not be performed systematically. 
­ If requested by the Sponsor (person designated in the contact details provided in the 
Investigator’s study file), provide anonymized copies of the documents that provide 
additional useful information. 
­ Fulfil Investigator regulatory obligations to the Competent Authorities and/or to the 
IRB/IEC, in accordance with local regulations. 
­ In case of an SAE occurring in a first-in-human study, if the Investigator establishes or even 
suspects a relationship with the study protocol, they must immediately suspend the 
administration of IMP (and AxMP if applicable) in all participants. In this case, the written 
consent of the enrolled participants must be obtained again before the study is resumed. 
Moreover, on request, the Investigator should provide the Sponsor with the documents required 
in Section 8.10.2.1. 
If an AE that is initially non-serious worsens and becomes an SAE, this must be reported 
immediately on an “Adverse Event” form of the eCRF. 
In case the eCRF is unavailable when the Investigator was informed of an AE to be reported 
immediately, the Investigator should: 
­ Immediately fill in a paper Adverse Event page: 
 For serious event, on a paper Adverse Event – Initial Information page. 
 For event initially non-serious, on a paper Adverse Event – Initial Information page, and 
the worsening leading to seriousness on a paper Adverse Event – Additional Information 
page. 
­ Immediately send the page(s) by email to the person(s) designated in the contact details 
provided in the Investigator’s study file or outside working hours, the 24-hour phone 
number. 
­ As soon as the eCRF becomes available, the Investigator should enter these data in the 
Adverse Event form of the eCRF.  

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8.10.3. Responsibilities of the Sponsor 
In accordance with international guidance, the assessment of the seriousness and the causality 
of AEs is usually made by the Investigator but falls also under Sponsor’s duties, who is 
responsible for ensuring that all suspected unexpected serious adverse reactions are reported to 
Competent Authorities and Ethics Committees.  
The Sponsor will review the seriousness of the AEs and the causality of (at least) the SAEs, 
whether reported by the Investigator or upgraded by the Sponsor. The causality and the 
seriousness may be upgraded (but never downgraded). Anonymized copies of documents 
providing useful information such as reports of further consultations, laboratory test reports, 
and reports of other examinations aiding diagnosis may be requested for the event assessment. 
If the assessments of the Investigator and the Sponsor are different, both will be reported in the 
clinical study report (CSR). 
In addition, the Sponsor is responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the IMP. 
Independently of the regulatory obligations of the Investigator, the Sponsor must report the 
pharmacovigilance data and any new safety finding likely to affect the benefit/risk balance of 
the product, required in ICH GCP guidelines and local regulations, to the appropriate 
Authorities, to all the Investigators involved, and to the trial participants involved (through the 
Investigators) as described in Section 13.4. Responsibilities of Data Review Committee 
During the Safety Lead-in phase, the DRT, composed of Investigator(s) and the Sponsor’s 
medical, safety, and statistical representative(s), will meet to evaluate clinical and laboratory 
safety data in order to make decisions regarding determination of the RCD. The DRT will meet 
at minimum:  
­ Before deciding that a dose is the RCD and the Expansion phase can be opened. 
­ If the rate of DLTs indicates that the dose should be de-escalated, the DRT will meet to 
determine if the 250 mg QD dose should be tested.  
­ If either the 500 mg and/or the 250 mg dose is determined to have unacceptable toxicity. 
8.12. Dose Modification and Management for Adverse Events 
8.12.1. Study Treatment Dose Modification and Management Associated with Ivosidenib 
For any AE, including AEs not specifically mentioned in Table (8.12.1) 1, the Investigator may 
decide to delay dosing or modify the dose of ivosidenib based on clinical judgment. These 
decisions should be discussed with the Sponsor prior to implementation. Dose modifications of 
ivosidenib from 500 mg to 250 mg will be permitted on study for management of AEs 
(Table (8.12.1) 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. Re-
escalation may be allowed with approval from the Sponsor. 

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Dose delays are discouraged, except as needed for management of AEs. Dose delays up to 
28 days will be permitted at the discretion of the Investigator in consultation with the Sponsor 
for reasons including management of AEs and for mitigating circumstances (e.g., planned 
procedures). Palliative biliary decompression procedures will be permitted on study and will 
not require interruption of ivosidenib (see Section 8.12.5). 
If the subject cannot resume ivosidenib within 28 days, the subject should be discontinued from 
ivosidenib. Other reasons for treatment termination are provided in Section 5.4.1. If ivosidenib 
is discontinued, the subject may continue receiving nivolumab and ipilimumab or nivolumab 
alone. If subject permanently discontinues treatment from all three drugs, the EOT and Safety 
Follow-up visits will be completed as well as the PFS follow-up (if disease has not progressed) 
and Survival Follow-up visits. Exemptions may be considered for those subjects 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 subject should resume the study at the next planned 
visit within a dosing cycle. 
If a strong CYP3A4 inhibitor must be co-administered, reduce the ivosidenib dose to 250 mg 
QD. If the strong inhibitor is discontinued, increase the ivosidenib dose (after at least 5 half-
lives of the strong CYP3A4 inhibitor) to the recommended dose of 500 mg QD. 
Table (8.12.1) 1 - Management of Ivosidenib related QT Prolongation and Adverse Events 
by NCI CTCAE Grade 
NCI CTCAE Grade 
Management 
Grade 2: Average QTc interval greater 
than 480 msec up to 500 msec 
• 
Monitor and supplement electrolyte levels as clinically 
indicated. 
• 
Review and adjust concomitant medications with known QTc 
interval-prolonging effects. 
• 
Interrupt ivosidenib. 
• 
Restart ivosidenib at 500 mg once daily after the QTc interval 
returns to less than or equal to 480 msec.  
• 
Monitor ECGs should be conducted at least weekly for 2 weeks 
following resolution of QTc prolongation. 
Grade 2 nausea or vomiting (related or 
unrelated) 
• 
Consider holding dose of ivosidenib until resolution of adverse 
event (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: Average QTc interval greater 
than 500 msec  
• 
Monitor and supplement electrolyte levels as clinically 
indicated.  
• 
Review and adjust concomitant medications with known QTc 
interval-prolonging effects. 
• 
Interrupt ivosidenib. 
• 
Resume ivosidenib at a reduced dose of 250 mg once daily 
when QTc interval returns to within 30 msec of baseline or less 
than or equal to 480 msec.  
• 
Monitor ECGs at least weekly for 2 weeks following resolution 
of QTc prolongation.  
• 
Consider re-escalating the dose of ivosidenib to 500 mg daily 
if an alternative etiology for QTc prolongation can be 
identified. 

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NCI CTCAE Grade 
Management 
Grade 3 AEs (related, first event) 
• 
Interrupt ivosidenib until toxicity resolves to Grade 1or lower, 
or baseline, then resume at 250 mg, or re-escalation to 500 mg 
with Sponsor approval. 
• 
If Grade 3 toxicity recurs (a second time), interrupt ivosidenib 
dose until the toxicity resolves, then resume 250 mg daily.  
• 
If Grade 3 toxicity recurs (a third time), discontinue ivosidenib. 
Grade 4 AEs (related) including QTc 
interval prolongation with 
signs/symptoms of life-threatening 
arrhythmia  
• 
Discontinue ivosidenib permanently. 
Abbreviations  ECG = electrocardiogram; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; QTc 
= heart rate-corrected QT interval; QTcF = heart rate-corrected QT interval using Fridericia’s method. 
Note  Per NCI CTCAE, version 4.03. 
8.12.2. Dose Modifications and Management Associated with Nivolumab and/or 
Ipilimumab  
Dose delay criteria apply for all drug-related adverse events (regardless of whether the event is 
attributed to nivolumab or ipilimumab or both). Delay administration of both nivolumab and 
ipilimumab if any of the delay criteria are met. Delay nivolumab and ipilimumab dosing for 
any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, warrants delaying the dose of study medication.  
For subjects who require the delay of nivolumab and ipilimumab, re-evaluate weekly, or more 
frequently, if clinically indicated and resume dosing when criteria to resume treatment are met. 
Continue tumor assessments per protocol even if dosing is delayed. 
If discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with 
nivolumab may continue; if nivolumab is discontinued, however, ipilimumab will not continue 
as monotherapy. 
If a subject meets criteria for discontinuation of nivolumab/ipilimumab and Investigator is 
unable to determine whether the event is related to both or one study drug, the participant must 
discontinue both nivolumab and ipilimumab. Subjects may continue receiving ivosidenib. If 
subject permanently discontinues treatment from all three drugs, EOT and Safety Follow-up 
Visits will be completed, as well as PFS follow-up (if disease has not progressed) and survival 
follow-up visits.  
Subjects may resume treatment with nivolumab/ipilimumab if they have completed AE 
management (i.e. corticosteroid taper) or are on ≤ 10 mg prednisone or equivalent, and meet 
the requirements per Appendix 8 and Appendix 9. 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 8 weeks for Q3 
week treatment and 10 weeks for Q4 week treatment, the Medical Monitor (or designee) must 
be consulted.  

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8.12.3. Dose Modification for Ivosidenib, Nivolumab and Ipilimumab 
When study interventions are administered in combination, attribution of an AE to a single 
component is likely to be difficult. When an AE cannot be clearly attributed to any one or 
combination of drugs, the most stringent criteria for dose modification (based on Dose 
modification for ivosidenib and ipilimumab/nivolumab - Table (8.12.1) 1 and Appendix 8) 
must be used for all three drugs.  
Dose delay: When study interventions are administered in combination, if the AE is considered 
immune-related, both nivolumab and ipilimumab interventions should be held according to 
recommended dose modifications (Appendix 8). QTc prolongation and other Grade3 or higher 
adverse events that are possibly related to ivosidenib should be managed according to dose 
modification recommendations in Table (8.12.1) 1. 
Re-starting Study Interventions: Subjects may not have any dose modifications (no change in 
dose or schedule) of nivolumab and/or ipilimumab in this study. At the 250 mg QD dose level, 
no dose re-escalation is allowed for ivosidenib. If the toxicity does not resolve or the criteria 
for resuming treatment are not met, the subject must be discontinued from all study 
interventions. If the toxicities do resolve and conditions are aligned with what is defined in 
Appendix 8 and Table (8.12.1) 1 ivosidenib, nivolumab and/or ipilimumab may be restarted at 
the discretion of the Investigator.  
8.12.4. Treatment of Related Infusion Reactions Associated with Nivolumab and 
Ipilimumab 
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they 
are unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if 
such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. 
Report all Grade 3 or 4 infusion reactions within 24 hours as an SAE if it meets the criteria. 
Treatment recommendations are provided below based on NCI CTCAE v5.0 grading 
definitions and may be modified based on local treatment standards and guidelines, as 
appropriate: 
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
­ Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1,000 mg at least 30 minutes 
before additional nivolumab administrations. 

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For Grade 2 symptoms (therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (e.g., antihistamines, non-steroidal anti-inflammatory drugs, narcotics, 
IV fluids); prophylactic medications indicated for ≤ 24 hours): 
­ Stop the study drug infusion, begin an IV infusion of normal saline, and treat the participant 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1,000 mg; remain at bedside and monitor participant until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor participant closely. If symptoms 
recur, then no further study medication will be administered at that visit. 
­ For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1,000 mg 
administered at least 30 minutes before nivolumab and/or ipilimumab infusions. If 
necessary, corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used. 
For Grade 3 or 4 symptoms (severe reaction, Grade 3: prolonged [e.g., not rapidly responsive 
to symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for clinical sequelae. Grade 4: life-
threatening consequences; urgent intervention indicated): 
­ Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline and 
treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Monitor participant until the 
Investigator judges that the symptoms will not recur. Study drug will be permanently 
discontinued. Follow institutional guidelines for the treatment of anaphylaxis. Remain at 
bedside and monitor participant until recovery of the symptoms. 
In 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). 
8.12.5. Biliary Tract Obstruction During Treatment 
In the event of the development of obstructive jaundice due to biliary tract obstruction, the 
appropriate measures will be taken to diagnose and relieve the obstruction. Study treatment 
interruption is not required but will be permitted at the discretion of the Investigator. 
9. OTHER ASSESSMENTS NOT SPECIFICALLY RELATED TO EFFICACY OR 
SAFETY 
9.1. Assessments Related to Inclusion Criteria 
All Screening procedures must be performed within 28 days prior to first dose for subjects in 
the Safety Lead-in or the Expansion phase. A legally authorized representative may consent on 
behalf of a subject who is otherwise unable to provide informed consent if acceptable to and 
approved by the site’s IRB/IEC.  

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Inclusion and Exclusion Criteria  
Inclusion and exclusion criteria (Section 5.1 and Section 5.2, respectively) will be reviewed for 
each potential subject and documented in the subject medical record and eCRF.  
Demographic Data, and Medical, Surgical, and Disease History 
Subject demographic data, including sex, year of birth, age, race, and ethnicity, will be obtained 
during Screening and according to applicable local regulations.  
A complete medical, surgical, and disease history, and the date of initial diagnosis of the 
underlying CCA, will be obtained during Screening. The medical history is to include all 
relevant prior medical history as well as all current medical conditions.  
All medications administered and procedures conducted within 28 days before the first dose of 
IMP through 30 days after last dose of IMP should be reported in the eCRF. 
9.2. Measurement of Drug Concentration 
9.2.1. 
 Sample Collection Time Points 
Serial or sparse blood samples will be drawn before and after dosing of study treatment in order 
to determine circulating plasma and tissue concentrations of ivosidenib. The blood samples will 
also be used for the determination of 2-HG concentrations (see Section 9.3). 
Blood samples will be drawn on Day 1 of Cycle 2 (for Safety Lead-in phase) or Day 1 of Cycle 4 
(for Expansion phase) at the following time points: pre-dose (within 30 minutes before 
ivosidenib dose), 2, 3, 4, and 6 hours (± 10 minutes) post-dose. Additional blood samples for 
ivosidenib PK and 2-HG PD assessments will be drawn pre-dose (within 30 minutes before 
ivosidenib dose) on C1D1, C1D15, C2D1, C3D1, C4D1, C5D1, and Day 1 of every cycle 
through Cycle 13, and Day 1 of every other cycle thereafter. 
Sparse blood samples will also be drawn before and after dosing of study treatment in order to 
determine circulating serum concentrations of nivolumab and ipilimumab. Specifically, for 
nivolumab serum concentration assessment, blood samples will be drawn at pre-dose (within 
30 minutes before the ivosidenib dose) on C1D1, C2D1, C3D1, and C4D1, followed by pre-
dose collection on Day 1 of every 4 cycles up to 2 years, and at end of infusion after first dose 
of nivolumab on C1D1. For ipilimumab serum concentration assessment, blood samples will 
be drawn at pre-dose (within 30 minutes before the ivosidenib dose) on C1D1, C2D1, C3D1, 
and C4D1, and at end of infusion after first dose of ipilimumab on C1D1. Predose samples for 
all three IMPs may be collected in one blood draw. 
If enough material is available, tumor tissue (fresh-frozen) may be used to determine tumor 
drug concentration of ivosidenib in order to evaluate tumor exposure of ivosidenib on C1D1 
and C3D1. Tumor sample collection is detailed in Section 9.3. 
9.2.2. 
Sampling Methods 
Blood for assessment of PK parameters of ivosidenib and 2-HG concentrations will be collected 
and processed according to the laboratory manual. Every effort will be made to collect PK 
samples at the time points specified. No additional samples will be collected without formal 
amendment to this protocol. Analysis will be performed at a central laboratory (Specialty 
Laboratory) using validated bioanalytical methods. A detailed laboratory manual specifying 

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sample collection, processing, handling, storage, and shipment will be provided to the study 
sites; retention time for specimens will be specified therein. If a collected plasma sample is 
inadequate or insufficient for PK analysis, the analysis of PK can be done using samples for 
biomarker studies. 
9.3. Pharmacodynamics Measurements 
Samples of blood for measuring the plasma concentrations of 2-HG will be obtained before the 
first dose of ivosidenib given on C1D1 (within 30 minutes before the ivosidenib dose). 
Additional PD samples include single pre-dose blood samples that will be collected prior to 
dosing ivosidenib (within 30 minutes before the ivosidenib dose) on C1D15, C2D1, C3D1, 
C4D1, C5D1, and Day 1 of every cycle through Cycle 13, and Day 1 of every other cycle 
thereafter (e.g., Cycles 15, 17, etc.). 
Subjects will be requested to have tumor tissue newly collected at Screening for baseline tumor 
2-HG measurement and other exploratory biomarker assessment. A post-dose tumor sample 
will be collected on C3D1 for 2-HG measurement and other exploratory biomarker 
assessments. 
All time points are described in the investigational schedule. 
Biopsies can be collected at Screening and on C3D1 from a similar site as screening. At each 
time point, tumor biopsies must include at a minimum 3 core needle samples (3 to 4 core 
samples if feasible). If a subject cannot undergo a biopsy at Screening, archived fresh-frozen 
tumor biopsy, if available, can be used for the measurement of baseline 2-HG. 
If a required tumor biopsy (any time point) cannot be performed due to concerns around subject 
safety, a discussion with the Sponsor is required and biopsy can be omitted.  
The tissue obtained by core needle biopsy will be: 
­ Fixed in 10% normal buffered formalin and later embedded in paraffin to produce slides for 
biomarker assessments (detailed in Section 9.5). 
­ Processed as fresh-frozen tissue for assessment of concentrations of 2-HG (using liquid 
chromatography with tandem mass spectrometry).  
­ If there is enough material, samples may also be used for determining tumor drug 
concentrations of ivosidenib or for assessment of other exploratory biomarkers. 
Detailed instructions for the collection, handling, processing, storage, and shipment conditions 
will be outlined in the laboratory manual (or equivalent) for the study and provided to the study 
sites.  
9.4. Anti-Drug Antibody Measurements 
Sparse blood samples will be drawn before and after dosing of study treatment in order to 
determine circulating serum concentrations ADA to nivolumab and/or ipilimumab that may 
arise during treatment. Specifically, for nivolumab serum ADA concentration assessment, 
blood samples will be drawn at pre-dose (within 30 minutes before the ivosidenib dose) on 
C1D1, C2D1, C3D1, C4D1, followed by pre-dose collection on Day 1 of every 4 cycles up to 
2 years. 
For ipilimumab serum ADA concentration assessment, blood samples will be drawn at pre-
dose (within 30 minutes before the ivosidenib dose) on C1D1, C2D1, C3D1, and C4D1.  

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9.5. Assessment of Biomarkers 
The purpose of the exploratory biomarker assessments of pre-treatment samples is to identify 
and validate cells, proteins, and/or expression/mutation of genes that may predict which 
subjects are likely to respond to the study treatment. Comparison of pre- and post-treatment 
samples aims to identify the mechanism of action and/or mechanism of resistance of the study 
drug(s).  
Tumor biopsies or archival tissue sections will be collected at Screening. If a subject cannot 
undergo a biopsy at Screening, collection of archival tumor tissue from the most recent 
biopsy/resection of at least 20 freshly cut, unstained formalin-fixed paraffin-embedded slides 
(4-5 µm each) plus 1 H&E slide will be submitted at a later time, for future exploratory 
biomarker analyses, together with the pathology report upon sponsor’s request. Detailed 
instructions for tumor tissue collection and shipping for central testing will be provided in a 
separate laboratory manual. Tumor biopsies will also be collected at post-treatment (at Cycle 
3), and at EOT from similar anatomical locations. Additional unscheduled tumor biopsy(ies) 
collected as standard of care, if any, will be used for the optional analysis of biomarkers. 
Biomarkers, which will be analyzed from the tumor biopsies, include but are not limited to the 
analysis of immune checkpoint proteins and other proteins, tumor microenvironment, presence 
and/or frequencies of IDH1 and other oncogenic gene alterations. 
Liquid biopsies such as peripheral blood mononuclear cells (PBMCs) and circulating tumor 
DNA (ctDNA) will be derived from blood and will be collected longitudinally at each cycle 
until C6D1, followed by every 6 months thereafter, and at EOT. Biomarkers that will be 
analyzed from PBMCs and ctDNA will include but are not limited to gene alteration, immune 
cell, and protein (cytokine) assessments at baseline and/or longitudinally. 
While the goal of the biomarker assessments is to provide supportive data for the clinical study, 
there may be circumstances when a decision is made to stop a sampling collection, or not 
perform or discontinue an analysis due to either practical or strategic reasons (e.g., inadequate 
sample number, issues related to the quality of the sample or issues related to the assay that 
preclude analysis, impossibility to perform correlative analyses). Therefore, depending on the 
results obtained during the study, sample collection analysis may be omitted at the discretion 
of the Sponsor. 
9.5.1. 
Mandatory Assessment 
Participation in the study implies a systematic participation in the mandatory investigation. All 
participants will have to consent to this investigation by signing the main information and 
consent form for participation in the study. In addition, in case of consent withdrawal, related 
samples will be destroyed after mandatory assessment is completed and in any case before the 
CSR final version is made available. 
9.5.2. 
Sampling, Processing, and Storage 
Detailed instructions for the collection, handling, processing and storage conditions are outlined 
in the laboratory manual (or equivalent) for the study. All samples (except the ones dedicated 
to retrospective analysis and ADA) have to be destroyed at the latest when the CSR final version 
is made available. If they are optional assessments and participant withdrawn consent, please 
refer to Section 9.5.5. 

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Structures in charge of collecting, processing, storing, and assaying samples are described in 
Section 1. Labelling and Transfer to Analytical Center 
Samples will be single coded with a unique number and thus will not carry any personal 
identifiers. Sample collection information must be entered as required on the appropriate 
sample collection eCRF page(s) and requisition form(s). Detailed instructions for the sample 
labelling and shipments are outlined in the laboratory manual (or equivalent) for the study. 
9.5.4. 
Transfer of Analytical Results 
Final analytical results will be transferred to Data Management according to section Data 
Management (Section 14.2).  
9.5.5. 
Optional Assessment 
Participation in the study does not imply a mandatory or systematic participation in the optional 
analysis of biomarkers on tumor biopsy(ies) that may be collected as standard of care. 
Biomarkers, which will be analyzed from the tumor biopsies, include but are not limited to the 
analysis of immune checkpoint proteins and other proteins, tumor microenvironment, presence 
and/or frequencies of IDH1 and other oncogenic gene alterations. Participants who agree to 
participate in the optional analysis of the biomarkers must provide consent for this analysis in 
the ICF, which can be withdrawn at any time without compromising the participation in the 
overall clinical study investigations. In addition, in case of consent withdrawal, related samples 
will be destroyed before any further optional assessment is completed.  
The goal of the optional analysis of biomarkers on unscheduled biopsy(ies) collected as per 
standard of care is to provide supportive data for the clinical study. Depending on the results 
obtained during the study and at the discretion of the Sponsor, analysis may be omitted, or 
discontinued for practical or strategic reasons (e.g. inadequate number of samples, issues related 
to the quality of the sample or the assay that preclude analysis, impossibility to perform 
correlative analyses, etc.).Overall results of the genomic biomarkers assessment may be 
transmitted to the participant upon request at the end of the study.  
There will be no communication of individual results to the Investigator or to the participant 
unless these results are proven to impact the therapeutic strategy.  
9.5.5.1. 
Retrospective Analyses  
Retrospectives analyses involving human biological samples are considered as optional 
assessments and are performed after the end of the study (planned or not in the clinical study 
protocol). 
Participation in these retrospective analyses is optional and is not mandatory for the inclusion 
of a given participant in the study (please refer to Section 9.5.5).  
If the participant agrees, some additional samples/remaining biomarker samples may be stored 
after the end of the study.  
They could be further analyzed to address scientific questions related to the product or disease 
including research related to improvements or enhancements in the development of 
bioanalytical methods.  

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A decision to perform such exploratory biomarker research studies will be based on outcome 
data from this study or from new scientific findings related to the drug class or disease, as well 
as reagent and assay availability.  
Samples will be kept in suitable conditions in a central bio-repository specialized in storage of 
biological samples until further notification from the Sponsor and may be stored up to 25 years 
after study closure completion.  
10. STATISTICS 
This section is a general outline of the statistical methods that will be implemented in this trial. 
More details will be specified in the statistical analysis plan (SAP). 
10.1. Statistical Analysis 
10.1.1. General Methods 
Study data will be summarized for disposition, demographic and baseline characteristics, 
safety, PK, PD, and clinical anti-tumor activity. 
Categorical data will be summarized by frequency distributions (number and percentages of 
participants) and continuous data will be summarized by descriptive statistics (mean, standard 
deviation, median, minimum, and maximum). In each cohort of the Expansion phase, 
participants treated during the Safety Lead-in phase will be pooled with those receiving the 
same dose of ivosidenib during the Expansion phase, unless otherwise specified. All 
summaries, listings, figures, and analyses will be performed by dose level and total in the Safety 
Lead-in phase, and by cohort and total in the Expansion phase, unless specified otherwise. 
The study data will be analyzed and reported in the CSR based on all participants’ data from 
both the Safety Lead-in and Expansion phases.  
10.1.2. Analysis Sets 
The following analysis sets will be evaluated and used for presentation of the data: 
­ DLT-Evaluable Set: All participants enrolled during the Safety Lead-in phase who have 
received any dose of the combination therapy and experienced a DLT through Cycle 2, or 
who have received at least 2 doses of nivolumab and ipilimumab, respectively, and at least 
75% of ivosidenib at the planned dose through Cycle 2 without experiencing a DLT through 
Cycle 2 will be considered evaluable for DLT assessment. This analysis set will be the 
primary set to determine the RCD, which will be further investigated at the Expansion phase. 
­ Safety Analysis Set: All participants enrolled who have received any amount of study 
treatment (ivosidenib in combination with nivolumab and ipilimumab). The Safety Analysis 
Set will be the primary analysis set for clinical anti-tumor activity, safety, and other analyses, 
unless otherwise specified.  
­ Response-Evaluable Set: All participants in the Safety Analysis Set for whom a baseline 
disease assessment and at least one post-baseline response assessment are available and 
evaluable. The Response-Evaluable Set will be used for the supportive analysis for the 
primary endpoint of objective response.  

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­ Pharmacokinetic Analysis Set: All participants who have had at least one blood sample 
providing evaluable PK data for ivosidenib in combination with nivolumab and ipilimumab. 
­ Pharmacodynamic Analysis Set: All participants who have had at least one blood sample 
providing evaluable plasma 2-HG data for ivosidenib in combination with nivolumab and 
ipilimumab. 
­ ADA Analysis Set: All participants with a baseline ADA assessment and at least one post-
treatment ADA assessment.  
10.1.3. Disposition and Baseline Characteristics 
The participants’ disposition and baseline characteristics will be described in the Safety 
Analysis Set. The number of participants and the reasons for exclusion will be listed as well as 
the disposition of participants, including reasons for treatment discontinuation and study 
withdrawal. Major protocol deviations will be summarized. Protocol deviations will be listed. 
Characteristics of participants including demography, characteristics of the disease at diagnosis 
and study entry, medical history, and prior therapy will be summarized. 
10.1.4. Exposure 
Study drug exposure, including number of doses administered, total dose, duration of treatment, 
the proportion of participants with dose modifications, the dose intensity (computed as the ratio 
of actual dose received and actual duration), and relative dose intensity (computed as the ratio 
of dose intensity and planned dose received/planned duration) will be listed and summarized 
using descriptive statistics for each drug separately.  
The Safety Analysis Set will be the primary analysis set. 
10.1.5. Analysis of Primary Endpoints 
10.1.5.1. Safety Lead-in Phase: Estimation of the RCD - Ivosidenib in Combination with 
Nivolumab and Ipilimumab 
One of the primary endpoints during the Safety Lead-in phase is DLT through Cycle 2. The 
criteria of DLT rate < 33% will be used to determine the RCD for ivosidenib in combination 
with nivolumab and ipilimumab. DLT rate will be calculated based on the DLT-Evaluable Set 
by dose level. The DRT will review the aggregate treatment-emergent safety data in addition 
to DLTs to determine the RCD. 
10.1.5.2. Expansion Phase: Objective Response per Investigator Assessment of 
Anti-tumor Activity (Using RECIST v1.1) 
The primary endpoint during the Expansion phase is the objective response per RECIST v1.1 
for solid tumors [Appendix 5]) (Eisenhauer et al, 2009).  
The primary estimand of interest is the ORR. The attributes of the primary estimand are defined 
as follows:  
­ Treatment: ivosidenib plus nivolumab and ipilimumab. 
­ Population: Safety Analysis Set. 
­ Variable: ORR (for the primary efficacy endpoint). 
­ Summary measure: objective response (Yes, No). 
­ Intercurrent events (IE): 

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1. Early treatment discontinuation 
2. Administration of further anti-cancer therapy 
Primary analysis 
The primary analysis for the primary endpoint of objective response will be based on the Safety 
Analysis Set. 
The ORR will be calculated as the proportion of participants who achieve confirmed CR or PR 
with the 2-sided exact binomial 95% CI by cohort. Participants treated at the RCD and enrolled 
during the Safety Lead-in phase will be pooled with those receiving the same dose of ivosidenib 
during the Expansion phase for each cohort as appropriate. 
Supportive Analysis 
A supportive analysis for the primary endpoint of objective response will be based on the 
Response-Evaluable Set. 
Additional sensitivity analysis may be conducted based on retrospective central review if 
available. 
Other estimands of interest for the primary endpoint of objective response may be analyzed as 
appropriate. 
10.1.6. Analysis of Secondary Endpoints 
10.1.6.1. Analysis of Secondary Efficacy Endpoints 
The primary analysis for response-related secondary efficacy endpoints will be based on 
Investigator assessment. Additional sensitivity analysis may be conducted based on 
retrospective central review if available. Two-sided 95% CIs for the response rates will be 
calculated where appropriate. Duration of response (DOR) and PFS determined by Investigator 
per RECIST v1.1 will be assessed using Kaplan-Meier methods for each cohort to estimate the 
median and quantiles of the relevant endpoint where appropriate. 
­ Best overall response (BOR) will be determined per participant as the best response recorded 
(either CR, PR, SD or PD) from the start of the treatment until disease progression, end of 
treatment, or initiation of subsequent anti-cancer therapy, whichever occurs first. 
­ DOR: Among responders with confirmed CR or confirmed PR, DOR will be calculated as 
the date of the first occurrence of confirmed response to the date of documented disease 
progression or death, whichever occurs first. Participants without disease progression or 
death will be censored at the last evaluable response assessment date. Additional details of 
censoring rules will be defined in the SAP. 
­ Disease control rate (DCR): Disease control rate is defined as the rate of confirmed CR, 
confirmed PR, and SD maintained for at least 5 months. 
­ Time to response (TTR): TTR will be calculated as the date of the first dose to the date of 
the first occurrence of a confirmed CR or confirmed PR, whichever occurs first. 
­ PFS is defined as the time from the date of the first dose of the study medication to the date 
of first documentation of disease progression as determined by the Investigator or death due 
to any cause, whichever occurs first. Detailed censoring rules will be defined in the SAP. 
­ OS is defined as the time from the date of the first dose to the date of death due to any cause.  

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10.1.6.2.  Analysis of Secondary Safety Endpoints 
Safety summaries will contain only data collected during the on-treatment period, unless 
otherwise specified. Safety data will be summarized. In general, the on-treatment period is 
defined as the time from the date of the first dose of study drugs to 30 days from the last dose 
of study drugs. For immune-mediated adverse events, the on-treatment period is defined as the 
time from the date of the first dose of study drugs to 100 days from the last dose of nivolumab. 
10.1.6.2.1. Adverse Events 
Summary tables for AEs will include TEAEs, which are AEs that start or worsen during the on-
treatment period. The incidence of TEAEs will be summarized according to Medical Dictionary 
for Regulatory Activities (MedDRA) by System Organ Class and/or Preferred Term, severity 
(based on NCI CTCAE grades), type of event, and relation to study treatment. The following 
summaries will be generated: 
­ All TEAEs. 
­ Most common TEAEs (i.e., reported by ≥ 10% of participants for each cohort). 
­ Treatment-related TEAEs. 
­ Grade 3 or higher TEAEs. 
­ Grade 3 or higher treatment-related TEAEs. 
­ SAEs. 
­ TEAEs leading to treatment discontinuation. 
­ TEAEs leading to dose reduction. 
­ AEs leading to on-treatment death. 
By-participant listings will be provided for AEs leading to on-treatment death, and TEAEs, 
SAEs, and TEAEs leading to treatment discontinuation. 
10.1.6.2.2. Laboratory Abnormality 
For laboratory tests covered by the NCI CTCAE version 5.0 or later, grades will be assigned 
for these tests, and Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
For laboratory tests not covered by the 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 and chemistry laboratory 
tests: 
­ Descriptive statistics for the actual values (and/or change from baseline) or frequencies of 
clinical laboratory parameters over time. 
­ Shift tables using NCI CTCAE grades to compare baseline with the worst post-baseline 
value (for laboratory tests for which NCI CTCAE grades are not defined, shift tables using 
the low/normal/high/[low and high] classification to compare baseline with the worst post-
baseline value may be generated). 
In addition to the above-mentioned tables and listings, graphical displays of key safety 
parameters, such as scatter plots of actual or change in laboratory tests over time or box plots, 
may be specified in the SAP. 

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10.1.6.2.3. Other Safety Data 
The actual values (and/or the changes from baseline) of physical examination over time and 
vital signs over time will be listed by participant.  
Descriptive statistics of ECOG performance status scores over time will be summarized. Shift 
tables may be generated for ECOG performance status scores from baseline to worst value of 
post-baseline assessments.  
Descriptive statistics for the actual values and changes from baseline in ECG data over time 
will be summarized. QTc will be calculated using Fridericia’s correction. In addition, a 
categorical analysis of QTc may be performed for each time point. Maximum QTc and 
maximum changes from baseline may also be summarized similarly. ECG abnormalities, if 
collected, will be presented in a listing. 
10.1.6.2.4. Prior and Concomitant Medications 
Prior medications taken prior to the start of study drugs will be listed by participant and 
summarized. 
Concomitant medications taken at the time of or after the start of study drugs and prior to the 
last dose plus 35 days will be listed by participant and summarized.  
10.1.7. Analysis of Exploratory Endpoints 
All participants with evaluable sample measurements will be included in the analysis. Actual 
values or changes/shifts from baseline of exploratory biomarkers will be summarized over time 
and may be displayed graphically. 
There may be circumstances when a decision is made to stop collection, not perform, or 
discontinue the analysis of PD or biomarker samples due to either practical or strategic reasons 
(e.g., inadequate sample numbers, issues related to the quality of samples, or issues related to 
the assay that precludes the analysis of samples). Under such circumstances, the sample size 
may be too small to perform any data analysis and the available data will only be listed as 
applicable. 
Additional analyses may be planned and reported separately from this study. 
10.1.8. Handling of Missing Values and Discontinuation 
For continuing events (e.g., AEs, concomitant medications), the status of the event continuing 
will be denoted in the listings. Other missing data will simply be noted as missing in appropriate 
tables/listings. 
For the purposes of reporting, participants continuing to receive study drug will have time-to-
event data (e.g., DOR) censored at the date of last documented disease assessment prior to the 
data cutoff date.  
Further details of censoring rules for efficacy analyses will be documented in the SAP. 
Participants who have disease progression and continue to receive treatment after progression 
will be considered as having documented progressive disease at the time of first progression. 

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10.3. Pharmacokinetic Analyses and PK/PD Analysis 
10.3.1. Pharmacokinetic Interpretation 
Concentrations of ivosidenib, nivolumab and ipilimumab might be used alone or combined with 
data from other studies for modelling activities such as population PK modelling and 
physiological based pharmacokinetic modeling, in order to support the development of 
ivosidenib. Pharmacokinetic parameters will be estimated using noncompartmental analysis 
methods. Descriptive statistics (i.e., number of subjects, mean, standard deviation, geometric 
mean and coefficient of variation, median, minimum, and maximum) will be used to summarize 
PK parameters of ivosidenib given in combination with nivolumab and ipilimumab for each 
dose and cohort; and where appropriate, for the entire population. Such parameters may include 
(but are not limited to) area under the concentration-vs-time curve (AUC) from 0 to time of last 
measurable concentration (AUC0-t), AUC from 0 to infinity (AUC0-∞), AUC over 1 dosing 
interval at steady state (AUCtau,ss), time to maximum concentration (Tmax), maximum 
concentration (Cmax), trough concentration (Ctrough), t½, apparent volume of distribution (Vd/F), 
and apparent clearance (CL/F). 
The relationships between dose and both Cmax and AUC will be explored graphically for dose 
proportionality where appropriate. Descriptive statistics (i.e., number of subjects, mean, 
standard deviation, geometric mean and coefficient of variation, median, minimum, and 
maximum) will be summarized for the PK concentration data over planned time points. 
The Pharmacokinetic Analysis Set will be used for summaries of PK data, as well as listings of 
derived parameters and concentration data for ivosidenib, nivolumab, and ipilimumab. 
Descriptive statistics will be used to summarize PK concentrations at different nominal time 
points across participants by dose and cohort. 
10.3.2. PK/PD Interpretation When Applicable 
Descriptive statistics, including but not limited to number of subjects, mean, and standard 
deviation, will be used to summarize plasma and tissue 2-HG concentrations at different 
nominal time points across participants by dose and cohort. The potential relationship between 
plasma exposure of ivosidenib and plasma 2-HG levels will be explored with descriptive and 
graphical methods as appropriate. Similar evaluation will be performed using tissue exposure 
of ivosidenib and tissue 2‑HG levels, if data permit.  
The Pharmacodynamic Analysis Set will be the primary analysis set for summaries and listing 
of 2‑HG concentrations and changes from baseline in circulating concentrations 2-HG. 
Details of the PK and PD analyses will be described in an analysis plan. 
CCI

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10.4. Interim Analyses 
A Bayesian 2-stage design with a futility interim analysis will be implemented for each 
expansion cohort. Futility analysis will be conducted for each cohort when approximately 
20 response-evaluable subjects have completed at least 4 cycles of treatment or discontinued 
study treatment. The following futility rule will be considered for the futility analysis:  
­ Cohort 1, anti-PD1/L1–naïve subpopulation: If there are 2 or fewer responders (based on 
unconfirmed CR or unconfirmed PR) of 20 subjects, enrollment may stop; otherwise, 
enrollment will continue. 
­ Cohort 2, anti-PD1/L1 previously treated subpopulation: If there are 0 or 1 responders (based 
on unconfirmed CR or unconfirmed PR) of 20 subjects, enrollment may stop; otherwise, 
enrollment will continue. 
Additional interim analyses may be conducted during the Expansion phase if necessary. The 
Sponsor may determine to terminate or further expand cohorts after the interim analyses.  
11. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigator will allow the monitors, the persons responsible for the audit, the 
representatives of the IRB/IEC, and of the Competent Authorities to have direct access to source 
data/documents. 
12. QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. Study Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
GCP, and with applicable regulatory requirement(s).  
Monitoring for this study will be performed by the structure mentioned in Section 1.  
If on-site monitoring cannot be accomplished, remote Source Data Verification may be 
performed in accordance with local regulations. 
Details of clinical site monitoring are documented in a Monitoring Plan. The Monitoring Plan 
describes in detail who will conduct the monitoring, at what frequency monitoring will be done, 
at what level of detail monitoring will be performed, and the distribution of monitoring reports. 
12.1.1. Before the Study 
The Investigator will allow the monitor to visit the site and facilities where the study will take 
place to ensure compliance with the protocol requirements. 
Training sessions may be organized for the Investigators and/or instruction manuals may be 
given to the Investigators. 

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12.1.2. During the Study 
The Investigator will allow the monitor to: 
­ review of the study site’s processes and procedures, 
­ verify appropriate clinical Investigator supervision of study site staff and third-party 
vendors, 
­ inspect the site, the facilities, and the material used for the study, 
­ meet all members of the team involved in the study, 
­ consult the documents relevant to the study, 
­ have access to the eCRFs and service provider’s database, 
­ check that the eCRFs have been filled out correctly, 
­ directly access source documents for comparison of data therein with the data in the eCRFs, 
­ verify that the study is carried out in compliance with the protocol and local regulatory 
requirements. 
The study monitoring will be carried out at regular intervals, depending on the recruitment rate 
and/or the investigation schedule, and arranged between the Investigator and monitor. 
All information dealt with during these visits will be treated as strictly confidential. 
12.2. Computerized Medical File 
If computerized medical files are used, and if the computer system allows, no change made in 
the medical files by the Investigator should obscure the original information. The record must 
clearly indicate that a change was made and clearly provide a means to locate and read the prior 
information (i.e., audit trail). The Investigator will save data at regular intervals. 
The Investigator must guarantee the integrity of the study data in the medical files by 
implementing security measures to prevent unauthorized access to the data and to the computer 
system. 
If the computerized medical files are considered as not validated by the Sponsor, the 
Investigator undertakes: 
­ at the start of the study, to print the medical files of all participants allowing a reliable 
verification of the study criteria (e.g., medical history/previous treatments/ characteristics of 
the studied disease documented within the period of time defined by the study protocol), 
­ during the study, to print in real time each data entry and each data change. 
The Investigator will personally sign, date, and give the number of pages on the first or last 
page of each print-out. At each visit by the monitor, the Investigator will provide all the print-
outs of the medical files of the participants. The monitor will personally sign and date the first 
(or last) page then initial all pages in each paper print-out. 
If the computer system allows the tracking of the changes made to the medical files, the 
Investigator will supply the monitor, at each visit, with a print-out of the medical files of the 
participants and the records of the changes made. Each print-out will be personally dated and 
signed by the Investigator and the monitor on the first page. The number of pages will also be 
indicated by the Investigator and the monitor on the first page. 

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If the computerized medical files are considered as validated by the Sponsor, the Investigator 
undertakes to give access to the monitor to the computerized medical files of all participants. If 
the monitor cannot access to the tracking of the changes made to the medical files, the 
Investigator will supply the monitor, at each visit, with a print-out of the records of the changes 
made to the medical files of the participants. Each print-out will be personally dated and signed 
by the Investigator and the monitor on the first page. The number of pages will also be indicated 
by the Investigator and the monitor on the first page. 
The Investigator undertakes to keep: 
­ all medical file print-outs signed and dated by the Investigator and by the monitor when the 
computer system is considered as not validated by the Sponsor, 
­ if the computer system used allows changes to be made, the print-outs of the audit trail when 
the computer system is considered as not validated by the Sponsor or when the monitor 
cannot access to the audit trail in the computer system, 
­ all original source documents (originals of specific examinations, informed consent forms, 
RTSM reports, or equivalent document). 
12.3. Audit - Inspection 
The Investigator should be informed that an audit by the Sponsor or its representative may be 
carried out before, during, or after the end of the study. 
If on-site auditing cannot be accomplished and is required, remote audit may be performed in 
accordance with local regulations. 
The Investigator should be informed that the Competent Authorities may also carry out an 
inspection in the facilities of the Sponsor and/or the study center(s). The Sponsor will inform 
the Investigators concerned immediately upon notification of a pending study center inspection 
in case the notification is not sent directly to the Investigator. Likewise, the Investigator will 
inform the Sponsor of any pending inspection notification received related to the study. 
The Investigator must allow the representatives of the Competent Authorities and persons 
responsible for the audit:  
­ to inspect the site, facilities, and material used for the study, 
­ to meet all members of the team involved in the study, 
­ to have direct access to study data and source documents, 
­ to consult all the documents relevant to the study. 
If the computerized medical file is considered as not validated, the Investigator undertakes to 
provide all the source documents and the print-outs of the medical files of the participants and, 
if the computer system used allows, the record of the changes made during the study. 
If the computerized medical file is considered as validated, the Investigator undertakes to: 
­ give access to the representatives of the Competent Authorities and persons responsible for 
the audit to the computerized medical files of all participants, 
­ provide the print-outs of the changes made during the study, if the tracking of the changes 
made to the medical files cannot be accessed in the computer. 

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12.4. Supervisory Committees 
Not applicable. 
13. ETHICS 
13.1. Institutional Review Board(s)/Independent Ethics Committee(s) 
The study protocol, the “Participant information and consent form” document, the “Legal 
representative information and consent form” document, the list of Investigators document, the 
insurance documents, and the SmPC or IB of administered IMPs will be submitted to (an) 
IRB(s)/IEC(s) by the Investigator(s) or the national coordinator(s) or the Sponsor in accordance 
with local regulations. 
The study will not start in a center before written approval by corresponding IRB/IEC(s) has 
been obtained, the local regulatory requirements have been complied with, and the signature of 
the clinical study protocol of each contractual party involved has been obtained. 
13.2. Study Conduct 
The study will be performed in accordance with the ethical principles stated in the Declaration 
of Helsinki 1964 (see Appendix 1), with GCP, and with the applicable regulatory requirements. 
13.3. Participant Information and Informed Consent 
In any case, the participant (and/or his/her legal representative, when required) must be 
informed that he/she is entitled to be informed about the outcome of the study by the 
Investigator. 
The Investigator or a person designated by him/her is required to collect written consent from 
each participant before his/her participation in the study. Prior to this, the Investigator or his/her 
delegate must inform each participant of the objectives, benefits, risks and requirements 
imposed by the study, as well as the nature of the IMPs. If applicable, the Investigator may 
advise the participant about donation and cryopreservation of germ cells in line with 
recommendations on contraception provided. The participant must be informed that he/she has 
the possibility not to participate in the study and that he/she is free to reconsider his/her consent 
at any time. 
The participant will be provided with an information and consent form in clear, simple 
language. He/she must be allowed ample time to inquire about details of the study and to decide 
whether or not to participate in the study. 
One, or two if required by local regulation, original information and consent form(s) must be 
completed, dated and signed personally by the participant and by the person responsible for 
collecting the informed consent. 
According to each study participant own preference, ICF could be made available both printed 
on paper or/and electronically through a HIPAA, 21 CFR part 11 and GDPR compliant web-
based platform. Local regulations permitting, the electronic signature for the ICF could be made 
available to interested study participants. 

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If the participant is unable to read, an impartial witness should be present during the entire 
informed consent discussion. The participant must give consent orally and, if capable of doing 
so, complete, sign and personally date the information and consent form(s). The witness must 
then complete, sign and date the form(s) together with the person responsible for collecting the 
informed consent. 
The participant will be given one signed copy (or original if required by local regulation) of the 
information and consent form. A signed original will be kept by the Investigator. A copy of the 
information and consent form in the language(s) of the country is given in the “Participant 
information and consent form” document attached to the protocol.  
Interested study participants will be offered the possibility to replace certain in-person visits to 
the research site by televisits (where possible). This means that some study visits could be 
conducted using a HIPAA, 21 CFR part 11 and GDPR compliant web-based platform, as per 
each study participant own preference. 
This follow-up (for survival status until the end of the study) can be done remotely by using 
various telecommunication technologies including but not limited to phone, web-based remote 
video-calling, and shared electronic medical records. 
13.4. Modification of the Information and Consent Form 
Any change to the information and consent form constitutes an amendment to this document 
and must be submitted for approval to the IRB/IEC(s), and if applicable to the Competent 
Authorities. 
A copy of the new version(s) of the information and consent form(s) in the language(s) of the 
country will be given in the amendment to the “Participant Information and consent form”. 
Such amendments may only be implemented after written approval of the IRB/IEC has been 
obtained and compliance with the local regulatory requirements, except for an amendment 
required to eliminate an immediate risk to the study participants. 
Each participant affected by the amendment must complete, date and co-sign one, or two if 
required by local regulation, original(s) of the new version of the information and consent form 
together with the person who collected the informed consent (and an independent witness, if 
applicable). They will receive one signed copy (or original, if required by local regulation) of 
the amendment to the information and consent form(s). The signed original(s) will be kept by 
the Investigator. 

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14. DATA HANDLING AND RECORD KEEPING 
14.1. Study Data 
A 21 CFR Part 11-compliant electronic data capture system will be used in this study. An eCRF 
is designed to record the data required by the protocol and collected by the Investigator. 
The eCRF will be produced by I.R.I.S. or Servier Full Service Provider (FSP) Data 
Management in compliance with its specifications. The Investigator or a designated person 
from his/her team will be trained for the use of the eCRF by the Sponsor, or Servier FSP Data 
Management. 
Data entry at the Investigator’s site will be performed by the Investigator or by the designated 
person from his/her team after completion of the participant’s Medical File. 
The Investigator or the designated person from his/her team agrees to complete the eCRF, at 
each participant visit, and all other documents provided by the Sponsor (e.g., documents 
relating to the IMP management). 
Data recorded directly on the eCRF and considered as source data (see Section 4.3) must be 
collected immediately in the eCRF. The other eCRF forms must be completed as soon as 
possible following each visit. 
All corrections of data on the eCRF must be made by the Investigator or by the designated 
person from his/her team in electronic data capture (EDC) system according to the provided 
instructions. All data modification will be recorded using the audit trail feature of EDC system, 
including date, reason for modification, and identification of the person who has made the 
change.  
To ensure confidentiality and security of the data, usernames and passwords will be used to 
restrict system access to authorized personnel only, whether resident within the Investigator’s 
sites, the Sponsor, or third parties. Data will be verified in accordance with the monitoring 
strategy defined for the study. After comparing these data to the source documents, the monitor 
will request correction/ clarification from the Investigator using electronic data clarifications 
that should be answered and closed as quickly as possible.  
Data can be frozen during the study after their validation. However, the Investigator has the 
possibility to modify a data if deemed necessary via a request to the Sponsor. 
The Investigator or authorized member for sign-off must confirm the authenticity of the data 
recorded in the eCRF by signing-off the eCRF in a timely manner as defined in the eCRF guide.  
14.2. Data Management 
Data are collected via an eCRF and stored in a secured database. 
In case of data exceptionally collected on paper form, the clinical Data Management of I.R.I.S. 
or the CRO is responsible for the data entry processing. 

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For data collected on the eCRF, Servier FSP Data Management is responsible for data 
processing including data validation performed according to a specification manual describing 
the checks to be carried out. As a result of data validation, data may require some changes. A 
query is submitted in the EDC system (Clinical One) for the Investigator/site to respond to and 
make any necessary changes to the data.  
The Medical Review Department is responsible for data coding including:  
­ medical/surgical history, AEs, and procedures using MedDRA  
­ medications using World Health Organization, Drug Dictionary (WHO-Drug) 
The coding process is described in a specification manual. 
The Investigator ascertains he/she will apply due diligence to avoid protocol deviations. Under 
no circumstances should the Investigator contact the Sponsor or its representatives monitoring 
the study, if any, to request approval of a protocol deviation, as no deviations are permitted. If 
the Investigator feels a protocol deviation would improve the conduct of the study, this must be 
considered as a protocol amendment, and unless such an amendment is agreed upon by the 
Sponsor and approved by the IRB/IEC, it cannot be implemented. All-important protocol 
deviations will be recorded and reported in the CSR. 
When data validation is achieved, a review of the data is performed according to the Sponsor 
standard operating procedure, as applicable. When the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis. 
14.3. Archiving 
The Investigator will keep all information relevant to the study for at least 25 years after the 
end of the study, or more if specified by the local regulation.  
At the end of the study, the Investigator or an authorized member of his/her team will download 
an electronic copy of each participant’s data from the eCRF and should keep it in a reliable, 
secure, and durable location. The file includes all data and comments reported in the eCRF, the 
history of all queries and signatures, and the full audit trail reports.  
The file must include appropriate restrictions (password protection) and adequate protection 
from loss, physical damage, or deterioration for the duration of the archiving period. 
15. INSURANCE 
I.R.I.S., or any affiliated company of SERVIER GROUP in charge of the management of 
clinical trials, is insured under the liability insurance program subscribed by LES 
LABORATOIRES SERVIER to cover its liability as Sponsor of clinical trials on a worldwide 
basis. 
Where an indemnification system and/or a mandatory policy are in place, I.R.I.S. or any 
affiliated company of SERVIER GROUP will be insured under a local and specific policy in 
strict accordance with any applicable law.  
All relevant insurance documentation is included in the file submitted to any authorities’ 
approval of which is required. 

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16. OWNERSHIP OF THE RESULTS – DATA SHARING POLICY AND 
PUBLICATION POLICY 
I.R.I.S., acting as the Study Sponsor, assumes full responsibilities relating to this function and 
retains exclusive property rights over the results of the study, which it may use as it deems fit.  
I.R.I.S. will ensure that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report, the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
Any project of publication and/or communication relative to the study and/or relative to the 
obtained results during the study or after the study end shall be submitted to the Sponsor in 
accordance with the guidelines set forth in the applicable publication policy or financial 
agreement. 
The Investigator, who submitted the project, shall take the Sponsor’s comments into due 
consideration.  
Servier’s Data Sharing Policy is available at https://clinicaltrials.servier.com/data-request-
portal/. Researchers can ask for a study protocol, subject-level and/or study-level clinical trial 
data including CSRs. 
They can ask for all interventional clinical studies: 
­ submitted for new medicines and new indications approved after 01 January 2014 in the 
European Economic Area (EEA) or the US 
­ where Servier or an affiliate is the Marketing Authorization Holder. The date of the first 
Marketing Authorization of the new medicine (or the new indication) in one of the EEA 
Member States will be considered within this scope. 
In addition, Servier’s Data Sharing Policy includes all interventional clinical studies in subjects: 
­ sponsored by Servier 
­ with a first subject enrolled as of 01 January 2004 onward 
­ for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for 
which development has been terminated before any Marketing Authorization approval 
The datasets generated and/or analyzed during the current study will be available upon request 
from www.clinicaltrials.servier.com after the Marketing Authorization has been granted. 
Summary results and a lay summary will be published on www.clinicaltrials.servier.com within 
12 months after the end of the study. 
17. ADMINISTRATIVE CLAUSES 
17.1. Concerning the Sponsor and the Investigator 
17.1.1. Persons to Inform 
In accordance with local regulations, the Investigator and/or the Sponsor will inform the 
Director of the medical institution, the pharmacist involved in the study, and the Director of the 
analysis laboratory. 

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17.1.2. Substantial Protocol Amendment and Amended Protocol 
If the protocol must be altered after it has been signed, the modification or substantial 
amendment must be discussed and approved by the Investigator and the Sponsor. 
The substantial protocol amendment must be drafted in accordance with the Sponsor standard 
operating procedure and an amended protocol must be signed by both parties. Both documents 
must be kept with the initial protocol. 
All substantial amendments and corresponding amended protocols must be sent by the 
Investigator(s) or the coordinator(s) or the Sponsor, in accordance with local regulations, to the 
IRB/IEC that examined the initial protocol. They can be implemented only after a favourable 
opinion of the IRB/IEC has been obtained, local regulatory requirements have been complied 
with, and the amended protocol has been signed, except for a measure required to eliminate an 
immediate risk to the study participants. 
When the submission is performed by the Investigator or the coordinator, the latter must 
transmit a copy of IRB/IEC’s new written opinion to the Sponsor, immediately upon receipt. 
Furthermore, the substantial amendment and amended protocol are to be submitted to the 
Competent Authorities in accordance with local regulations. 
17.1.3. Final Study Report 
The study report will be drafted by the Sponsor in compliance with I.R.I.S. standard operating 
procedure. 
The Sponsor’s representative and the Investigator must mutually agree on the final version. One 
copy of the final report must be dated and signed by the Investigator and the Responsible 
Medical Officer of the concerned Therapeutic Area. 
The CSR, the summary of the results of the clinical trial together with a summary that is 
understandable to a layperson will be submitted where applicable within 1 year after the end of 
the clinical trial worldwide. 
If the clinical trial is still ongoing but ended in the European countries, the statistical analysis 
will not be relevant before the end of the study worldwide. Therefore, the timelines defined 
above still apply.Concerning the Sponsor 
The Sponsor undertakes to: 
­ supply the Investigator with adequate and sufficient information concerning the IMP 
administered during the study to enable him/her to carry out the study, 
­ supply the Investigator with IB if the test drug is not marketed, 
­ supply the Investigator with SmPC, the one best suited to ensure participant safety, and any 
potential updated version during the study: 
 for the test drug if marketed, to be appended to the IB (Section 4 Guidance for the 
Investigator), 
 for all reference products used in the study. 
­ obtain any authorization to perform the study and/or import license for the IMP administered 
that may be required by the local authorities before the beginning of the study, 
­ provide the Investigator annually, or with another frequency defined by the local regulations, 
with a document describing study progress which is to be sent to the IRB/IEC(s), 

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­ take all the necessary precautions to maintain the safety of the processed data, in particular 
their confidentiality, their integrity and their availability, by assessing risks identified 
concerning personal data protection. The following measures will be implemented (non-
exhaustive):  
 Management of authorization to access to personal data (eCRF), 
 Identification and authentication measures before accessing personal data (eCRF), 
 Traceability measures for the access to and modification of personal data (eCRF), 
 Secured data transfer, 
 Time limit for storing personal data. 
­ handle any security breach by implementing an internal committee (including CISO, DPO, 
communication department) in order to qualify the security incident (information systems, 
nature and number of personal data impacted), to define an action plan for corrective actions 
and to notify to relevant person (authority and/or if needed individuals). 
17.3. Concerning the Investigator 
17.3.1. Confidentiality - Use of Information 
All documents and information given to the Investigator by the Sponsor with respect to 
ivosidenib and Study CL1-95031-006 are strictly confidential. 
The Investigator expressly agrees that data on his/her professional and clinical experience is 
collected by the Sponsor on paper and computer and stored for its sole use relating to its 
activities as the Sponsor of clinical trials, in accordance with GCP.  
He/she has a right to access, modify, and delete his/her own personal data by applying to the 
Sponsor. 
In case a participant wants to exercise his/her rights regarding personal data protection, he/she 
will contact the Investigator. The Investigator will forward the request to the Sponsor (see 
Appendix 6).  
The Investigator agrees that he/she and the members of his/her team will use the information 
only in the framework of this study, for carrying out the protocol. This agreement is binding as 
long as the confidential information has not been disclosed to the public by the Sponsor. The 
clinical study protocol given to the Investigator may be used by him/her or his/her colleagues 
to obtain the informed consent of study participants. The clinical study protocol as well as any 
information extracted from it must not be disclosed to other parties without the written 
authorization of the Sponsor. 
The Investigator must not disclose any information without the prior written consent from 
I.R.I.S., except to the representatives of the Competent Authorities, and only at their request. 
In the latter case, the Investigator commits himself/herself to informing I.R.I.S. prior to 
disclosure of information to these authorities. 
A participant screening log and a full identification and enrolment list of each participant will 
be completed and kept in a safe place by the Investigator who should agree to provide access 
on site to the auditor and/or the representatives of the Competent Authorities. The information 
will be treated in compliance with professional secrecy. 

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The participant screening log must be completed from the moment the Investigator checks that 
a participant could potentially take part in the study (by assessment of participant medical 
history during a visit or by examination of the medical file). 
17.3.2. Organization of the Center 
Every person to whom the Investigator delegates under his/her responsibility a part of the 
follow-up of the study (co-Investigator, nurse) and any other person involved in the study for 
this center (cardiologist, pharmacist) must figure in the “Organization of centre” document. 
This document should be filled in at the beginning of the study and updated at any change of a 
person involved in the study in the center. 
17.3.3. Documentation Supplied to the Sponsor 
The Investigator undertakes before the study begins: 
­ to provide his/her dated and signed English curriculum vitae (CV) (maximum 2 pages) or to 
complete in English the CV form provided by the Sponsor and to send it to the Sponsor, 
together with that of his/her co-Investigator(s), 
­ to provide a detailed description of the methods, techniques, and investigational equipment, 
and the reference values for the parameters measured, 
­ to provide any other document required by local regulation (e.g., Food & Drug 
Administration 1572 form), 
­ to send, a copy of the IRB/IEC’s opinion with details of its composition and the 
qualifications of its constituent members. 
The CVs of other members of the team involved in the study (if possible, in English) will be 
collected during the study (at least, members involved in the participants’ medical follow-
up/study-related decision process and persons involved in the measurement of main assessment 
criteria). 
17.3.4. Notification of a Serious Breach 
A serious breach is defined as any deviation of the approved protocol version or the clinical 
trial regulation that is likely to affect the safety, the rights of trial participants and/or data 
reliability and robustness to a significant degree in a clinical trial. 
The Investigator should immediately report any events that might meet the definition of a 
serious breach to the contact point designated by the Sponsor. S/he should ensure that the study 
site is able to identify the occurrence of a (suspected) serious breach and that any suspected 
serious breach is promptly reported to the Sponsor or delegated party. 

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Kendre Gajanan, Karthikeyan Murugesan, Tilman Brummer, Oreste Segatto, Anna Saborowski, and Arndt 
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Kim BJ, Yoo C, Kim KP, Hyung J, Park SJ, Ryoo BY, and Chang HM. 'Efficacy of fluoropyrimidine-based 
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Kim RD, Chung V, Alese OB, El-Rayes BF, Li D, Al-Toubah TE, Schell MJ, Zhou JM, Mahipal A, Kim BH, 
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Klein O, Kee D, Nagrial A, Markman B, Underhill C, Michael M, Jackett L, Lum C, Behren A, Palmer J, Tebbutt 
NC, Carlino MS, and Cebon J. 'Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in 
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Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, Falk S, Gillmore R, Wadsley J, Patel K, 
Anthoney A, Maraveyas A, Iveson T, Waters JS, Hobbs C, Barber S, Ryder WD, Ramage J, Davies LM, 
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versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, 
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Kumamoto, Koichi Taniguchi, and Itaru Endo. 'Single-institution experience with gemcitabine–cisplatin 
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Notarangelo G, Spinelli JB, Perez EM, Baker GJ, Kurmi K, Elia I, Stopka SA, Baquer G, Lin JR, Golby AJ, 
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P, Li W, Wu S, Zhang Q, Rebelatto MC, and Kim JW. 'Gemcitabine and cisplatin plus durvalumab with or 
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Rugo HS, de Braud F, Varga AI, Hansen A, Wang H, Krishnan S, Norwood KG, and Doi T. 'Efficacy and safety 
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Saborowski, A, Lehmann U, and Vogel A. 'FGFR inhibitors in cholangiocarcinoma: what's now and what's 
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Wu MJ, Shi L, Dubrot J, Merritt J, Vijay V, Wei TY, Kessler E, Olander KE, Adil R, Pankaj A, Tummala KS, 
Weeresekara V, Zhen Y, Wu Q, Luo M, Shen W, Garcia-Beccaria M, Fernandez-Vaquero M, Hudson C, 
Ronseaux S, Sun Y, Saad-Berreta R, Jenkins RW, Wang T, Heikenwalder M, Ferrone CR, Goyal L, Nicolay B, 
Deshpande V, Kohli RM, Zheng H, Manguso RT, and Bardeesy N. 'Mutant IDH Inhibits IFNgamma-TET2 
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CPMP/ICH/377/95. 
DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001 on 
the approximation of the laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use). 
Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials 
on medicinal products for human use. 

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19. APPENDICES 
 
 

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Appendix 1: World Medical Association Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles. 
General Principles 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my subject will be my first consideration,” and the International Code of Medical 
Ethics declares that “A physician shall act in the subject’s best interest when providing 
medical care.” 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights 
of subjects, including those who are involved in medical research. The physician’s 
knowledge and conscience are dedicated to the fulfilment of this duty. 
5. 
Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. 
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
7. 
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 

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8. 
While the primary purpose of medical research is to generate new knowledge, this goal 
can never take precedence over the rights and interests of individual research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, even though they have given consent. 
10. 
Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
11. 
Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12. 
Medical research involving human subjects must be conducted only by individuals with 
the appropriate ethics and scientific education, training and qualifications. Research on 
subjects or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
13. 
Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. 
Physicians who combine medical research with medical care should involve their subjects 
in research only to the extent that this is justified by its potential preventive, diagnostic 
or therapeutic value and if the physician has good reason to believe that participation in 
the research study will not adversely affect the health of the subjects who serve as research 
subjects. 
15. 
Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
Risk, Burdens, and Benefits 
16. 
In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the risks and burdens to the research subjects. 
17. 
All medical research involving human subjects must be preceded by careful assessment 
of predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected 
by the condition under investigation. 

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Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. 
Physicians may not be involved in a research study involving human subjects unless they 
are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 
Vulnerable Groups and Individuals 
19. 
Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. 
Medical research with a vulnerable group is only justified if the research is responsive to 
the health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
22. 
The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, Sponsors, institutional affiliations, potential 
conflicts of interest, incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 

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Research Ethics Committees 
23. 
The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the Sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research 
is to be performed as well as applicable international norms and standards, but these must 
not be allowed to reduce or eliminate any of the protections for research subjects set forth 
in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without consideration 
and approval by the committee. After the end of the study, the researchers must submit a 
final report to the committee containing a summary of the study’s findings and 
conclusions. 
Privacy and Confidentiality 
24. 
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent 
25. 
Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members 
or community leaders, no individual capable of giving informed consent may be enrolled 
in a research study unless he or she freely agrees. 
26. 
In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, 
any possible conflicts of interest, institutional affiliations of the researcher, the anticipated 
benefits and potential risks of the study and the discomfort it may entail, post-study 
provisions and any other relevant aspects of the study. The potential subject must be 
informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to deliver 
the information. 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely 
given informed consent, preferably in writing. If the consent cannot be expressed in 
writing, the non-written consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 

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27. 
When seeking informed consent for participation in a research study the physician must 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28. 
For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
29. 
When a potential research subject who is deemed incapable of giving informed consent 
is able to give assent to decisions about participation in research, the physician must seek 
that assent in addition to the consent of the legally authorised representative. The potential 
subject’s dissent should be respected. 
30. 
Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious subjects, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research group. 
In such circumstances the physician must seek informed consent from the legally 
authorised representative. If no such representative is available and if the research cannot 
be delayed, the study may proceed without informed consent provided that the specific 
reasons for involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved by a 
research ethics committee. Consent to remain in the research must be obtained as soon as 
possible from the subject or a legally authorised representative. 
31. 
The physician must fully inform the subject which aspects of their care are related to the 
research. The refusal of a subject to participate in a study or the subject’s decision to 
withdraw from the study must never adversely affect the subject-physician relationship. 
32. 
For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 

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Use of Placebo 
33. 
The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; 
or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention 
is necessary to determine the efficacy or safety of an intervention and the subjects who 
receive any intervention less effective than the best proven one, placebo, or no 
intervention will not be subject to additional risks of serious or irreversible harm as a 
result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. 
In advance of a clinical trial, Sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. 
Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. 
Researchers, authors, Sponsors, editors and publishers all have ethical obligations with 
regard to the publication and dissemination of the results of research. Researchers have a 
duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere 
to accepted guidelines for ethical reporting. Negative and inconclusive as well as positive 
results must be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not 
be accepted for publication. 
Unproven Intervention in Clinical Practice 
In the treatment of an individual subject, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed 
consent from the subject or a legally authorised representative, may use an unproven 
intervention if in the physician’s judgment it offers hope of saving life, re-establishing health 
or alleviating suffering. This intervention should subsequently be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available. 

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Appendix 2: Subject Registration Form 
Dose allocation - Subject Registration Form  
PARTICIPANT REGISTRATION FORM SAFETY LEAD IN / CL1-95031-006 
Centre n° : |__|__|__|__| - Participant n°(= e-CRF n°): |__|__|__|__|__| 
Please complete Section A and return to sponsor department  
by e-mail to S95031-006@servier.com 
Section A 
To be completed once Informed Consent Form signed 
Participant identification : 
Year of birth (yyyy): |__|__|__|__|      Gender:  Male  Female 
Diagnosis of the primary tumor type :………………………………  
Participant Informed Consent Form signature date (dd/mm/yyyy): |__|__| / |__|__| / |__|__|__|__| 
Expected baseline completion date (dd/mm/yyyy): |__|__| / |__|__| / |__|__|__|__| 
Section A completed by:……………………………… 
Please complete Section B and return to sponsor department  
by e-mail to S95031-006@servier.com 
Section B 
To be completed after baseline period 
Investigator name: ……………………………… 
Does the Participant comply with all inclusion/exclusion criteria?  Yes  No 
If yes, inclusion date (dd/mm/yyyy) : |__|__| / |__|__| / |__|__|__|__|  
Section B completed by:…………………………… 
Date: |__|__| / |__|__| / |__|__|__|__|    Signature:……………….…………………………………….. 
Section C 
Sponsor or its designee 
IVOSIDENIB dose: 
|__|__|__| mg  
Section C completed by:…………………………… 
Date and signature of the sponsor Medical Monitor:……………….……………………. 
 
Filing in Sponsor TMF (if applicable) and Investigator TMF 
 

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Appendix 3: Subject Performance Status 
Status 
Karnofsky 
Grade 
Status 
ECOG* - ZUBROD / WHO 
Normal, no complaints; no evidence of 
disease. 
100 
0 
Fully active, able to carry on all pre-
disease performance without 
restriction. 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
90 
 
Normal activity with efforts; some signs or 
symptoms of disease. 
80 
1 
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or sedentary 
nature, e.g., light housework, office 
work. 
Cares for self; unable to carry on normal 
activity or to do active work. 
70 
Requires occasional assistance but is able to 
care for most of his personal needs. 
60 
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. 
Requires considerable assistance and 
frequent medical care. 
50 
Disabled; requires special care and 
assistance. 
40 
3 
Capable of only limited self-care,  
confined to bed or chair more than 
50% of waking hours. 
Severely disabled; hospital admission is 
indicated although death not imminent. 
30 
Very sick; hospital admission necessary; 
Active supportive treatment necessary. 
20 
4 
Completely disabled.  
Cannot carry on any self-care.  
Totally confined to bed or chair. 
Moribund; fatal processes progressing 
rapidly. 
10 
Dead 
0 
5 
Dead 
* As published in Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and Response Criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol 1982,5 649-655. 

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Appendix 4: New Response Evaluation Criteria in Solid Tumors: Revised RECIST 
Guideline (Version 1.1), Eisenhauer, 2009 
Measurability of tumor at baseline 
At baseline, tumor lesions/lymph nodes will be categorised measurable or non-measurable as 
follows: 
Measurable 
Tumor lesions: Must be accurately measured in at least one 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 calliper measurement by clinical exam (lesions which cannot be accurately measured 
with callipers 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 ≥ 15 mm in short axis when assessed by CT-scan (CT-scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed.  
Non-measurable 
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. Lesions 
considered truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial 
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. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
­ Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be 
used to confirm the presence or disappearance of bone lesions. 
­ Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
­ Blastic bone lesions are non-measurable. 
Cystic lesions: 
­ Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
­ ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same subject, these are preferred for selection as target lesions. 

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Lesions with prior local treatment: 
­ Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such 
lesions would be considered measurable. 
Tumor response evaluation 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. 
Only subjects with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint. Measurable disease is defined by the presence 
of at least one measurable lesion. In studies where the primary endpoint is tumor progression 
(either time to progression or proportion with progression at a fixed date), the protocol must 
specify if entry is restricted to those with measurable disease or whether subjects having non-
measurable disease only are also eligible. 
Baseline Documentation of ‘Target’ and ‘Non-target’ Lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where subjects have only 1 or 2 organ sites involved a maximum of 2 and 4 lesions 
respectively will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal, or coronal). The smaller of these measures is the short axis. 
For example, an abdominal node that is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis ≥ 10 mm 
but < 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm 
are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterise any objective tumor regression 
in the measurable dimension of the disease. 

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All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not required, 
and these lesions should be followed as ‘present’, ‘absent’, or in rare cases, ‘unequivocal 
progression’ (more details to follow). In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (e.g., ‘multiple 
enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
Evaluation of target lesions: 
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. 
Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive disease: At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered 
progression). 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for progressive disease, taking as reference the smallest sum diameters while on study. 
Special Notes on the Assessment of Target Lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when lymph 
nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if CR criteria 
are met because a normal lymph node is defined as having a short axis of < 10 mm. Case report 
forms or other data collection methods may therefore be designed to have target nodal lesions 
recorded in a separate section where, in order to qualify for CR, each node must achieve a short 
axis < 10 mm. For PR, SD, and progressive disease, the actual short axis measurement of the 
nodes is to be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT-scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being ‘too small 
to measure’. When this occurs, it is important that a value be recorded on the eCRF. If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned (Note: It is less likely that this rule will 
be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well). This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness). The 
measurement of these lesions is potentially non-reproducible; therefore, providing this default 

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value will prevent false responses or progressions based upon measurement error. To reiterate, 
however, if the radiologist is able to provide an actual measure, that should be recorded, even 
if it is below 5 mm. 
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
Evaluation of Non-target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete response (CR): Disappearance of all non-target lesions and normalisation of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-progressive disease: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive disease: Unequivocal progression (see comments below) of existing non-target 
lesions. (Note: the appearance of one or more new lesions is also considered progression). 
Special Notes on Assessment of Progression of Non-target Disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the subject also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to quality for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the subject has only non-measurable disease. This circumstance arises in some Phase 3 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are truly non-measurable) a useful test that can be applied when assessing subjects for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare progressive disease for measurable disease: i.e., an increase in tumor burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase 
diameter in a measurable lesion). Examples include an increase in a pleural effusion from 
‘trace’ to ‘large’, an increase in lymphangitic disease from localised to widespread, or may be 
described in protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal 
progression’ is seen, the subject should be considered to have had overall progressive disease 
at that point. While it would be ideal to have objective criteria to apply to non-measurable 
disease, the very nature of that disease makes it impossible to do so, therefore the increase must 
be substantial. 

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New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e., not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the subject’s baseline lesions show PR or CR. For example, necrosis of a liver 
lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the subject who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The subject’s brain metastases are considered to be evidence 
of progressive disease even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, then progression should be declared using the date of the initial scan. 
While fluorodeoxyglucose (FDG)-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning 
in assessment of progression (particularly possible ‘new’ disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
­ Negative FDG-PET at baseline, with a positive FDG-PET (a ‘positive’ FDG-PET scan lesion 
means one which is FDG avid with an uptake greater than twice that of the surrounding 
tissue on the attenuation corrected image) at follow-up is a sign of progressive disease based 
on a new lesion. 
­ No FDG-PET at baseline and a positive FDG-PET at follow-up: 
 If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is progressive disease. 
 If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of progressive disease will be the date of the initial 
abnormal FDG-PET scan). 
 If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not progressive disease. 
Evaluation of Best Overall Response 
The BOR is the best response recorded from the start of the study treatment until the end of 
treatment taking into account any requirement for confirmation. On occasion a response may 
not be documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of BOR. Protocols must specify how any 
new therapy introduced before progression will affect best response designation. The subject’s 
best overall response assignment will depend on the findings of both target and non-target 
disease and will also take into consideration the appearance of new lesions. Furthermore, 
depending on the nature of the study and the protocol requirements, it may also require 
confirmatory measurement. Specifically, in non-randomised trials where response is the 
primary endpoint, confirmation of PR or CR is needed to deem either one the BOR. 

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Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs. Table 1 
provides a summary of the overall response status calculation at each time point for subjects 
who have measurable disease at baseline. 
Table 1: Time Point Response: Subjects with Target (± Non-target) Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations  CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable. 
When subjects have non-measurable disease only (therefore non-target), Table 2 is to be used. 
Table 2: Time Point Response: Subjects with Non-target Disease Only 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
on-CR/non-PD1 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations  CR = complete response; PD = progressive disease; NE = not evaluable. 
1 = Non-CR/non-PD’ is preferred over stable disease’ for non-target disease since SD is increasingly used as endpoint for assessment of 
efficacy in some trials so to assign this category when no lesions can be measured is not advised. 
Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular time point, the subject is NE at that 
time point. If only a subset of lesion measurements are made at an assessment, usually the case 
is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point 
response. This would be most likely to happen in the case of progressive disease. For example, 
if a subject had a baseline sum of 50 mm with 3 measured lesions and at follow-up only 2 
lesions were assessed, but those gave a sum of 80 mm, the subject will have achieved 
progressive disease status, regardless of the contribution of the missing lesion. 
Best Overall Response: All Time Points 
The BOR is determined once all the data for the subject is known. 
Best response determination in trials where confirmation of CR or PR is not required: best 
response in these trials is defined as the best response across all time points (for example, a 
subject who has SD at first assessment, PR at second assessment, and progressive disease on 
last assessment has a best overall response of PR). When SD is believed to be best response, it 
must also meet the protocol specified minimum time from baseline. If the minimum time is not 
met when SD is otherwise the best time point response, the subject’s best response depends on 
the subsequent assessments. For example, a subject who has SD at first assessment, progressive 
disease at second and does not meet minimum duration for SD, will have a best response of 

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progressive disease. The same subject lost to follow-up after the first SD assessment would be 
considered inevaluable. 
Best response determination in trials where confirmation of CR or PR is required: CR or PR 
may be claimed only if the criteria for each are met at a subsequent time point as specified in 
the protocol (generally 4 weeks later). In this circumstance, the BOR can be interpreted as in 
Table 3. 
Table 3: Best Overall Response When Confirmation of CR and PR Required 
Overall response 
First time point 
Overall response 
Subsequent time point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR1 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
Abbreviations  CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable. 
1 = If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to 
baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whether minimum 
duration for SD was met. However, sometimes CR’ may be claimed when subsequent scans suggest small lesions were likely still present and 
in fact the subject had PR, not CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that subjects with CR may 
not have a total sum of ‘zero’ on the eCRF. 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression. For 
example, in most trials it is reasonable to consider a subject with time point responses of PR-
NE-PR as a confirmed response. 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such subjects is to be determined by evaluation of target and non-target disease as shown in 
Tables 1 through 3. 

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Conditions that define ‘early progression, early death and inevaluability’ are study specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use 
of FDG-PET in this circumstance should be prospectively described in the protocol and 
supported by disease specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
Frequency of Tumor Re-evaluation 
Frequency of tumor re-evaluation while on treatment should be protocol specific and adapted 
to the type and schedule of treatment. However, in the context of Phase 2 studies where the 
beneficial effect of therapy is not known, follow-up every 6 to 8 weeks (timed to coincide with 
the end of a cycle) is reasonable. Smaller or greater time intervals than these could be justified 
in specific regimens or circumstances. The protocol should specify which organ sites are to be 
evaluated at baseline (usually those most likely to be involved with metastatic disease for the 
tumor type under study) and how often evaluations are repeated. Normally, all target and non-
target sites are evaluated at each assessment. In selected circumstances certain non-target 
organs may be evaluated less frequently. For example, bone scans may need to be repeated only 
when CR is identified in target disease or when progression in bone is suspected. 
After the end of the treatment, the need for repetitive tumor evaluations depends on whether 
the trial has as a goal the response rate or the time to an event (progression/death). If ‘time to 
an event’ (e.g., time to progression, disease-free survival, PFS) is the main endpoint of the 
study, then routine scheduled re-evaluation of protocol specified sites of disease is warranted. 
In randomised comparative trials in particular, the scheduled assessments should be performed 
as identified on a calendar schedule (for example: every 6–8 weeks on treatment or every 
3-4 months after treatment) and should not be affected by delays in therapy, drug holidays, or 
any other events that might lead to imbalance in a treatment arm in the timing of disease 
assessment. 
Confirmatory Measurement/Duration of Response 
Confirmation 
In non-randomised trials where response is the primary endpoint, confirmation of PR and CR 
is required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, i.e., in 
randomised trials (Phase 2 or 3) or studies where SD or progression are the primary endpoints, 
confirmation of response is not required since it will not add value to the interpretation of trial 
results. However, elimination of the requirement for response confirmation may increase the 
importance of central review to protect against bias, in particular in studies which are not 
blinded. 

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In the case of SD, measurements must have met the SD criteria at least once after study entry 
at a minimum interval (in general not less than 6–8 weeks) that is defined in the study protocol. 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease 
is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment (in randomised trials, from date of 
randomisation) until the criteria for progression are met, taking as reference the smallest sum 
on study (if the baseline sum is the smallest, this is the reference for calculation of progressive 
disease). 
The clinical relevance of the duration of SD varies in different studies and diseases. If the 
proportion of subjects achieving SD for a minimum period of time is an endpoint of importance 
in a particular trial, the protocol should specify the minimal time interval required between 
2 measurements for determination of SD. 
Note: The duration of response and SD as well as the PFS are influenced by the frequency of 
follow-up after baseline evaluation. It is not in the scope of this guideline to define a standard 
follow-up frequency. The frequency should take into account many parameters including 
disease types and stages, treatment periodicity, and standard practice. However, these 
limitations of the precision of the measured endpoint should be taken into account if 
comparisons between trials are to be made. 
 

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Appendix 6: Instructions to Investigator for Handling Data Rights Requests 
 
DATA PROTECTION / GDPR (General Data Protection Regulation of 27 April 2016 
n°2016/679)–  
INSTRUCTIONS 
TO 
INVESTIGATOR 
FOR 
HANDLING 
DATA 
RIGHTS 
REQUESTS 
In the framework of a research study/clinical trial, a participant to the study may exercise his/her 
rights, i.e., may ask I.R.I.S. (as data controller) for:  
­ access to his/her data 
­ rectification of inaccurate/incomplete information 
­ restriction of processing of data 
­ objection to processing of data 
­ data portability (receiving his/her data in a readable format) 
 
In accordance with the Informed Consent Form and information notice provided to participant, 
we requested participant to contact you first for exercising their rights.  
Request for exercise of rights: 
20. has to be a written one (either originating from mail or email from a participant or from 
request expressed orally to you and put in written) 
21. has to be sent by you by email or by mail to I.R.I.S. (as data controller) to central address 
dataprivacy@servier.com or local Servier address as mentioned in ICF/information 
notice provided/available  
 
DO 
Instructions to be followed by you 
DO NOT 
What you should not do 
Email title: Data protection rights 
Do not forward participant email (if applicable) 
Study name/number 
 
Participant number 
No information regarding participant 
identity:  
No participant’s name, email address, 
participant’s signature 
As soon as possible without exceeding a 
week 
 
 

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I.R.I.S. and INVESTIGATOR responsibilities  
GDPR requirement:  
It is mandatory for I.R.I.S. as data controller to provide an answer to 
participant/volunteer within 1 month following the request (article 12 of GDPR) 
Clinical trials requirements:  
It is prohibited for I.R.I.S. as a Sponsor to know the identity of the 
participants/volunteer participating to studies  
 
 
I.R.I.S. responsibility 
Investigator responsibility 
Forward/inform I.R.I.S. 
of the request 
 
YES 
Timelines  
Answer within 1 month 
once expressed by the 
participant 
Request: transmitted to I.R.I.S. 
as soon as expressed by the 
participant 
 
Answer: transmitted by you to 
participant as soon as sent by 
I.R.I.S.  
Answer the request 
YES 
 
 
 
 

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Appendix 7: Contraception Considerations 
Definition of women of childbearing potential and contraception methods 
Women of childbearing Potential 
A woman is considered of childbearing potential (WOCBP), i.e., fertile, following menarche 
and until becoming postmenopausal unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A 
postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
Contraception methods 
Definition of highly effective contraception methods for the study:  
Highly effective methods of birth control refer to those which result in a low failure rate (i.e. 
less than 1% per year), when used consistently and correctly, such as combined hormonal 
contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), 
progestogen-only hormonal contraception when associated with inhibition of ovulation (oral, 
injectable, implantable), some intra-uterine devices, intrauterine hormone-releasing system, 
true sexual abstinence (when this is in line with the preferred and usual lifestyle of the 
participant), bilateral tubal occlusion, male sterilization (vasectomy).  
Definition of acceptable contraception methods for the study:  
Acceptable contraception methods for the study are those considered as highly effective 
methods, male or female condom with or without spermicide, cap, diaphragm or sponge with 
spermicide. 
 
 

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Appendix 9: Management Algorithms for Studies Under CTCAE Version 5.0 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology (IO) agents and regimens. 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
Corticosteroids are a primary therapy for IO drug-related AEs. The oral equivalent of the 
recommended IV doses may be considered for ambulatory subjects with low-grade toxicity. 
The lower bioavailability of oral corticosteroids should be taken into account when switching 
to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the IO agent or regimen being used. 

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Appendix 10: ECOG Performance Status and Prohibited Concomitant Medications 
Table 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, e.g., light housework, 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 MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5 649-655. 
 
Table 2 
Prohibited Concomitant Medications 
Prohibited medications and certain foods are not allowed in this study while subjects 
are receiving study drug. 
Strong CYP3A Inducers 
CYP3A Substrates with a Narrow Therapeutic 
Window 
Avasimibe, carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, rifabutin, St. 
John’s wort 
Alfentanil, astemizole1, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, everolimus, sirolimus, tacrolimus, 
terfenadine1 
Note 
that 
this 
is 
not 
an 
exhaustive 
list. 
For 
an 
updated 
list, 
see 
the 
following 
link  
http //www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm08 0499.htm 
“CYP 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 (e.g., Torsades de Pointes). 
1 Withdrawn from the United States market because of safety reasons. 
 
Table 3 
New York Heart Association Classification 
Class 
Symptomatology 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
II 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
III 
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. 
 

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Fridericia’s Formula 
QTcF = QT/RR1/3 
Table 4 
Medications Known to Prolong the QT Interval 
amiodarone 
dofetilide 
grepafloxacin 
moxifloxacin 
quinidine 
astemizole 
dolasetron 
halofantrine 
norfloxacin 
sevoflurane 
azithromycin 
domperidone 
haloperidol 
ofloxacin 
sotalol 
bepridil 
droperidol 
ibutilide 
ondansetron 
sparfloxacin 
chloroquine 
erythromycin 
itraconazole 
palonosetron 
terfenadine 
chlorpromazine 
escitalopram 
ketoconazole 
pentamidine 
thioridazine 
ciprofloxacin 
flecainide 
levofloxacin 
pimozide 
voriconazole 
citalopram 
gatifloxacin 
levomethadyl 
posaconazole 
 
clarithromycin 
gemifloxacin 
mesoridazine 
probucol 
 
disopyramide 
granisetron 
methadone 
procainamide 
 
For a complete and updated (ongoing) list of medications, please use the following link  https //crediblemeds.org/healthcare-providers/ 
 
Table 5 
Examples of Strong and Moderate CYP3A4 Inhibitors 
Moderate CYP3A4 Inhibitors 
Aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, 
dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, verapamil 
Strong CYP3A4 Inhibitors 
Boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole 
Ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole 
Ritonavir, saquinavir, telaprevir, telithromycin, voriconazole 
Note  Based on FDA guidelines; Investigators should follow local institutional guidelines, where appropriate. 
 
 

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Appendix 11: Examples of Low-Fat and High-Fat, High-Calorie Meals 
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) 
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. 
 
 
 

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Appendix 12: National Cancer Institute Common Terminology Criteria 
for Adverse Events 
The 
NCI 
CTCAE, 
version 
5.0 
can 
be 
accessed 
at 
the 
following 
location: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
RECIST v1.1 
Tumor lesions are to be categorized as measurable versus non-measurable and target versus 
non- target based on RECIST v1.1 (Eisenhauer 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 calliper measurement by clinical exam (lesions which cannot be accurately measured 
with callipers 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 ≥ 15 mm 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 pericardial 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. 
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.’ 

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The following criteria outlined in Table 6 and Table 7 will be used to assess response to 
treatment. 
Table 6: 
Disease Response Criteria for Target and Non-target Lesions 
Category 
Response 
Criteria 
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 
Not applicable 
Stable disease (SD) / 
incomplete response 
Neither sufficient shrinkage to qualify 
for PR 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 
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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Appendix 13: Local modification of the clinical study protocol (GBR) 
FINAL VERSION DATE: 
20 December 2023 
COUNTRY CONCERNED: 
United Kingdom 
CENTRES CONCERNED:  
All centres in United Kingdom 
NATURE OF MODIFICATIONS 
 
- 
Update of inclusion criteria 4 and Appendix 7 to clarify acceptable contraception 
methods.  
 
- 
In line with CTFG guidance, an additional pregnancy test to be performed at the end 
of the relevant systemic exposure; at the 100-day safety follow up visit.  
 
- 
Clarification added to section 8.4 that all SAEs must be reported to the sponsor 
immediately and within 24 hours of awareness at the latest.  
 
 
Paragraph impacted 5.1 Inclusion Criterion- 4 - Sex and Contraceptive/Barrier requirements 
Amended text:  
 
Women of childbearing potential (WOCBP) must agree to abstain from sexual intercourse or 
to use 2 forms of contraception, one of which must be highly effective and one a barrier method 
(Appendix 7) highly effective (Appendix 7) forms of contraception, at least one of which must 
be a barrier method, from the time of giving informed consent throughout the study, and for 
5 months after the last dose of study treatment. 
 
Paragraph impacted Appendix 7 - Contraception considerations 
Amended text:  
 
Definition of acceptable contraception methods for the study: Acceptable contraception 
methods for the study are those considered as highly effective methods, In addition to a highly 
effective method, the second form of contraception may include male or female condom with 
or without spermicide, cap, diaphragm or sponge with spermicide. 
 
Paragraph impacted 4.1.2 Investigational Schedule  
Amended text: a new cross (X) is present in the Table (4.1.2) 1 column safety follow-up 100 
(+5) Days After Last Nivolumab Dose and line pregnancy test. 
 
 

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Table (19) 1 - Schedule of Assessments for Subjects in the Safety Lead-in Phase and Expansion Phase 
Visit/Cycle 
Screening1 
Cycle 1 (21 Days) 
Cycle 2 
(21 Days) 
Cycles 3 
and 4 
(21 Days) 
Cycle 5 and 
Beyond 
(28 Days 
Each Cycle) 
End of 
Treatment2 
Safety Follow-up2 
PFS 
Follow-
up3 
Survival 
Follow-
up 
Study Day 
D-28 to  
D-1 
D1 
D8 
D15 
(± 2 
Days) 
D1 
(± 2 
Days) 
D15 
(± 2 
Days) 
D1 
(± 2 Days) 
D1 
(± 2 Days) 
Within 7 
Days After 
Last Dose 
30 (+5) 
Days 
After 
Last 
Dose 
100 (+5) 
Days After 
Last 
Nivolumab 
Dose 
 
Every 
12 
weeks 
(± 2 
weeks) 
Allocation to 
IMP4 
 
X 
 
 
X 
 
X 
X 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusio
n Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Disease History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical 
Exam  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical 
Exam  
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Height and 
Weight5 
X 
X 
 
 
X 
 
X 
X 
 
 
 
 
 
ECOG 
Performance 
Status 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
 
Vital Signs6 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
12-lead ECG7,8 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
LVEF (ECHO, 
MUGA scan, or 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Visit/Cycle 
Screening1 
Cycle 1 (21 Days) 
Cycle 2 
(21 Days) 
Cycles 3 
and 4 
(21 Days) 
Cycle 5 and 
Beyond 
(28 Days 
Each Cycle) 
End of 
Treatment2 
Safety Follow-up2 
PFS 
Follow-
up3 
Survival 
Follow-
up 
Study Day 
D-28 to  
D-1 
D1 
D8 
D15 
(± 2 
Days) 
D1 
(± 2 
Days) 
D15 
(± 2 
Days) 
D1 
(± 2 Days) 
D1 
(± 2 Days) 
Within 7 
Days After 
Last Dose 
30 (+5) 
Days 
After 
Last 
Dose 
100 (+5) 
Days After 
Last 
Nivolumab 
Dose 
 
Every 
12 
weeks 
(± 2 
weeks) 
by other method 
according to 
institutional 
practice) 
 
 
 
Hematology9  
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Serum 
Chemistry10 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Coagulation 
Studies11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test12 
X12 
X12 
 
 
X12 
 
X12 
X12 
X12 
 
X 
 
 
Thyroid Function 
Tests13 
X 
X 
 
 
 
 
X (only at 
C3D1) 
X (every 
other cycle) 
X 
 
 
 
 
Radiographic 
Evaluation of 
Disease14 
X (D-21) 
 
 
 
 
 
X (only 
C3D1)15 
X15 (every 
other cycle) 
X15,16 
 
 
X 
 
Ivosidenib 
Administration17 
 
 
X 
 
 
 
 
 
Nivolumab 
Administration18 
 
X 
 
 
X 
 
X 
X (every 
cycle) 
 
 
 
 
 
Ipilimumab 
Administration19 
 
X 
 
 
X 
 
X  
 
 
 
 
 
 
IMP Compliance20 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
Tumor Biopsy21 
X 
 
 
 
 
 
X (± 7 
days for 
biopsy 
collection) 
 
X 
 
 
 
 

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Visit/Cycle 
Screening1 
Cycle 1 (21 Days) 
Cycle 2 
(21 Days) 
Cycles 3 
and 4 
(21 Days) 
Cycle 5 and 
Beyond 
(28 Days 
Each Cycle) 
End of 
Treatment2 
Safety Follow-up2 
PFS 
Follow-
up3 
Survival 
Follow-
up 
Study Day 
D-28 to  
D-1 
D1 
D8 
D15 
(± 2 
Days) 
D1 
(± 2 
Days) 
D15 
(± 2 
Days) 
D1 
(± 2 Days) 
D1 
(± 2 Days) 
Within 7 
Days After 
Last Dose 
30 (+5) 
Days 
After 
Last 
Dose 
100 (+5) 
Days After 
Last 
Nivolumab 
Dose 
 
Every 
12 
weeks 
(± 2 
weeks) 
Buccal Swab for 
Germ-line 
Mutation 
Analyses22 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sampling 
for Exploratory 
Biomarkers23 
X 
 
 
 
X 
 
X 
X 
X 
 
 
 
 
Adverse Events24 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Prior and 
Concomitant 
Medications/Proce
dures25 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Subsequent Anti-
cancer Therapy 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Survival Status26 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations  AE = adverse event; C = Cycle; CFR = Code of Federal Regulations; CT = computed tomography; D = Day; ECG = electrocardiogram; ECHO = echocardiography; ECOG = Eastern Cooperative 
Oncology Group; eCRF = electronic case report form; EOT = End of Treatment; FFPE = formalin-fixed paraffin-embedded; GDPR = General Data Protection Regulation; HIPAA = Health Insurance Portability and 
Accountability Act; ICF = informed consent form; IDH1 = Isocitrate dehydrogenase-1; IMP = investigational medicinal product; IV = intravenous; LVEF = left ventricular ejection fraction; MRI = magnetic resonance 
imaging; MUGA = multiple gated acquisition; PFS = progression-free survival; Q3W = once every 3 weeks; Q4W = once every 4 weeks; QTcF = heart rate-corrected QT interval by Fridericia’s method; RTSM = 
Randomisation and Trial Supply Management; SAE = serious adverse event. 
Note  One, or two if required by local regulation, original information and consent form(s) must be completed, dated, and signed personally by the participant and by the person responsible for collecting the informed 
consent. According to each study participant’s own preference, the ICF could be made available both printed on paper or/and electronically through a HIPAA, 21 CFR Part 11, and GDPR compliant web-based platform. 
Local regulations permitting, the electronic signature for the ICF could be made available to interested study participants. Interested study participants will be offered the possibility to replace certain in-person visits to 
the research site by televisits. This means that some study visits could be conducted using a HIPAA, 21 CFR Part 11, and GDPR compliant web-based platform, as per each study participant’s own preference. Follow-
up (for survival status until the end of the study) can be done remotely by using various telecommunication technologies including but not limited to phone, web-based remote video-calling, and shared electronic medical 
records. 

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1. 
Day -28 is relative to first dose of IMP. 
2. 
All subjects will undergo an EOT assessment within 7 days after the last dose of IMP (for combination, this is to occur after all 3 IMPs have been discontinued). However, when this is not possible (e.g., dose delay 
more than 7 days), EOT assessment can be performed at the 30-day safety follow-up visit. A second Safety Follow-up will occur 100 (+5) days after last nivolumab dose or ipilimumab if no other anti-cancer therapy 
is initiated.  
3. 
Subjects who discontinue study treatment for reasons other than disease progression or withdrawal of consent and are alive by EOT will enter PFS follow-up with the same schedule of assessments as before study 
treatment discontinuation, until documented disease progression, death, start of subsequent anti-cancer therapy, withdrawal of consent, or the end of study/study termination. 
4. 
Allocation of IMP will occur via RTSM. 
5. 
Height is to be obtained only at Screening assessment. 
6. 
Systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature. Assessments should be conducted while the subject is seated or supine. 
7. 
Subjects with a QTcF of ≥ 450 msec at baseline will not be allowed to enroll in the study. Up to three 12 lead ECG tests under stable condition can be performed at each visit during screening and throughout 
treatment and study follow-up.  
8. 
ECG can be performed at any time during the study visit (on-site or at local clinic); however, it is required once weekly for the first 3 weeks of treatment, and then once every cycle for the duration of therapy.  
9. 
Hematocrit, hemoglobin, red blood cell count, white blood cell count with differential, and platelet count. Hemoglobin criteria of ≥ 9.0 g/dL or ≥ 5.6 mmol/L at Screening must be met without packed red blood cell 
transfusion within the prior 2 weeks. Subjects can be on stable dose of erythropoietin (≥ approximately 3 months). On C1D1, assessments should be conducted prior to IMP administration. 
10. Sodium, potassium, chloride, calcium, magnesium, phosphorus, carbon dioxide, albumin, glucose, blood urea nitrogen (BUN)/UREA, creatinine, alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, gamma glutamyl transferase, total bilirubin, direct bilirubin, and indirect bilirubin. On C1D1, assessments should be conducted prior to IMP administration.  
11. Activated partial thromboplastin time and either prothrombin time or international normalized ratio. 
12. For women of childbearing potential, a serum pregnancy test will be performed at Screening, and a urine pregnancy test will be conducted on the day of IMP administration and is to be confirmed negative prior to 
dosing. If the urine pregnancy test is positive and cannot be confirmed negative, a serum pregnancy test must be performed and shown to be negative within 24 hours prior to the first day of IMP administration. An 
extension up to 72 hours prior to the start of study treatment is permissible in situations where the results cannot be obtained within the standard 24-hour window.  
13. Thyroid function test includes triiodothyronine (T3) or free T3, free thyroxine, and thyroid stimulating hormone. Thyroid function tests are to be performed every 6 weeks for the first 4 cycles and then every 8 weeks 
starting from Cycle 5 and to be performed at EOT. On C1D1, assessments should be conducted prior to IMP administration. Thyroid function test results obtained after the visit are acceptable so long as the value at 
screening was normal or considered not clinically significant per investigator assessment. 
14. Tumor assessments will include all known or suspected disease sites. CT imaging of the chest, abdomen, and pelvis (torso) with triphasic IV contrast should be performed at baseline and on study. For subjects with 
allergy to IV iodine contrast, CT chest without IV contrast and MRI abdomen with IV contrast should be performed at baseline and on study. Brain scans with CT or MRI should be performed at baseline in subjects 
with known treated brain metastases and on study at the same imaging time points as torso imaging. Additional anatomy should be imaged based on the signs and symptoms of individual subjects at baseline and 
follow-up. Radiographic assessment (CT or MRI or other imaging modalities as appropriate per RECIST v1.1 Appendix 4) for evaluation of disease response to be conducted at Screening (Day -21 to Day -1), every 
6 weeks (±7 days) for the first 2 assessments (i.e., through Week 12), and then every 8 weeks (± 7 days) thereafter independent of dose delays and/or dose interruptions, and/or at any time when progression of 
disease is suspected. Tumor assessment frequency can be reduced to every 12 weeks after 2 years of treatment initiation. 
15. Response to treatment is to be assessed at this visit if the subject discontinues treatment for reasons other than disease progression or start of another anticancer therapy.  
16. If a subject goes off treatment for reasons other than disease progression or withdrawal of consent from treatment, response assessments will be conducted at the EOT visit  
17. Ivosidenib is to be taken daily. Subjects should be instructed to take their daily dose at approximately the same time each day. Each daily dose should be taken with or without food. Subjects taking ivosidenib with 
food should be advised to avoid grapefruit or grapefruit products and avoid consuming a high-fat meal. If the subject forgets to take the daily dose, then they should take ivosidenib within 12 hours after the missed 
dose. If more than 12 hours have elapsed, then that dose should be omitted, and the subject should resume treatment with the next scheduled dose. The dose on C1D1, C1D15, and Day 1 of each cycle thereafter is 
to occur in-clinic to allow for pre-treatment assessments and to accommodate PK sampling. In subjects receiving the combination, on days when nivolumab and ipilimumab are administered, ivosidenib should be 
administered approximately 30 minutes before the start of the nivolumab infusion. 
18. Nivolumab is to be administered over an approximately 30-minute IV infusion. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of 
infusion pumps from site to site, a window between -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes (-5 minutes/+10 minutes). When study treatments nivolumab and ipilimumab are to be 
administered on the same day, nivolumab is to be administered first. Nivolumab infusion must be promptly followed by a flush of diluent to clear the line of nivolumab before starting the ipilimumab infusion. The 
second infusion will always be the ipilimumab study treatment and will start after the infusion line has been flushed, filters changed, and subject has been observed to ensure that no infusion reaction has occurred. 
19. Ipilimumab is to be administered over an approximately 30-minute IV infusion. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of 
infusion pumps from site to site, a window between -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes (-5 minutes/+10 minutes). When study treatments nivolumab and ipilimumab are to be 
administered on the same day, nivolumab is to be administered first. Nivolumab infusion must be promptly followed by a flush of diluent to clear the line of nivolumab before starting the ipilimumab infusion. The 
second infusion will always be the ipilimumab study treatment and will start after the infusion line has been flushed, filters changed, and subject has been observed to ensure that no infusion reaction has occurred. 
The time in between nivolumab and ipilimumab infusions is expected to be within approximately 30-minutes. 
20. Treatment compliance for ivosidenib is to be assessed based on the drug diary and/or return of unused drug. 
21. Tumor tissue for retrospective central laboratory confirmation of IDH1 gene mutation status and exploratory biomarker analysis at Screening is requested. Subjects will have locally documented presence of the 
IDH1 gene mutation for inclusion. If a subject cannot undergo a biopsy at Screening, collection of archival tumor tissue from the most recent biopsy/resection of at least 20 freshly cut, unstained FFPE slides (4-

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5 µm each) plus 1 H&E slide will be submitted at a later time together with the pathology report upon sponsor’s request. Tumor biopsies are to be collected at baseline, C3D1, and EOT from similar anatomical 
locations for exploratory biomarker analyses including PK/PD. In case of limited tissue amounts, biopsy samples will be formalin fixed and paraffin embedded. Please refer to the laboratory manual for priorities in 
tissue processing. If a required tumor biopsy (any time point) cannot be performed due to concerns around subject safety, a discussion with the Sponsor is required and biopsy can be omitted. Further details on 
screening and on-treatment biopsy collections are provided in the laboratory manual. 
22. A buccal swab for germ-line mutation analysis will be obtained at Screening. 
23. Blood samples for exploratory biomarker assessments, including plasma circulating tumor DNA, will be collected at Screening and Day 1 of every cycle through Cycle 6, followed by every 6 months thereafter, and 
at EOT. 
24. From the time of informed consent signing through the first dose of IMP, SAEs resulting from a study-related procedure and assessed as related to that procedure, as well as all fatal AEs whether or not related to 
research procedures, must be recorded. All AEs will be recorded from all subjects from the date of first dose through 30 days following the last dose of ivosidenib and/or nivolumab or ipilimumab, whichever occurs 
later. Following the 30-day Safety Follow-up period, any SAEs that occur within 100 days after last dose of immunotherapy are to be reported, or until the subject initiates another anti-cancer therapy, whichever is 
earlier. Only SAEs that are considered as related to either IMP by the Investigator are to be reported after the respective Safety Follow-up periods. Fatal events, related or not to the research, occurring after ICF 
signature and before first IMP administration, must be reported on an AE form.  
25. All concomitant medications/procedures within 21 days of the first dose of IMP through 30 days (+ 5 days) after the last dose of ivosidenib and/or immunotherapy and through 100 days after the last dose of 
immunotherapy (whichever is later) are to be reported on the eCRF. 
26. Subjects will be contacted every 12 weeks (± 2 weeks) after the subject experiences documented disease progression or begins subsequent anti-cancer therapy for up to 2 years after the last subject has been enrolled, 
or until death, lost to follow-up, withdrawal of consent from overall study participation, or Sponsor ending study, whichever occurs first 

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Paragraph impacted 8.4 Definition of Serious Adverse Events  
Amended text:  
 
An SAE is any AE that, at any dose:  
 results in death,  
 is life-threatening(1),  
 requires insubject hospitalization or prolongation of existing hospitalization,  
 is medically significant(2),  
 results in persistent or significant disability/incapacity(3),  
 is a congenital anomaly/birth defect(4). 
All SAEs must be reported to the sponsor immediately, i.e., without delay and within 24 hours 
of awareness at the latest. 
 
(1) Life-threatening in this context refers to an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe.  
(2) Any event that might not be immediately life-threatening or result in death or hospitalization, but 
might jeopardize the participant or might require intervention to prevent one of these outcomes (for 
example: oedema or allergic bronchospasm that required intensive treatment at home, blood dyscrasia, 
convulsions that do not result in hospitalization, or development of drug dependence or drug abuse). 
The Investigator should exercise his/her scientific and medical judgement to decide whether or not such 
an event requires expedited reporting to Sponsor. 
(3) Disability/incapacity in this context refers to any event that seriously disrupts the ability of the 
participant to lead a normal life, in other words leads to a persistent or permanent significant change, 
deterioration, injury or perturbation of the participant’s body functions or structure, physical activity 
and/or quality of life. 
(4) Congenital anomaly or birth defect refers to the exposure to the IMP before conception (in men or 
women) or during pregnancy that resulted in an adverse outcome in the child.