Conditions: Biliary Tract Cancer (BTC) Colorectal Cancer (CRC) Endometrial Cancer Gastroesophageal Cancer (GC) Ovarian Cancer Solid Tumors
Keywords: INCB001158 arginase inhibitor oxaliplatin leucovorin 5 fluorouracil gemcitabine cisplatin paclitaxel solid tumors colorectal cancer biliary tract cancer gastroesophageal cancer endometrial cancer ovarian cancer
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 149
Healthy volunteers: no

Brief summary:
The purpose of this open-label nonrandomized Phase 1/2 study is to evaluate INCB001158 in combination with chemotherapy in participants with advanced/metastatic solid tumors.

Detailed description:

Arms:
arm 1: INCB001158 + FOLFOX arm 2: INCB001158 + gemcitabine/cisplatin arm 3: INCB001158 + paclitaxel

Interventions: intervention 1: INCB001158 intervention 2: Oxaliplatin intervention 3: Leucovorin intervention 4: 5-Fluorouracil intervention 5: Gemcitabine intervention 6: Cisplatin intervention 7: Paclitaxel
Intervention descriptions: intervention 1: Phase 1: INCB001158 administered orally twice daily at the protocol-defined dose. Phase 2: INCB001158 administered orally twice daily at the recommended dose from Phase 1. intervention 2: Oxaliplatin administered intravenously at the protocol-defined dose and schedule. intervention 3: Leucovorin at the protocol-defined dose and regimen. intervention 4: 5-Fluorouracil at the protocol-defined dose and regimen. intervention 5: Gemcitabine at the protocol-defined dose and regimen. intervention 6: Cisplatin at the protocol-defined dose and regimen. intervention 7: Paclitaxel at the protocol-defined dose and regimen.

Protocol document:
Prot_000.pdf: 
Official Title: A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Efficacy of 
INCB001158 in Combination With Chemotherapy, in Subjects With Advanced or Metastatic 
Solid Tumors 
NCT Number: NCT03314935 
Document Date: Protocol Amendment (Version) 4: 09-December-2020


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Incyte Corporation 
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Protocol INCB 01158-203 Am 4 
Version 4 
09 DEC 2020 
VV-CLIN-000593 
CONFIDENTIAL 
INVESTIGATOR'S AGREEMENT 
I have read the INCB 01158-203 Protocol Amendment 4 (Version 4 dated 09 DEC 2020) and 
agree to conduct the study as outlined.  I agree to maintain the confidentiality of all information 
received or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 


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Protocol INCB 01158-203 Am 4 
Version 4 
09 DEC 2020 
VV-CLIN-000593 
CONFIDENTIAL 
SYNOPSIS 
Name of Investigational Product:  INCB001158 
Title of Study:  A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Efficacy of INCB001158 
in Combination With Chemotherapy, in Subjects With Advanced or Metastatic Solid Tumors 
Protocol Number:  INCB 01158-203 
Study Phase:  1/2 
Indication: 
Phase 1:  advanced or metastatic solid tumors 
Phase 2:  advanced/metastatic microsatellite stable colorectal cancer (MSS-CRC), biliary tract cancer 
(BTC), gastroesophageal cancer (GC), and endometrial cancer (EC) and recurrent ovarian cancer (OC) 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• Phase 1:  To assess the safety and tolerability 
and determine the recommended Phase 2 dose 
(RP2D) of INCB001158 in combination with 
chemotherapy. 
• Safety, tolerability, dose-limiting toxicities (DLTs), 
and RP2D of INCB001158 in combination with 
chemotherapy, as assessed by adverse events (AEs), 
clinical laboratory tests, physical examination results, 
and 12-lead electrocardiogram (ECG) results. 
• Phase 2:  To evaluate the objective response 
rate (ORR) of INCB001158 in combination with 
chemotherapy. 
• ORR, defined as the percentage of subjects having a 
complete response (CR) or partial response (PR), as 
determined by investigator assessment of radiographic 
disease as per RECIST v1.1. 
Secondary 
• Phase 2:  To assess the safety, tolerability, and 
RP2D of INCB001158 in combination with 
chemotherapy. 
• Safety, tolerability, and RP2D of INCB001158 in 
combination with chemotherapy, as assessed by AEs, 
clinical laboratory tests, physical examination results, 
and 12-lead ECG results. 
• To evaluate the antitumor effect of INCB001158 
in combination with chemotherapy. 
• ORR, defined as the percentage of subjects having a 
CR or PR, as determined by investigator assessment 
of radiographic disease as per RECIST v1.1 (Phase 1 
only).   
• Duration of response (DOR), defined as the time from 
earliest date of CR or PR (as determined by 
investigator assessment of radiographic disease 
assessment per RECIST v1.1) until the earliest date of 
disease progression or death due to any cause, if 
occurring sooner than disease progression. 
• Disease control rate (DCR), defined as the percentage 
of subjects having CR, PR, or stable disease (SD) for 
at least 8 weeks, as determined by investigator 
assessment of radiographic disease as per RECIST 
v1.1. 
• Progression-free survival (PFS), defined as the time 
from the date of first dose of study drug until the 
earliest date of disease progression (as determined by 
investigator assessment of radiographic disease 
assessment per RECIST v1.1), or death due to any 
cause, if occurring sooner than progression. 


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Protocol INCB 01158-203 Am 4 
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• To determine the pharmacokinetics (PK) of 
INCB001158 in subjects treated with 
INCB001158 in combination with 
chemotherapy. 
• PK of INCB001158 will be assessed by summarizing 
Cmin, Cmax, tmax, AUC0-t, and AUC0-τ. 
Overall Study Design:  This is an open-label, nonrandomized, Phase 1/2 study to evaluate the safety, 
tolerability, and antitumor activity of INCB001158 in combination with 3 different chemotherapy 
regimens.  Phase 1 will consist of dose-escalation using a Bayesian Optimal Interval (BOIN) design 
and will determine the RP2D of INCB001158 when given in combination with each chemotherapy 
regimen; efficacy will also be explored.  Subjects with advanced or metastatic solid tumors for whom 
treatment with one of the chemotherapy regimens is appropriate will be enrolled in Phase 1.  Phase 2 
will evaluate ORRs using a Simon 2-stage design to determine whether the combinations have 
sufficient antitumor activity to warrant further testing in subsequent clinical studies and will further 
evaluate the safety and tolerability of the RP2D of INCB001158 when given in combination with 
chemotherapy.  Subjects with advanced or metastatic CRC, BTC, OC, GC, and EC will be enrolled in 
the Phase 2 expansion cohorts.   


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Phase 1 Dose Escalation 
In Phase 1, a BOIN design will be used to determine the RP2D of the combination of INCB001158 and 
chemotherapy in 21-day (for gemcitabine/cisplatin) or 28-day (for mFOLFOX6 or paclitaxel) 
treatment cycles in subjects with advanced or metastatic solid tumors.  The RP2D will then be further 
assessed in tumor expansion cohorts in Phase 2. 
Subjects with advanced or metastatic solid tumors will be assigned to 1 of the treatment groups 
summarized below based on the chemotherapy regimen most appropriate for the subject's tumor type.  
Treatment Group A 
INCB001158 
mFOLFOX6 
25-150 mg PO BID continuous daily 
dosing 
Oxaliplatin 85 mg/m2 IV on Day 1 and 
Day 15 of a 28-day cycle 
Leucovorin 400 mg/m2 IV on Day 1 and 
Day 15 of a 28-day cycle 
5-Fluorouracil 400 mg/m2 IV bolus on 
Day 1, then 1200 mg/m2 per day IV 
infusion over 46 hours for a total dose of 
2400 mg/m2 on Day 1 and Day 15 of a 
28-day cycle 
Treatment Group B 
INCB001158  
Gemcitabine and cisplatin 
25-150 mg PO BID continuous daily 
dosing 
Gemcitabine 1000 mg/m2 IV infusion on 
Days 1 and 8 of a 21-day cycle 
Cisplatin 30 mg/m2 IV infusion on Days 
1 and 8 of a 21-day cycle 
Treatment Group C 
INCB001158  
Paclitaxel 
25-150 mg PO BID continuous daily 
dosing 
Paclitaxel 80 mg/m2 IV infusion on 
Days 1, 8, and 15 of a 28-day cycle 
BID = twice daily; IV = intravenous; PO = orally. 


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Protocol INCB 01158-203 Am 4 
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CONFIDENTIAL 
Dose escalation will begin with starting doses of INCB001158 at least 2 dose levels below the 
maximum tolerated and tested dose from the INCB 01158-101 study (likely to be 50 mg BID or 75 mg 
BID – see Table below, column A and B, respectively. 
The doses of INCB001158  to be evaluated and scenarios for dose escalation and de-escalation are 
summarized below:  
INCB001158 Dose Cohort 
INCB001158 Dose Levels for Phase 1 
A.  Starting Dose of 50 mg BID 
B.  Starting Dose of 75 mg BID 
-1 
25 mg BID 
50 mg BID 
1 (starting dose) 
50 mg BIDa 
75 mg BIDb 
2 
75 mg BID 
100 mg BID 
3 
100 mg BID 
150 mg BID 
4 
150 mg BID 
N/A 
BID = twice daily. 
a If INCB001158 50 mg BID is not tolerated within a treatment group, INCB001158 25 mg BID may be evaluated. 
b If INCB001158 75 mg BID is not tolerated within a treatment group, INCB001158 50 mg BID may be evaluated. 
If the starting dose is not 1 of those 2 dose levels, dose escalation will follow the same pattern, and the 
exact dose escalation table will be provided to sites.  The INCB001158 dose will be escalated using an 
open-label BOIN design in each chemotherapy regimen, and a pharmacologically active dose (PAD) or 
the maximum tolerated dose (MTD) will be determined, or the maximum dose of INCB001158 
(150 mg BID) will be reached.  A PAD of INCB001158 is defined as a dose that achieves a trough 
(Cmin) plasma concentration of INCB001158 at steady state of ≥ 1 μM that is equivalent to the IC90 for 
arginase 1.  This definition may be modified based on emerging data from the INCB 01158-101 
first-in-human study, upon agreement between the medical monitor and the study investigators.  The 
MTD is the maximum tolerated or tested dose of INCB001158, such that fewer than 33% of the 
subjects receiving the combination experience a DLT during the first 28 days on study drug.  After the 
dose escalation is completed, one of the INCB001158 dose levels that is pharmacologically active and 
tolerable in combination with each chemotherapy regimen (ie, MTD or lower), will be the RP2D. 
Dose interruptions and/or modifications may be implemented based on toxicity.  Dose modifications 
should not be made during the DLT observation period without discussion with the medical monitor.  
Intrasubject dose escalation is not permitted. 
Phase 2:  Expansion Cohorts  
To determine whether the combinations result in adequate ORRs to warrant further testing in 
subsequent clinical studies, a Simon 2-stage design will be used for each tumor expansion cohort to 
evaluate the ORR of the RP2D of INCB001158 determined in Phase 1 in combination with 
chemotherapy and further evaluate the safety and tolerability of the combination.  If, at the time of 
completion of enrollment in Stage 1, it is not known whether the target ORR to proceed to Stage 2 will 
be met, then enrollment will be paused until and unless the ORR to proceed has been met. 
Enrollment in a specific expansion cohort will begin when the RP2D of INCB001158 for the 
corresponding treatment group in Phase 1 has been determined. 
The expansion cohorts will be limited to the following advanced/metastatic or recurrent tumor types:  
• Cohort A1:  CRC (INCB001158 + mFOLFOX6) 
• Cohort B1:  BTC (INCB001158 + gemcitabine/cisplatin) 
• Cohort B2:  OC (INCB001158 + gemcitabine/cisplatin) 
• Cohort C1:  GC (INCB001158 + paclitaxel) 
• Cohort C2:  EC (INCB001158 + paclitaxel) 
• Cohort C3:  OC (INCB001158 + paclitaxel) 


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Subjects will be assigned to the expansion cohorts summarized below based on the chemotherapy 
regimen most appropriate for the subject's tumor type:  
Expansion Cohort A1 
INCB001158 
mFOLFOX6 
PO BID continuous daily dosing 
Oxaliplatin 85 mg/m2 IV on Day 1 and 
Day 15 of a 28-day cycle 
Leucovorin 400 mg/m2 IV on Day 1 and 
Day 15 of a 28-day cycle 
5-Fluorouracil 400 mg/m2 IV bolus on 
Day 1, then 1200 mg/m2 per day IV 
infusion over 46 hours for a total dose of 
2400 mg/m2 on Day 1 and Day 15 of a 
28-day cycle 
Expansion Cohort B1 
INCB001158 
Gemcitabine and Cisplatin 
PO BID continuous daily dosing 
Gemcitabine 1000 mg/m2 IV infusion on 
Days 1 and 8 of a 21-day cycle 
Cisplatin 25 mg/m2 IV infusion on 
Days 1 and 8 of a 21-day cycle 
Expansion Cohort B2 
INCB001158 
Gemcitabine and Cisplatin 
PO BID continuous daily dosing 
Gemcitabine 750 mg/m2 IV infusion on 
Days 1 and 8 of a 21-day cycle 
Cisplatin 30 mg/m2 IV infusion on 
Days 1 and 8 of a 21-day cycle 
Expansion Cohorts 
C1, C2, and C3 
INCB001158 
Paclitaxel 
PO BID continuous daily dosing 
Paclitaxel 80 mg/m2 IV infusion on 
Days 1, 8, and 15 of a 28-day cycle 
BID = twice daily; IV = intravenous; PO = orally. 
Continuous evaluation of toxicity events will be performed in the expansion cohorts.  If the cumulative 
incidence of ≥ Grade 3 INCB001158-related AEs or ≥ Grade 3 chemotherapy-related AEs is > 40% 
after 10 subjects are enrolled in a specific expansion cohort within Phase 2, then further enrollment in 
that cohort will be interrupted until the sponsor and investigators determine the appropriate course of 
action.  If an expansion cohort is discontinued due to toxicity, a new cohort may be initiated at a 
previously tested lower dose level. 
 
 
 
 
 
 
 
 


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Study Population: 
Phase 1 Dose Escalation:  Subjects with previously treated advanced solid tumors who have progressed 
on or were either ineligible or intolerant to standard anti-cancer therapy will be enrolled. 
Phase 2 Expansion Cohorts:  Subjects with histologically or cytologically confirmed advanced or 
metastatic MSS-CRC, BTC, OC, GC, and EC. 
Key Inclusion Criteria: 
• Men or women aged 18 years or older. 
• Presence of measurable disease per RECIST v1.1. 
Note:  If subjects have only 1 measurable lesion per RECIST v1.1, this lesion should not have been 
in the field of prior irradiation unless there is documented progression of the lesion(s). 
• ECOG performance status 0 to 1. 
• 
 
 
 
• Willingness to undergo pretreatment and on-treatment tumor biopsies, until at least 5 evaluable 
paired specimens are collected in each cohort. 
• Have resolution of all toxicities and any toxic effect(s) of the most recent prior therapy to Grade 1 or 
less (except alopecia). 
• Adequate renal, hepatic, and hematologic functions as defined by laboratory parameters within 
≤ 7 days before treatment initiation. 
- Absolute neutrophil count ≥ 1.5 × 109/L. 
- Platelets ≥ 100 × 109/L. 
- Hemoglobin ≥ 9 g/dL. 
- Measured or calculated creatinine clearance (glomerular filtration rate can also be used in place of 
creatinine or creatinine clearance) ≥ 50 mL/min. 
Note:  Creatinine clearance should be calculated per institutional standard. 
- Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with 
total bilirubin levels > 1.5 × ULN. 
- If there is no institutional normal range available for the direct bilirubin, the direct bilirubin should 
be < 40% of the total bilirubin. 
- In no case can total bilirubin exceed 3.0 × ULN. 
- Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine 
aminotransferase (serum glutamic pyruvic transaminase) ≤ 2.5 × ULN. 
- International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN unless subject is 
receiving anticoagulant therapy as long as PT or INR is within therapeutic range of intended use of 
anticoagulants. 
- Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless subject is receiving 
anticoagulant therapy, as long as aPTT is within therapeutic range of intended use of 
anticoagulants. 
• Albumin > 3.0 g/dL. 
• Phase 1 dose escalation only 
- Subjects with histologically or cytologically confirmed advanced or metastatic solid tumors that 
have failed prior standard therapy (disease progression, subject refusal, or intolerance is also 
allowable). 
Note:  There is no limit to the number of prior treatment regimens. 
- Locally advanced disease must not be amenable to resection with curative intent. 


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• Phase 2 Expansion Cohort A1:  MSS-CRC subjects only 
- Subjects with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of 
the colon or rectum. 
Note:  Should have documented microsatellite stable (MSS) status, or consent to local institutional 
microsatellite instability (MSI) testing during the screening period. 
Note:  Must have received at least 1, but not more than 2, prior chemotherapy regimens for locally 
advanced/metastatic CRC, including fluoropyrimidine-, oxaliplatin-, or irinotecan-based 
chemotherapy; with or without anti-vascular endothelial growth factor therapy (if no 
contraindication). 
Note:  Subjects who completed a fluoropyrimidine-, irinotecan-, or oxaliplatin-based 
chemotherapy regimen as adjuvant, neoadjuvant, or part of a course of chemoradiation therapy and 
progressed ≥ 6 months after completing therapy will be eligible.  If progression occurred 
< 6 months after completing therapy, then the subject will not be eligible. 
• Phase 2 Expansion Cohort B1:  BTC subjects only 
- Subjects with histologically or cytologically confirmed nonresectable advanced or metastatic BTC 
(intra- or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary carcinoma). 
Note:  Should not have received prior systemic chemotherapy for metastatic or inoperable locally 
advanced BTC (not including adjuvant therapy completed at least 6 months prior to enrollment). 
• Phase 2 Expansion Cohort B2:  OC subjects only 
- Subjects with histologically confirmed recurrent epithelial ovarian, peritoneal, or fallopian tube 
carcinoma and carcinosarcomas (Sertoli-Leydig or germ cell cancers are excluded) that have 
progressed within 6 months of prior cytotoxic chemotherapy. 
Note:  Should have received at least 1 and no more than 4 prior therapies, and failed at least 
1 standard line of chemotherapy. 
Note:  Adjuvant regimens given within 6 months of screening would be counted as first-line 
therapy. 
• Phase 2 Expansion Cohort C1:  GC subjects only 
- Subjects with histologically or cytologically confirmed advanced or metastatic adenocarcinoma of 
the stomach, esophagus, or gastroesophageal junction. 
Note:  Should have received only 1 prior chemotherapy regimen for advanced or metastatic 
disease (not including neoadjuvant and/or adjuvant therapy).  Adjuvant regimens given within 
6 months of screening would be counted as first-line therapy. 
• Phase 2 Expansion Cohort C2:  EC subjects only 
- Subjects with histologically or cytologically confirmed advanced or metastatic endometrial 
carcinoma. 
Note:  Should have documented MSI status (eg, MSI-high, MSI-low, MSS), or consent to local 
institutional MSI testing during the screening period. 
Note:  Should have received at least 1, but not more than 2, prior chemotherapy regimens for 
advanced or metastatic disease (not including neoadjuvant and/or adjuvant therapy).  Adjuvant 
regimens given within 6 months of screening would be counted as first-line therapy. 
Note:  May have received prior hormonal and/or biological therapy in addition to prior systemic 
chemotherapy, which will not count as prior therapy. 
• Phase 2 Expansion Cohort C3:  OC subjects only 
- Subjects with histologically confirmed recurrent epithelial ovarian, peritoneal or fallopian tube 
carcinoma and carcinosarcomas that have progressed within 6 months of prior cytotoxic 
chemotherapy (Sertoli-Leydig or germ cell cancers are excluded). 
Note:  Should have received no more than 5 prior therapies and failed at least 1 standard 
(platinum-containing) chemotherapy regimen and be considered platinum resistant. 
Note:  Adjuvant regimens given within 6 months of screening would be counted as first-line 
therapy. 


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Key Exclusion Criteria: 
• Participation in any other study in which receipt of an investigational study drug or device occurred 
within 28 days or 5 half-lives (whichever is longer) before first dose.  For investigational agents with 
long half-lives (eg, 5 days), enrollment before the fifth half-life requires medical monitor approval. 
• Has received a prior monoclonal antibody within 4 weeks or 5 half-lives (whichever is shorter) 
before administration of study drug. 
- Exception:  Washout of immune checkpoint inhibitor therapy is NOT required. 
- Exception:  Denosumab may be used. 
• Has had prior chemotherapy or targeted small molecule therapy within 2 weeks before 
administration of study treatment. 
• Has received prior approved radiotherapy within 14 days of study therapy (exception for radiation to 
central nervous system [CNS], which requires ≥ 28-day washout as described below). 
Note:  Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, 
and not have had radiation pneumonitis.  A 1-week washout is permitted for palliative radiation 
(≤ 2 weeks of radiation therapy) to non-CNS disease 
• Subjects must not have received therapy with an arginase inhibitor. 
Note:  Prior immunotherapy treatment with an anti–programmed death-1 receptor, anti–programmed 
death-1 receptor ligand, anti–programmed death-2 receptor ligand, anti–cytotoxic T-lymphocyte–
associated protein 4, anti-CD137, or any other antibody or drug specifically targeting immune 
checkpoint pathways is allowed. 
• Has had major surgery within 4 weeks before enrollment (C1D1). 
• Has had known additional malignancy that is progressing or requires active treatment, or history of 
other malignancy within 2 years of study entry with the exception of cured basal cell or squamous 
cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in 
situ of the cervix, or other noninvasive or indolent malignancy, or cancers from which the subject 
has been disease-free for > 1 year, after treatment with curative intent. 
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (exceeding 
10 mg daily of prednisone equivalent in dose) or any other form of immunosuppressive therapy 
within 7 days before the first dose of study treatment. 
• Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use 
of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Note:  Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. 
• Has a known history of human immunodeficiency virus (HIV) infection.  HIV testing is not required 
unless mandated by the local health authority. 
• Has a known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) 
or hepatitis C. 
Note:  Testing must be performed to determine eligibility. 
- Hepatitis B virus DNA must be undetectable and HBsAg negative at screening visit. 
- Hepatitis C antibody testing is allowed for screening purposes in countries where hepatitis C virus 
(HCV) RNA is not part of standard-of-care treatment.  In these cases, HCV antibody-positive 
patients will be excluded. 
- Subjects who have had definitive treatment for HCV are permitted if HCV RNA is undetectable at 
screening visit. 
• Has known active CNS metastases and/or carcinomatous meningitis. 
Note:  Subjects with previously treated brain metastases may participate provided that they are stable 
(without evidence of progression by imaging for at least 28 days before the first dose of study drug 
and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases or cerebral edema, and have not required steroids for at least 14 days before the first dose 
of study drug. 


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Note:  Subjects with evidence of cerebral edema or those with < 28 days since radiation therapy to 
the CNS will be excluded from study. 
• Has not recovered to ≤ Grade 1 from toxic effects of previous therapy and/or complications from 
previous surgical intervention before starting study therapy. 
Note:  Subjects with stable chronic AEs (≤ Grade 2) not expected to resolve (eg, alopecia) are 
exceptions and may enroll. 
Note:  Subjects with a history of peripheral neuropathy ≥ Grade 2 will be excluded. 
• Has a known or suspected defect in the function of the urea cycle, including a known deficiency of 
carbamoyl phosphate synthetase I, ornithine transcarbamylase, argininosuccinate synthetase, 
argininosuccinate lyase, N-acetyl glutamate synthetase, or arginase. 
• Evidence of interstitial lung disease or active, noninfectious pneumonitis. 
• Inability to swallow food or any condition of the upper gastrointestinal tract that precludes 
administration of oral medications. 
• Active infection requiring systemic therapy. 
• Has known hypersensitivity to any of the active substances or any of their excipients, including 
mannitol. 
• Women who are pregnant or breastfeeding. 
INCB001158, Dosage, and Mode of Administration:   
In Phase 1 dose escalation, INCB001158 will be administrated PO BID with the dose corresponding to 
cohort assignment.  In Phase 2 expansion cohorts, INCB001158 will be administrated PO BID at the 
RP2D determined in the dose escalation as long as the subject is deriving benefit and has not met any 
of the Protocol-defined conditions for treatment withdrawal. 
INCB001158 will be administrated PO BID in 28- or 21-day cycles depending on the chemotherapy 
regimens. 
Chemotherapies, Dosage, and Mode of Administration: 
5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) will be administered on Day 1 and 
Day 15 of each 28-day cycle.  Subjects will receive oxaliplatin 85 mg/m2 IV concurrently with 
leucovorin 400 mg/m2 IV over 2 hours (± 15 minutes), followed by a 5-fluorouracil 400 mg/m2 IV 
bolus (administration time per institutional practice), then 1200 mg/m2 per day IV continuous infusion 
over 46 hours for a total dose of 2400 mg/m2.  Investigators may reduce or discontinue oxaliplatin for 
peripheral neuropathy; if discontinued, investigators have the option to discontinue 5-fluorouracil and 
leucovorin.  Subjects may receive prophylactic granulocyte-colony stimulating factor (G-CSF) support 
after completion of Cycle 1. 
Gemcitabine and cisplatin will be administered on Day 1 and Day 8 of a 21-day cycle.  For Phase 1 
dose escalation, subjects with advanced or metastatic disease will receive gemcitabine 1000 mg/m2 IV 
over 30 minutes (± 5 min) and cisplatin 30 mg/m2 IV over 30 minutes (± 5 min) on Days 1 and 8 of 
each 21-day cycle.  For Phase 2 tumor expansion, subjects will receive the gemcitabine/cisplatin 
regimen that is the standard dose and schedule used for the corresponding tumor type patients: 
• In Cohort B1 (BTC), subjects will receive gemcitabine 1000 mg/m2 IV over 30 minutes (± 5 min) 
and cisplatin 25 mg/m2 IV over 30 minutes (± 5 min) on Days 1 and 8 of each 21-day cycle. 
• In Cohort B2 (OC), subjects will receive gemcitabine 750 mg/m2 IV over 30 minutes (± 5 min) and 
cisplatin 30 mg/m2 IV over 30 minutes (± 5 min) on Days 1 and 8 of each 21-day cycle. 
Subjects may receive prophylactic G-CSF support after completion of Cycle 1. 
Paclitaxel will be administrated weekly at 80 mg/m2 IV infusion over 1 hour (± 10 minutes), on 
Days 1, 8, and 15 of a 28-day cycle. 


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Study Schedule/Procedures: 
Subjects will have regularly scheduled study visits at the clinical site on Day 1 of each cycle.  
Additional study visits may be required during some cycles to monitor for safety, for efficacy, 
 
 evaluations.  Study visits are as follows:  
Screening:  Up to 21 days before enrollment.  Screening will begin at the time that the subject signs 
the informed consent and will continue until the date that the subject is enrolled in the study (Cycle 1 
Day 1). 
Treatment: 
Cycle 1:  Day 1 and Days 8 and 15 (± 3 days).   
All other treatment cycles:  Day 1, Day 8, and Day 15 (± 3 days).   
NOTE:  As of Protocol Amendment 4, the only safety data that will be collected will be related to 
SAEs, AESIs, and pregnancy. 
Efficacy assessments:  Every 8 weeks (± 7 days). 
NOTE:  As of Protocol Amendment 4, no further efficacy assessments will be required beyond 
Week 96.  Imaging should continue per standard of care after Week 96.  
End of treatment:  + 7 days of discontinuing treatment. 
Safety follow-up:  30 days and 90 days (± 7 days) after end of treatment (or last dose of study drug if 
the end-of-treatment visit was not performed).  These follow-up visits may be completed remotely 
(such as by televisit). 
Disease status follow-up:  Subjects who discontinue treatment for reasons other than disease 
progression will continue to be assessed for their disease status during the follow-up phase and should 
continue to have tumor assessments every 8 weeks (± 7 days) until a new cancer therapy is started, 
disease progression, death, or the end of the study. 
NOTE:  As of Protocol Amendment 4, no further disease status follow-up assessments will be required 
beyond the last safety follow-up visit. 
 
 
 
 
Estimated Duration of Participation: 
After signing the informed consent form, subject study participation, including screening and 
post-treatment follow-up is expected to average approximately 12 to 18 months per individual subject.  
Note that the treatment period will last as long as subjects are deriving benefit, are tolerating the 
regimen, and do not meet any of the withdrawal criteria. 
Estimated Number of Subjects: 
Up to a total of 222 subjects (if starting dose level is 75 mg in Phase 1) or up to a total of 249 (if 
starting dose level is 50 mg in Phase 1) are planned for enrollment. 
• Phase 1 dose escalation – Up to 87 (if starting dose level is 75 mg in Phase 1) or up to 114 (if starting 
dose level is 50 mg in Phase 1) evaluable subjects. 
• Phase 2 tumor expansion (Simon 2-stage) – Approximately 55 to 135 evaluable subjects. 
Coordinating Principal Investigator:  TBD 
Statistical Methods: 
Sample Size Method:  In Phase 1, the BOIN design will be used to determine the RP2D of 
INCB001158 given in combination with each chemotherapy regimen, in subjects with advanced or 
metastatic solid tumors.  Dose escalation and de-escalation will follow the BOIN design algorithm.  In 


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Phase 2, the sample size for each tumor type within a treatment group will be guided by the Simon 
2-stage design. 
Each Simon 2-stage design will have a stopping rule to allow early termination of a particular tumor 
type within the given cohort at the end of Stage 1 if there is insufficient response observed, while 
enrolling enough subjects to predict possible target responses worthy of cohort expansion and 
potentially further evaluation in future studies. 
The proposed designs for each tumor type will be used for any planned Simon 2-stage design.  Each 
Simon 2-stage design is set up to have a 1-sided Type I error of 0.1 and power of 80%.  The response 
rates for each tumor type will be estimated with 95% confidence intervals.   
Phase 2:  Simon 2-Stage Design 
Cohort 
(Tumor Type) 
Background 
ORR 
Target 
ORR 
Alpha 
Power 
N for 
Stage 1 
ORR to 
Proceed 
N for 
Stage 2 
ORR for 
Positive 
Cohort 
A1 (MSS-CRC) 
10% 
30% 
0.1 
80 
7 
≥ 1/7 
11 
≥ 4/18 
B1 (BTC) 
20% 
40% 
0.1 
80 
12 
≥ 3/12 
13 
≥ 8/25 
B2 (OC) 
15% 
35% 
0.1 
80 
9 
≥ 2/9 
14 
≥ 6/23 
C1 (GC) 
15% 
35% 
0.1 
80 
9 
≥ 2/9 
14 
≥ 6/23 
C2 (EC)  
15% 
35% 
0.1 
80 
9 
≥ 2/9 
14 
≥ 6/23 
C3 (OC)  
15% 
35% 
0.1 
80 
9 
≥ 2/9 
14 
≥ 6/23 
 
Primary Analysis: 
The following safety and efficacy analyses will be assessed for all subjects in each treatment 
combination: 
• Phase 1:  Safety/tolerability/DLTs/RP2D, in all patients receiving at least 1 dose of study drug 
(safety population), as assessed by AEs, clinical laboratory assessments (including urine orotic acid), 
physical examination results, and 12-lead ECG results. 
• Phase 2:  ORR, defined as the percentage of subjects having a CR or PR, as determined by 
investigator assessment of radiographic disease as per RECIST v1.1 will be summarized for by 
expansion cohort. 
Secondary Analyses: 
The following safety and efficacy analyses will be assessed for all subjects in each treatment 
combination: 
• Phase 2:  Safety/tolerability/DLTs/RP2D, in all patients receiving at least 1 dose of study drug 
(safety population), as assessed by AEs, clinical laboratory assessments (including urine orotic acid), 
physical examination results, and 12-lead ECG results. 
• ORR, defined as the percentage of subjects having a CR or PR, as determined by investigator 
assessment of radiographic disease as per RECIST v1.1 (Phase 1 only). 
• DOR, defined as the time from earliest date of CR or PR until the earliest date of disease progression 
per RECIST v1.1 or death due to any cause, if occurring sooner than progression. 
• DCR, defined as the percentage of subjects having CR, PR, or SD for at least 8 weeks, as determined 
by investigator assessment of radiographic disease as per RECIST v1.1. 
• PFS, defined as the time from date of first dose of study drug until the earliest date of disease 
progression (as determined by investigator assessment of objective radiographic disease assessments 
per RECIST v1.1) or death due to any cause, if occurring sooner than progression. 


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• The PK parameters of Cmax, tmax, Cmin, AUC0-t, and AUC0-τ (INCB001158) for first 12 subjects 
enrolled in Phase 2 will be calculated from the blood plasma concentrations of INCB001158 using 
standard noncompartmental (model independent) PK methods. 
Interim Analysis: 
In Phase 1, the BOIN design will be used to determine the RP2D of INCB001158 in combination with 
each chemotherapy regimen.  To avoid assigning too many subjects to an overly toxic dose, we use the 
dose elimination rule when implementing the BOIN design.  When ≥ 3 subjects have been treated, if 
the probability that the estimated toxicity rate that is above the target DLT rate is > 95% at a certain 
dose level, then this dose level and higher dose levels are assumed too toxic and will be eliminated. 
In Phase 2, the Simon 2-stage design will be applied for each tumor within a given expansion cohort.  
During Stage 1, n1 evaluable subjects treated at the recommended dose and schedule will be enrolled, 
and if r1 or fewer responses are observed, then the cohort will be discontinued. 
 


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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................23 
1. 
INTRODUCTION ......................................................................................................26 
1.1. 
Background .................................................................................................................26 
1.1.1. 
Role of the Immune System in Cancer .......................................................................26 
1.1.2. 
Targeting Myeloid-Derived Suppressor Cells and Arginase in Cancer .....................26 
1.1.3. 
Overview of INCB001158 ..........................................................................................28 
1.1.3.1. 
Activity of the Arginase 1 Inhibitor INCB001158 in Solid Tumors ..........................28 
1.1.4. 
Overview of FOLFOX in Colorectal Cancer ..............................................................28 
1.1.5. 
Overview of Gemcitabine/Cisplatin in Biliary Tract Cancer .....................................29 
1.1.6. 
Overview of Gemcitabine/Cisplatin and Paclitaxel in Ovarian Cancer .....................29 
1.1.7. 
Overview of Paclitaxel in Gastroesophageal Cancer ..................................................30 
1.1.8. 
Overview of Paclitaxel in Endometrial Cancer ..........................................................30 
1.2. 
Study Rationale ...........................................................................................................31 
1.2.1. 
Rationale for Combining INCB001158 With Chemotherapy ....................................31 
1.2.2. 
Rationale for Study Population ...................................................................................31 
1.2.2.1. 
Colorectal Cancer .......................................................................................................31 
1.2.2.2. 
Biliary Tract Cancer ...................................................................................................32 
1.2.2.3. 
Ovarian Cancer ...........................................................................................................32 
1.2.2.4. 
Gastroesophageal Cancer ............................................................................................33 
1.2.2.5. 
Endometrial Cancer ....................................................................................................34 
1.2.3. 
Rationale for the Dose and Schedule of INCB001158 ...............................................34 
1.2.4. 
Rationale for Study Endpoints ....................................................................................34 
1.2.4.1. 
Primary Endpoints ......................................................................................................34 
1.2.4.2. 
Secondary Endpoints ..................................................................................................35 
 
35 
1.3. 
Potential Risks and Benefits of the Treatment Regimen ............................................35 
1.3.1. 
Risks From INCB001158 ...........................................................................................35 
1.3.1.1. 
Potential Urea Cycle Toxicity ....................................................................................36 
1.3.1.2. 
Immune-Related Adverse Events ...............................................................................37 
1.3.1.3. 
Alterations in Hemodynamic Status ...........................................................................37 


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1.3.1.4. 
Clinical Experience .....................................................................................................38 
1.3.2. 
Risks From mFOLFOX6 ............................................................................................38 
1.3.3. 
Risks From Gemcitabine/Cisplatin .............................................................................38 
1.3.4. 
Risks From Paclitaxel .................................................................................................39 
1.3.5. 
Risks From the Combination of INCB001158 and Chemotherapy ............................39 
1.3.6. 
Benefits of the Combination of INCB001158 and Chemotherapy .............................40 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................41 
3. 
SUBJECT ELIGIBILITY ...........................................................................................43 
3.1. 
Subject Inclusion Criteria ...........................................................................................43 
3.2. 
Subject Exclusion Criteria ..........................................................................................46 
4. 
INVESTIGATIONAL PLAN .....................................................................................48 
4.1. 
Overall Study Design ..................................................................................................48 
4.1.1. 
Phase 1:  Dose Escalation of INCB001158 + Chemotherapy ....................................49 
4.1.2. 
Phase 2:  Tumor Expansion Cohorts of INCB001158 + Chemotherapy ....................52 
4.2. 
Measures Taken to Avoid Bias ...................................................................................54 
4.3. 
Number of Subjects ....................................................................................................55 
4.3.1. 
Planned Number of Subjects ......................................................................................55 
4.3.2. 
Replacement of Subjects .............................................................................................55 
4.4. 
Duration of Treatment and Subject Participation .......................................................55 
4.5. 
Overall Study Duration ...............................................................................................55 
4.6. 
Study Termination ......................................................................................................56 
5. 
TREATMENT ............................................................................................................56 
5.1. 
Treatment Assignment ................................................................................................56 
5.1.1. 
Subject Numbering and Treatment Assignment .........................................................56 
5.1.2. 
Randomization and Blinding ......................................................................................56 
5.2. 
Study Drug and Other Study Treatments ....................................................................56 
5.2.1. 
INCB001158 ...............................................................................................................57 
5.2.1.1. 
Description and Administration ..................................................................................57 
5.2.1.2. 
Supply, Packaging, and Labeling ...............................................................................57 
5.2.1.3. 
Storage ........................................................................................................................57 
5.2.1.4. 
Instruction to Subjects for Handling Study Drug (INCB001158) ..............................57 
5.2.2. 
mFOLFOX6 ................................................................................................................58 
5.2.2.1. 
Description and Administration ..................................................................................58 


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5.2.2.2. 
Supply, Packaging, Labeling, and Storage .................................................................59 
5.2.3. 
Gemcitabine/Cisplatin ................................................................................................59 
5.2.3.1. 
Description and Administration ..................................................................................59 
5.2.3.2. 
Supply, Packaging, Labeling, and Storage .................................................................59 
5.2.4. 
Paclitaxel .....................................................................................................................60 
5.2.4.1. 
Description and Administration ..................................................................................60 
5.2.4.2. 
Supply, Packaging, Labeling, and Storage .................................................................60 
5.3. 
Treatment Compliance ................................................................................................60 
5.4. 
Treatment Interruptions and Adjustments ..................................................................61 
5.4.1. 
Dose Modifications .....................................................................................................61 
5.4.1.1. 
INCB001158 ...............................................................................................................61 
5.4.2. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose in 
Phase 1 ........................................................................................................................61 
5.4.3. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ......................62 
5.4.4. 
Follow-Up of Dose-Limiting Toxicities .....................................................................63 
5.4.5. 
Procedures for Cohort Review and Dose Escalation ..................................................63 
5.4.6. 
Dose Modifications for Immune-Related Adverse Events and Adverse 
Events Related to Urea-Cycle Inhibition ....................................................................63 
5.4.7. 
Management of Chemotherapy-Related Adverse Events ...........................................68 
5.4.8. 
Supportive Care Guidelines for Management of Hyperammonemia .........................68 
5.4.9. 
Criteria for Permanent Discontinuation of Study Drug ..............................................68 
5.5. 
Withdrawal of Subjects From Study Treatment .........................................................69 
5.5.1. 
Withdrawal Criteria ....................................................................................................69 
5.5.2. 
Withdrawal Procedures ...............................................................................................70 
5.6. 
Concomitant Medications ...........................................................................................70 
5.6.1. 
Permitted Medications ................................................................................................71 
5.6.2. 
Restricted Medications ...............................................................................................71 
5.6.3. 
Prohibited Medications ...............................................................................................71 
6. 
STUDY ASSESSMENTS ..........................................................................................73 
6.1. 
Screening ....................................................................................................................85 
6.2. 
Treatment ....................................................................................................................86 
6.3. 
End of Treatment ........................................................................................................86 
6.4. 
Follow-Up ...................................................................................................................86 


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6.4.1. 
Safety Follow-Up ........................................................................................................86 
6.4.2. 
Disease Status Follow-Up ...........................................................................................87 
 
 
6.5. 
End of Study ...............................................................................................................88 
6.6. 
Unscheduled Visits .....................................................................................................88 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ...........................89 
7.1. 
Administration of Informed Consent Form ................................................................89 
7.2. 
Interactive Response Technology Procedure ..............................................................89 
7.3. 
Demography and Medical History ..............................................................................89 
7.3.1. 
Demographics and General Medical History .............................................................89 
7.3.2. 
Disease Characteristics and Treatment History ..........................................................89 
7.4. 
Prior and Concomitant Medications and Procedures ..................................................89 
7.5. 
Post-Treatment Anticancer Therapy Status ................................................................90 
7.6. 
Safety Assessments .....................................................................................................90 
7.6.1. 
Adverse Events ...........................................................................................................90 
7.6.2. 
Physical Examinations ................................................................................................90 
7.6.2.1. 
Comprehensive Physical Examination .......................................................................90 
7.6.2.2. 
Targeted Physical Examination ..................................................................................91 
7.6.3. 
Vital Signs ..................................................................................................................91 
7.6.4. 
Electrocardiograms .....................................................................................................91 
7.6.5. 
Laboratory Assessments .............................................................................................91 
7.6.5.1. 
Chemistries .................................................................................................................92 
7.6.5.2. 
Urinalysis ....................................................................................................................92 
7.6.5.3. 
Plasma Ammonia ........................................................................................................92 
7.6.5.4. 
Pregnancy Testing ......................................................................................................92 
7.6.5.5. 
CA 125 Monitoring.....................................................................................................93 
7.6.5.6. 
Hepatitis and HIV Screening Tests .............................................................................93 
7.6.5.7. 
Coagulation Panel .......................................................................................................93 
7.7. 
Efficacy Assessments .................................................................................................93 
7.7.1. 
Tumor Imaging and Assessment of Disease ...............................................................93 
7.7.1.1. 
Initial Tumor Imaging .................................................................................................94 
7.7.1.2. 
Tumor Imaging During the Study...............................................................................94 
7.7.1.3. 
End-of-Treatment and Follow-Up Imaging ................................................................95 


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7.7.1.4. 
RECIST v1.1 Assessment of Disease .........................................................................95 
 
95 
7.8. 
Performance and Quality-of-Life Assessments ........................................................100 
7.8.1. 
Eastern Cooperative Oncology Group Performance Status ......................................100 
7.9. 
Pharmacokinetic Assessments ..................................................................................100 
7.9.1. 
Blood Sample Collection ..........................................................................................100 
7.9.2. 
Bioanalytical Methodology and Analysis .................................................................101 
.101 
.101 
.101 
.101 
.101 
.102 
.102 
7.11. 
Other Study Procedures ............................................................................................102 
7.11.1. 
Distribution of Subject Reminder Cards and/or Subject Diaries ..............................102 
 
 
8. 
SAFETY MONITORING AND REPORTING .......................................................103 
8.1. 
Adverse Events .........................................................................................................103 
8.1.1. 
Definitions ................................................................................................................103 
8.1.2. 
Reporting ..................................................................................................................103 
8.2. 
Laboratory Test Abnormalities .................................................................................105 
8.3. 
Serious Adverse Events ............................................................................................105 
8.3.1. 
Definitions ................................................................................................................105 
8.3.2. 
Reporting ..................................................................................................................106 
8.4. 
Emergency Unblinding of Treatment Assignment ...................................................107 
8.5. 
Pregnancy .................................................................................................................107 
8.6. 
Warnings and Precautions ........................................................................................108 
8.7. 
Product Complaints ..................................................................................................108 
9. 
STATISTICS ............................................................................................................109 
9.1. 
Study Populations .....................................................................................................109 
9.2. 
Selection of Sample Size ..........................................................................................109 
9.2.1. 
Sample Size for Phase 1 ...........................................................................................109 


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9.2.2. 
Sample Size for Phase 2 ...........................................................................................109 
9.3. 
Level of Significance ................................................................................................110 
9.4. 
Statistical Analyses ...................................................................................................110 
9.4.1. 
Efficacy Analyses .....................................................................................................110 
9.4.1.1. 
Primary Efficacy Analyses .......................................................................................110 
9.4.1.2. 
Secondary Efficacy Analyses ...................................................................................110 
 
111 
9.4.2. 
Safety Analyses ........................................................................................................111 
9.4.2.1. 
Adverse Events .........................................................................................................111 
9.4.2.2. 
Clinical Laboratory Tests .........................................................................................111 
9.4.2.3. 
Vital Signs ................................................................................................................112 
9.4.2.4. 
Electrocardiograms ...................................................................................................112 
9.4.2.5. 
Adverse Events of Special Interest ...........................................................................112 
9.4.3. 
Pharmacokinetic Analysis ........................................................................................113 
 
113 
9.5. 
Interim Analyses .......................................................................................................113 
9.5.1. 
Interim Analysis for the BOIN Design .....................................................................113 
9.5.2. 
Interim Analysis for the Simon 2-Stage Design .......................................................113 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ........................................................................................................115 
10.1. 
Investigator Responsibilities .....................................................................................115 
10.1.1. 
Identification of the Coordinating Principal Investigator .........................................116 
10.2. 
Accountability, Handling, and Disposal of Study Drug ...........................................116 
10.3. 
Data Management .....................................................................................................117 
10.4. 
Data Privacy and Confidentiality of Study Records .................................................117 
10.5. 
Financial Disclosure .................................................................................................118 
10.6. 
Publication Policy .....................................................................................................118 
10.7. 
Study and Site Closure..............................................................................................119 
11. 
REFERENCES .........................................................................................................120 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS .............................................................................125 
APPENDIX B. PHARMACOKINETIC ANALYTICAL PARAMETERS ............................126 
APPENDIX C. DOSE MODIFICATIONS FOR MFOLFOX6 ...............................................127 


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APPENDIX D. DOSE MODIFICATIONS FOR GEMCITABINE/CISPLATIN ...................131 
APPENDIX E. DOSE MODIFICATIONS FOR PACLITAXEL ............................................135 
APPENDIX F. CYP2C8 AND CYP3A4 INHIBITORS AND INDUCERS ............................137 
APPENDIX G. PROTOCOL AMENDMENT SUMMARY OF CHANGES .........................146 
 
LIST OF TABLES 
Table 1: 
Study Objectives and Endpoints .................................................................................41 
Table 2: 
Treatment Groups for Subjects Enrolled in Phase 1 Dose Escalation ........................50 
Table 3: 
INCB001158 Dose Cohorts ........................................................................................50 
Table 4: 
Dose Escalation, De-Escalation, and Elimination Boundaries for Target DLT 
Rate of 33% in Phase 1 ...............................................................................................51 
Table 5: 
Dose Escalation, De-Escalation, and Elimination Boundaries for Target DLT 
Rate of 33% for Cohort Expansion in Phase 1 ...........................................................52 
Table 6: 
Expansion Cohorts for Subjects Enrolled in Phase 2 Tumor Expansion ....................53 
Table 7: 
Phase 2:  Simon 2-Stage Design .................................................................................54 
Table 8: 
Recommended Premedication Schedule.....................................................................60 
Table 9: 
Definition of Dose-Limiting Toxicity ........................................................................62 
Table 10: Dose Modification and Toxicity Management Guidelines for Adverse Events 
Related to INCB001158 .............................................................................................64 
Table 11: Schedule of Assessments for Subjects Treated With INCB001158 + 
mFOLFOX6 or INCB001158 + Paclitaxel .................................................................74 
Table 12: Schedule of Laboratory Assessments for Subjects Treated With 
INCB001158 + mFOLFOX6 or INCB001158 + Paclitaxel .......................................76 
Table 13: Schedule of Assessments for Subjects Treated With INCB001158 + 
Gemcitabine and Cisplatin ..........................................................................................79 
Table 14: Schedule of Laboratory Assessments for Subjects Treated With 
INCB001158 + Gemcitabine and Cisplatin ................................................................81 
Table 15: Schedule of Assessments for All Subjects (as of Protocol Amendment 4) ................84 
Table 16: Laboratory Tests:  Required Analytes ........................................................................85 
Table 17: Sample Collection Time Windows for Urine Assessments of Orotic Acid ...............92 
Table 18: Imaging and Treatment After First Radiologic Evidence of PD ................................99 
Table 19: Eastern Cooperative Oncology Group Performance Status Scoring ........................100 
Table 20: Extensive Sample Collection Time Windows for Pharmacokinetic 
Assessments for INCB001158 in the First 12 Subjects Enrolled in Each 
Chemotherapy Regimen in Phase 2 ..........................................................................100 


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Table 21: Sparse Sample Collection Time Windows for Pharmacokinetic Assessments 
for INCB001158 in Phase 1 and in the Thirteenth Subject Onwards Enrolled 
in Phase 2 ..................................................................................................................101 
Table 22: Criteria for Clinically Notable Vital Sign Abnormalities .........................................112 
Table 23: Criteria for Clinically Notable Electrocardiogram Abnormalities ...........................112 
Table 24: Probability of Early Termination for Simon 2-Stage Design ...................................114 
 
LIST OF FIGURES 
Figure 1: 
Arginase and Arginine in Cancer Patients ..................................................................27 
Figure 2: 
Study Design ...............................................................................................................49 
 


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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviation 
Definition 
5FU 
5-fluoroucil 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BID 
twice daily dosing 
BOIN 
Bayesian Optimal Interval 
BTC 
biliary tract cancer 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CrCl 
creatinine clearance  
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DCR 
disease control rate 
DKA 
diabetic ketoacidosis 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
EC 
endometrial cancer 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FOLFIRI 
folinic acid, 5FU, and irinotecan 
FOLFOX 
folinic acid, 5FU, and oxaliplatin 
mFOLFOX6 
modified FOLFOX6 
GC 
gastroesophageal cancer 
G-CSF 
granulocyte-colony stimulating factor 


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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
GEJ 
gastroesophageal junction 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
IB 
Investigator's Brochure 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
 
 
 
 
IEC 
independent ethics committee 
 
 
IN 
Investigator Notification 
INR 
international normalized ratio 
 
 
irAE 
immune-related adverse event 
IRB 
institutional review board 
 
 
 
IRT 
interactive response technology 
 
 
 
 
LFT 
liver chemistry test 
MDSC 
myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
 
 
MSI-H 
high microsatellite instability 
MTD 
maximum tolerated dose 
MSI 
microsatellite instability 
MSS 
microsatellite-stable 
NCI 
National Cancer Institute 
NO 
nitric oxide 
NSCLC 
non–small cell lung cancer 


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Abbreviation 
Definition 
OC 
ovarian cancer 
ORR 
objective response rate 
 
 
PAD 
pharmacologically active dose 
PD 
progressive disease 
PD-1 
programmed death-1 receptor 
PD-L1 
programmed death-1 receptor ligand 
PD-L2 
programmed death-2 receptor ligand 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PO 
orally 
PR 
partial response 
PT 
prothrombin time 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
RT 
radiation therapy 
SAE 
serious adverse event 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SmPC 
Summary of Product Characteristics 
SUSAR 
suspected unexpected serious adverse reaction 
T1DM 
Type 1 diabetes mellitus 
TEAE 
treatment-emergent adverse event 
Tregs 
regulatory T-cells 
ULN 
upper limit of normal 
USPI 
United States Package Insert 
VEGF 
vascular endothelial growth factor 


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1. 
INTRODUCTION 
1.1. 
Background 
1.1.1. 
Role of the Immune System in Cancer 
Although the immune system can recognize and kill transformed cells, clinically evident tumors 
have evaded immune destruction through different immune escape mechanisms.  A complex 
network of interacting mechanisms governs the establishment and maintenance of 
cancer-induced immunosuppression.  Immunosuppression is mediated through production of 
anti-inflammatory mediators, induction of T-cell anergy, and recruitment of immunoregulatory 
cells, such as Tregs and tolerogenic myeloid populations.  The promotion of suppressor cells and 
Tregs by tumors plays a central role in escape from immunosurveillance including induction of 
an immunosuppressive tumor microenvironment (Kumar et al 2016). 
Targeting the immune system is a proven effective approach for the treatment of cancer, and 
immunotherapy is now an accepted standard of care in several tumor types.  Immune checkpoint 
inhibitors targeting co-inhibitory receptors such as CTLA-4 and PD-1 provide a critical 
mechanism for restoring host immune response against the tumor (Chen and Mellman 2013). 
Evasion of tumor cells from immune elimination represents a major obstacle in cancer 
immunotherapy.  Although these agents have antitumor activity in patient subsets when 
administered as monotherapy, multiple immune inhibitory mechanisms are present concurrently 
within the tumor microenvironment, suggesting that combination therapies may be required for 
optimal therapeutic effect (Quezada et al 2013). 
1.1.2. 
Targeting Myeloid-Derived Suppressor Cells and Arginase in Cancer 
Myeloid-derived suppressor cells are immunosuppressive cells that play a critical role in 
maintaining normal homeostasis but under chronic inflammatory conditions can skew the 
environment toward supporting tumor development and metastasis (Meirow et al 2015).  The 
immunosuppressive tumor microenvironment is a key obstacle that has been described to hinder 
cancer immunity (Gabrilovich 2017).  Solid tumors have been shown to have moderate to 
extensive infiltration of immunosuppressive myeloid cells (Messmer et al 2015, Solito 
et al 2014).  MDSCs and neutrophils are present in multiple solid tumors and correlate with poor 
outcome (Gentles et al 2015).  MDSCs have been shown to be significantly increased in cancer 
patients of all stages relative to healthy volunteers, with a significant correlation between 
circulating MDSC, metastatic burden, and clinical cancer stage (Diaz-Montero et al 2009).  
Therefore, MDSCs are considered new therapeutic targets for the treatment of cancer 
(Wesolowski et al 2013).  MDSCs secrete anti-inflammatory cytokines and express 
immunosuppressive metabolic enzymes, such as arginase. 
Arginase catalyzes the hydrolytic conversion of arginine to ornithine and urea.  There are 
2 arginase isoforms, arginase 1 and arginase 2, that catalyze the same chemical reaction but 
differ in terms of their regulation, subcellular localization, and cellular/tissue expression.  
Arginase 1 is a cytosolic enzyme primarily and abundantly found in liver hepatocytes, where it 
plays a crucial role in ammonia detoxification by catalyzing the final step of the urea cycle.  
A separate gene encodes arginase 2 (gene symbol:  ARG2), a mitochondrial enzyme that is more 
widely expressed across cell types. 


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In the immune system, both granulocytic MDSCs and neutrophils contain the enzyme arginase 1 
within secretory granules.  Upon stimulation by factors within the tumor microenvironment 
(eg, pro-inflammatory cytokines, such as interleukin-8 [IL-8] and tumor necrosis factor-alpha 
[TNF-α]), arginase is released into the tumor microenvironment via degranulation, resulting in 
substantial local depletion of the amino acid arginine (Rotondo et al 2009, Raber et al 2012).  
Arginase-mediated arginine depletion is an effective way to control adaptive immune responses 
as adequate levels of arginine are crucial for T-cell proliferation and function (Munder 2009, 
Rodriguez et al 2007).  Arginine itself is a critical factor in the proliferation and activation of 
cytotoxic T cells and natural killer cells.  Antitumor activity has been reported in mice when 
arginase is knocked out in the myeloid lineage (Colegio et al 2014). 
Immunohistochemical (IHC) staining of tumor microarrays from multiple histotypes revealed 
that tumor cells themselves generally did not stain positive for arginase 1.  Instead, large 
numbers of infiltrating polymorphonuclear cells containing arginase 1 were found across many 
histotypes with the greatest frequency in lung, colorectal, gastric, and bladder cancers 
(Figure 1 [A]).  The positive arginase 1 IHC staining in tumor microarrays in this study was 
largely confined to polymorphonuclear cells based on morphology.  Analysis of plasma from 
cancer patients across multiple histotypes demonstrated elevated arginase 1 protein levels and 
lower arginine levels compared with normal healthy control subjects (Figure 1 [B, C]). 
 
 
 
Figure 1: 
Arginase and Arginine in Cancer Patients 
 
[A] Frequency of arginase 1 expressing cells infiltrating human solid tumors.  Digital quantification of arginase 
expression in myeloid cells was performed and the number of arginase 1–positive cells per mm2 is plotted.  
[B] Arginase protein and [C] arginine levels in plasma of cancer patients versus healthy volunteers. 


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1.1.3. 
Overview of INCB001158 
1.1.3.1. 
Activity of the Arginase 1 Inhibitor INCB001158 in Solid Tumors 
INCB001158 (formerly known as CB-1158) is a potent, selective, and reversible inhibitor of 
human recombinant arginase 1 and 2 (IC50 of 100 and 275 nM, respectively). 
In cell-based assays, INCB001158 reversed the growth suppressive effects of human neutrophils 
on human T-cells when co-cultured ex vivo with an EC50 of 162 nM.  Similarly, INCB001158 
reversed inhibition of T-cell growth by patient-derived MDSCs with similar potency.  In both 
cases, INCB001158 was able to antagonize the depletion of arginine mediated by neutrophils or 
MDSCs in a dose-dependent fashion.  INCB001158 has no direct growth inhibitory or cytotoxic 
activity on tumor cells or on immune effector cells. 
INCB001158 has single-agent and combination activity in syngeneic tumor models.  Oral BID 
administration of single-agent INCB001158 produced a dose-dependent reduction in the growth 
of subcutaneously implanted LLC (lung) tumors.  The efficacy of INCB001158 in LLC tumors is 
immune-mediated.  When LLC tumors were grown in immuno-compromised severe combined 
immunodeficiency mice, there was no antitumor activity of INCB001158.  The combination of 
INCB001158 with gemcitabine or paclitaxel in CT26 (colon), 4T1 (breast), LLC (lung) and 
paclitaxel plus anti–PD-L1 in B16-F10 (melanoma) tumor models resulted in enhanced 
antitumor activity.  INCB001158 combinations with an IDO inhibitor and/or 
anti–PD-L1 also demonstrated antitumoral activity. 
The safety and tolerability of INCB001158 in subjects with advanced or metastatic solid tumors 
is being evaluated in the ongoing first-in-human Phase 1 study, INCB 01158-101 (formerly 
CX-1158-101).  Early data from monotherapy dose-escalation cohorts (data cutoff date:  
24 APR 2017) showed that oral dosing of INCB001158 was well-tolerated at the first 3 doses 
tested (50, 100, and 150 mg BID); the steady-state trough levels of INCB001158 were above the 
IC90 for arginase inhibition at all dose levels, with 90% to 95% inhibition of plasma arginase and 
increases in plasma arginine, and there was preliminary evidence of peripheral immune 
modulation (Papadopoulos et al 2017). 
Refer to the IB for additional details of the INCB001158 preclinical experiments and updated 
data from the clinical study INCB 01158-101. 
1.1.4. 
Overview of FOLFOX in Colorectal Cancer 
CRC is the third most commonly diagnosed cancer and a leading cause of death worldwide.  
Patients with advanced or metastatic CRC receive combined chemotherapies, FOLFOX, and 
FOLFIRI as standard first-line treatment.  There are several different FOLFOX regimens that 
differ in the doses and ways in which the 3 drugs are given, and the modified regimen 
(mFOLFOX6) utilizes infusional administration of 5-FU.  The second-line therapy regimen 
usually includes agents that were not used in the first chemotherapy backbone (Van Cutsem 
et al 2016).  Thus, FOLFOX treatment can be used in the second and third-line setting after 
failure of a 5-FU– or an irinotecan-based prior line treatment, producing an ORR of 
approximately 10% with a PFS of approximately 5 months in second line (Guglielmi et al 2007).  
The anti-EGFR bevacizumab is approved in combination with a fluoropyrimidine-based regimen 
and is an option to consider in the second-line treatment, as well as other anti-angiogenic 
compounds, such as aflibercept or ramucirumab.  Studies with immune checkpoint inhibitors 


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reported ORRs in the range of 26% to 57% in refractory patients with MSI-H CRC compared to 
0% to 5% in MSS-CRC, indicating the need to improve the ORRs in MSS-CRC patients (Boland 
and Ma 2017). 
1.1.5. 
Overview of Gemcitabine/Cisplatin in Biliary Tract Cancer 
BTC is a relatively uncommon cancer in developed countries with approximately 1200 new 
cases in the United Kingdom and 9000 new cases in the United States per year.  Most patients 
present with locally advanced (nonresectable) or metastatic disease and recurrence is frequent, 
even when surgery is feasible.  The median survival with best supportive care in randomized 
studies is between 2.5 and 4.5 months.  Gemcitabine has been found to exhibit synergistic effects 
on cytotoxic activity in vitro and in vivo when combined with cisplatin.  The combination of 
gemcitabine with cisplatin for the treatment of BTC was initially studied in small observational 
and retrospective studies and then established in the Phase 2 ABC-01 study.  Based on the 
Phase 3 ABC-02 study, the gemcitabine-cisplatin combination therapy has been accepted as 
standard first-line chemotherapy treatment in patients with advanced BTC (Valle et al 2010).  
The median OS rate for the combination therapy group was 11.7 months compared with 
8.1 months for gemcitabine alone, and median PFS was 8.0 months compared with 5.0 months, 
respectively.  ORR was also higher in the gemcitabine-cisplatin group, and the combination 
therapy had an acceptable toxicity profile.  The gemcitabine-oxaliplatin regimen used in other 
studies produced a median OS rate of 10 months and median PFS of 4.2 months (Fiteni 
et al 2014).  ORRs of approximately 20% have been reported for gemcitabine-cisplatin as 
first-line treatment for patients with advanced BTC (Bridgewater et al 2016). 
1.1.6. 
Overview of Gemcitabine/Cisplatin and Paclitaxel in Ovarian Cancer 
Epithelial OC remains the most lethal gynecologic malignancy, with an overall 5-year survival 
rate of 45%.  Nearly 80% of patients with advanced stage OC will have tumor progression, or 
more commonly a recurrence.  The international standard for first-line treatment of advanced 
disease is surgery and a chemotherapy combination of a taxane (usually paclitaxel) and a 
platinum agent.  The PFS has remained fairly constant at about 18 months.  Platinum-resistant 
disease is defined as patients whose recurrence is documented within 6 months of 
platinum-based chemotherapy, and the prognosis is especially disappointing.  Treatment of 
recurrent platinum-resistant ovarian and peritoneal cancers represents a therapeutic challenge, 
and response rates with single-agent chemotherapy have been in the 10% to 20% range 
(Kumar et al 2010). 
Gemcitabine has been found to be active in women with primary and recurrent OC.  The addition 
of gemcitabine to cisplatin may have synergistic tumoricidal activity among women with 
recurrent OC, and response rates were reported in the range of 16% to 70%; median 
progression-free intervals were 4 to 7 months, and response rates were in the range of 20% in 
platinum-resistant tumors (Eltabbakh et al 2016). 
Paclitaxel is a front-line agent for OC chemotherapy, along with the platinum agents.  Paclitaxel 
has been one of the most promising drugs to enter into clinical studies in the setting of 
cisplatin-refractory OC.  Responses have been reported in both heavily and minimally pretreated 
OC patients (20%-37%), but myelotoxicity was found to be a major concern.  The activity of 
paclitaxel in epithelial OC is dose-dependent, and a randomized study (Rosenberg et al 2002) has 


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shown reduced toxicity and similar efficacy with weekly administration compared with every 
3 weeks.  Weekly paclitaxel has response rate of 20% to 25% in platinum-resistant, recurrent, 
OC patients and is associated with a favorable toxicity profile.  In a Phase 3 study comparing 
weekly paclitaxel 80 mg/m2 to paclitaxel 175 mg/m2 every 3 weeks, the ORRs were 27% and 
16%, respectively (Osman et al 2016). 
1.1.7. 
Overview of Paclitaxel in Gastroesophageal Cancer 
Gastric cancer is the fifth most common cancer worldwide, with the highest incidence in East 
Asia.  Most cases, especially in the United States and Europe, are diagnosed at a late stage after 
becoming metastatic.  Patients with advanced disease have a poor prognosis, with a median OS 
of 10 to 12 months (Digklia et al 2016).  Treatment options of metastatic disease are mostly 
restricted to cytotoxic chemotherapy, but even these are associated with poor outcomes.  
Although recent Phase 3 studies showed some benefit from chemotherapy regimens including 
docetaxel, capecitabine, irinotecan, cisplatin, and oxaliplatin (median OS and PFS in of 
approximately 5 months), there is no internationally accepted standard-of-care for second-line 
treatment (Bilici 2014).  Despite the availability of trastuzumab for patients with human 
epidermal growth factor receptor 2–positive disease and the approval of the anti-VEGFR2 
monoclonal antibody ramucirumab as a second-line therapy, there still remains a need for 
effective treatment options for advanced gastric cancer.  Ramucirumab in combination with 
paclitaxel in second-line treatment of GC improved median OS (9.6 months vs 7.4 months) and 
PFS (4.4 months vs 2.9 months) compared with paclitaxel alone (Wilke et al 2014). 
Paclitaxel and irinotecan are considered standard second-line treatments for metastatic GEJ and 
gastric adenocarcinoma patients following disease progression on first-line platinum- and 
fluoropyrimidine-containing combination therapies (Hironaka et al 2013).  Median OS was 
9.5 months in subjects treated with weekly paclitaxel and 8.4 months in the irinotecan group, 
while response rates were 20.9% and 13.6%, respectively.  Weekly paclitaxel produced a 
response rate of 7.3% in a Phase 3 study in subjects with gastric carcinoma or adenocarcinoma of 
the esophagogastric junction that had progressed after treatment with a 
fluoropyrimidine/platinum-containing regimen (Al-Batran et al 2017). 
1.1.8. 
Overview of Paclitaxel in Endometrial Cancer 
Endometrial cancer is the only gynecologic malignancy with a rising incidence and mortality 
(Longoria and Eskander 2015).  At the time of diagnosis, 67% of women have disease confined 
to the uterus and an associated 5-year survival rate of 95%, whereas patients with metastatic or 
recurrent disease have a 5-year survival rate of 16% (Siegel et al 2016).  The standard-of-care in 
first-line treatment of metastatic endometrial carcinoma is paclitaxel with carboplatin or 
cisplatin, with both regimens producing similar ORR (approximately 51%), PFS (median 8 to 
13 months), and OS (median 12 to 15 months) rates.  Women who progress on first-line 
cytotoxic chemotherapy have largely chemoresistant disease associated with poor prognosis, and 
there is currently no consensus on treatment in the second- and third-line settings 
(Colombo et al 2016).  Studies of cytotoxic therapies used in the second-line setting have 
generally produced RRs of 15% or lower, and only paclitaxel has consistently shown a response 
rate above 20%.  Studies with weekly paclitaxel as first-line and second-line treatment have 
reported anticancer activity with an acceptable toxicity profile in advanced EC.  Modest ORRs 
ranging from 0% to 24.5% were reported with targeted agents such as angiogenesis inhibitors, 


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EGFR inhibitors, and mTOR inhibitors in patients with advanced stage and recurrent EC 
(Fleming et al 2015). 
1.2. 
Study Rationale 
1.2.1. 
Rationale for Combining INCB001158 With Chemotherapy 
While chemotherapy has largely been thought to be immunosuppressive and exert its effect via 
direct cytotoxicity, there is an emerging body of evidence to suggest that some chemotherapies 
may influence an immune response in tumors via induction of immunogenic cell death, 
elimination of immunosuppressive cells, or sensitization of tumor cells to immune effector cells 
(Apetoh et al 2015).  Certain chemotherapeutic agents improve host immune responses and even 
break immune tolerance.  FOLFOX may induce a decrease in granulocytic MDSCs, high levels 
of which are associated with a poor prognosis (Kanterman et al 2014, Limagne et al 2016).  
Platinum agents have demonstrated immunogenic effects that can lead to immunogenic cell 
death, thereby stimulating the immune system.  Gemcitabine and cyclophosphamide have been 
shown to improve antitumor immunity by depleting Tregs, inhibiting their suppressor function, 
and leading to peripheral T-cell proliferation and natural killer cell activities (Ghiringhelli 
et al 2007, Le and Jaffee 2012, Shevchenko et al 2013).  Gemcitabine reduces granulocytic 
MDSCs but not monocytic MDSCs, and MDSC levels correlate with shorter survival in patients 
with pancreatic adenocarcinoma (Eriksson et al 2017, Gabitass et al 2011).  Paclitaxel and 
5-fluorouracil have been shown to kill MDSCs and restore antitumor activity of CD8+ T cells in 
experimental models (Sevko et al 2013, Apetoh et al 2011, Vincent et al 2010).  Low dose 
paclitaxel can stimulate tumor-associated macrophage–mediated cytotoxic immune response 
in vivo (Park et al 2013).  In summary, some standard chemotherapy agents can impact both the 
tumor and host immune system, which provide strong rationale for their combination with 
selective immunotherapeutic interventions (Bracci et al 2014, Hato et al 2014). 
Given these findings, the combination of different types of chemotherapy with the arginase 
inhibitor INCB001158 is a rational choice, especially in patients with limited or suboptimal 
treatment options.  It is, therefore, expected that arginase inhibitor agents used in combination 
with chemotherapy regimens, such as mFOLFOX6, gemcitabine/cisplatin, and paclitaxel, may 
result in greater immunomodulatory effects in the tumor microenvironment and thereby enhance 
the clinical benefit in subjects with advanced or metastatic solid tumors (Draghiciu et al 2015). 
1.2.2. 
Rationale for Study Population 
Subjects with previously treated advanced solid tumors who have progressed on or were either 
ineligible or intolerant to standard anticancer therapy will be enrolled in Phase 1. 
In Phase 2, the tumor expansion cohorts were selected based on preclinical data and elevated 
numbers of arginase-positive cells and MDSC infiltrates in tumor tissues and blood (see 
Section 1.1.2).  Therefore, combining the arginase inhibitor INCB001158 and chemotherapy 
may result in enhanced clinical benefit in subjects with advanced or metastatic solid tumors. 
1.2.2.1. 
Colorectal Cancer 
Cytotoxic therapies are thought to have an impact on the tumor microenvironment.  Oxaliplatin 
induces immunogenic death of colon cancer cells, and MDSCs are inhibited by 5-fluorouracil, 


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thereby diminishing the immunosuppressive effects on T cells (Vincent et al 2010).  While 
FOLFOX reduces circulating MDSCs, FOLFIRI enhances the suppressive environment 
(Limagne et al 2016, Kanterman et al 2014).  
Elevated levels of circulating or tumor-infiltrating MDSCs have been observed in CRC patients, 
and increased arginase 1–expressing MDSCs were reported in CRC tumor tissue compared with 
healthy donors (Toor et al 2016).  CRC has a high frequency of tumor-infiltrating arginase 1–
expressing MDSCs (see Figure 1), therefore, INCB001158 may be able to enhance the reduction 
of MDSCs observed with FOLFOX treatment.  Thus, a FOLFOX plus INCB001158 cohort will 
enroll patients with advanced/metastatic MSS-CRC. 
1.2.2.2. 
Biliary Tract Cancer 
Recognition that an activated tumor microenvironment exists in biliary cancers suggests that 
approaches to modulating the immune system, including reversing tumor cell–induced immune 
suppression are relevant (Goldstein et al 2017).  MDSCs freshly isolated from peripheral blood 
mononuclear cells are increased in patients with pancreatic or bile duct cancer as well as 
cholangiocarcinoma compared with those in healthy donors and correlate with clinical cancer 
stage (Xu et al 2016, Dunne et al 2016).  Moreover, serum arginase activity in patients with 
gallbladder cancer is higher with advanced stages of disease. 
Advanced or metastatic BTC patients will be treated with gemcitabine/cisplatin in this study, 
since this chemotherapy combination is the standard-of-care in the first-line setting.  Moreover, 
since gemcitabine depletes MDSCs and Tregs and improves survival in patients and animal 
models (Sumida et al 2012, Shevchenko et al 2013), a gemcitabine/cisplatin plus INCB001158 
cohort will enroll patients with advanced/metastatic BTC. 
1.2.2.3. 
Ovarian Cancer 
Immunotherapy is emerging as a promising approach to OC therapy (Coukos et al 2016).  
Tumor-infiltrating lymphocytes correlate with increased PFS and OS in advanced disease 
patients, whereas Treg infiltration negatively impacts survival.  Furthermore, reports indicate that 
VEGF-induced MDSCs inhibit local immunity and contribute to poor prognosis (Horikawa 
et al 2017), and MDSC infiltrates isolated from OC tumor tissue mediate T-cell immune 
suppression in vitro.  Therefore, immunotherapy approaches to restore antitumor immune 
responses might have the potential to influence prognosis in patients with epithelial OC, 
especially in patients with platinum-resistant disease (Mantia-Smaldone et al 2011). 
Arginase activity was higher in epithelial OC patient plasma compared to healthy donors and 
arginase levels were decreased after chemotherapy in OC patients (Coosemans et al 2015).  
Arginase 1 was reported to be involved in the formation of an immunosuppressive 
microenvironment through exosomal arginase 1 release in body fluids including plasma or 
ascites from OC patients, indicating that inhibition of arginase 1 activity may be an attractive, 
novel anticancer strategy (Czystowska et al 2017).  Despite optimal upfront surgery and the 
administration of front-line paclitaxel/carboplatin chemotherapy, approximately 70% of patients 
will relapse within the first 3 years.  The prognosis and probability of response to second-line 
therapy and subsequent lines drops significantly, depending in great part on the progression-free 
interval after the last dose of the preceding line of chemotherapy.  Furthermore, the category of 
'resistant' patients comprises patients whose disease recurs after one or several lines of treatment.  


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The biological behavior of the tumor in these groups may be very variable, with differing growth 
rates and distribution of symptoms requiring different approaches to treatment.  Treatment of 
patients with 'platinum-resistant' disease should be focused on quality of life and control of 
symptoms.  Traditionally, this is a poor prognosis population with a short expected OS, usually 
< 12 months.  Four different agents, weekly or 3-weekly paclitaxel, topotecan, PLD and 
gemcitabine, have been shown to have some activity in Phase 3 studies, with overall response 
rates not higher than 15% and a median PFS of 3 to 4 months (Luvero et al 2014).  Platinum 
drugs continue to be used in the 'platinum-resistant' population; however, as no agent has proven 
to be superior to another, the selection of therapy should be based on toxicity, clinical situation 
of the patient, and convenience of administration.  Accordingly, sequential single-agent therapy 
is the recommended management for this group of patients.  For those patients with a later 
relapse (ie, over 6 months and especially over 12 months) platinum-doublet should be the 
treatment of choice, and studies have included carboplatin compared with the same drug 
combined with paclitaxel, gemcitabine, or an anthracycline.  Based on the significant unmet 
need, encouraging preclinical data, and favorable safety profile of INCB001158, there is a robust 
rationale to combine the investigational drug with different chemotherapies without adding 
significant toxicity.  Therefore, a gemcitabine/cisplatin plus INCB001158 expansion cohort (B2) 
and a paclitaxel plus INCB001158 expansion cohort (C3) will enroll patients with recurrent 
platinum-resistant OC. 
1.2.2.4. 
Gastroesophageal Cancer 
Immunotherapy approaches in patients with advanced and metastatic gastroesophageal disease 
are encouraging and support the investigation of immune therapies for the treatment of GC.  
Indeed, enhanced CD8+ T-cell infiltration is observed in tumors and peritumoral interfaces in 
resected gastric cancers (Thompson et al 2017).  MDSCs are elevated in the blood from 
pancreatic, gastric, and esophageal cancer patients, as well as plasma arginase 1 and Tregs; 
MDSCs are a prognostic factor for GC, associated with the Th2 cytokine IL-13 (Gabitass 
et al 2011) and the proinflammatory protein S100A8/A9. 
In plasma obtained from GC patients, the levels of arginase 1 were higher than in healthy 
volunteers, and the levels of arginine were lower than in healthy volunteers, suggesting high 
arginase 1 expression in the tumor microenvironment (Figure 1).  Doublet or triplet 
platinum/fluoropyrimidine combinations are recommended for fit patients with advanced gastric 
cancer.  Second-line chemotherapy with a taxane (eg, docetaxel, paclitaxel), irinotecan, or 
ramucirumab as a single-agent or in combination with paclitaxel is recommended for patients 
who have an ECOG performance status of 0 to 1.  In patients of adequate PS, second-line 
treatment is associated with proven improvements in OS and quality of life compared with best 
supportive care, with treatment options including irinotecan, docetaxel, or paclitaxel, if not used 
before.  A randomized Phase 3 study directly comparing weekly paclitaxel with irinotecan has 
demonstrated similar efficacy for both regimens (Hironaka et al 2013).  The anti–VEGFR-2 
monoclonal antibody ramucirumab has shown activity in 2 randomized Phase 3 studies.  As a 
single agent, it is associated with a survival benefit comparable to cytotoxic chemotherapy in the 
second-line setting, whereas ramucirumab in addition to paclitaxel is associated with a survival 
benefit compared with paclitaxel alone (Wilke et al 2014).  Patients with metastatic esophageal 
cancer can be considered for different options of palliative treatment depending on the clinical 
situation.  Treatment of advanced esophageal carcinoma is managed mostly according to the 


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recommendations for gastric cancer with taxanes being recommended in first-line combinations 
or as monotherapy in second-line settings.  Therefore, based on the preclinical evidence, current 
standard-of-care and limited treatment options, a paclitaxel plus INCB001158 cohort will enroll 
patients with advanced/metastatic GC. 
1.2.2.5. 
Endometrial Cancer 
With the recognition of the limited antitumor activity of standard chemotherapy and of targeted 
therapy in advanced or recurrent EC patients (see Section 1.1.8), novel therapeutic approaches 
towards immunomodulation of the tumor microenvironment are warranted (Longoria and 
Eskander 2015).  Indeed, the presence of intraepithelial tumor infiltrating lymphocytes (TILs) is 
a robust predictor of a more favorable outcome.  MDSCs are detected in tumor specimens 
(Vanderstraeten et al 2014), and increased accumulation of MDSC in tumors is responsible for 
the development of chemotherapy resistance in G-CSF–producing cervical cancer (Kawano 
et al 2015).  MSI-H EC has increased immune cell infiltration compared to MSS tumors, which 
might increase immunogenicity and response to immunotherapy, similarly to CRC (Pakish 
et al 2017).  Therefore, the study will also include a paclitaxel plus INCB001158 cohort, which 
will enroll patients with advanced/ metastatic EC. 
1.2.3. 
Rationale for the Dose and Schedule of INCB001158 
The starting dose of INCB001158 in the Phase 1 dose-escalation portion of the study will be at 
least 2 dose levels below the highest dose of INCB001158 that is shown to be tolerable as a 
monotherapy in Study INCB 01158-101 but no lower than 50 mg BID. 
As INCB001158 inhibits arginase a key enzyme in the urea cycle, urinary orotic acid elevation 
has been closed monitored in Study INCB 01158-101 as a marker of urea cycle inhibition.  As of 
the 24 APR 2017 data cut-off, there were no DLTs or dose-limiting events at the 50 mg BID 
(n = 8) and 100 mg BID (n = 6) dose levels, and no DLTs but 2 asymptomatic dose-limiting 
event of elevated urinary orotic acid ≥ 5 × ULN at the 150 mg BID (n = 3) dose level.  Given 
that relatively small increases in INCB001158 doses in rats resulted in dramatic increases in 
urinary orotic acid levels (> 1000-fold) and toxicity (refer to the IB), it was decided to take a 
cautious approach and set the starting dose at least 2 dose levels below the maximum tolerated 
and tested dose from Study INCB 01158-101. 
In addition, dose escalation of INCB001158 in this study may go no higher than the maximum 
tolerated and tested monotherapy dose identified in Study INCB 01158-101. 
The criteria for the selection of the RP2D of INCB001158 given with each chemotherapy 
regimen is described in Section 4.1.1. 
1.2.4. 
Rationale for Study Endpoints 
1.2.4.1. 
Primary Endpoints 
In Phase 1, the primary safety endpoint will assess AEs, clinical laboratory assessments, physical 
examination results, and 12-lead ECG results to determine the RP2D of INCB001158 in 
combination with each of 3 chemotherapy regimens. 


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In Phase 2, the primary efficacy endpoint will evaluate the ORR of INCB001158 in combination 
with chemotherapy by RECIST v1.1.  This is a standard endpoint for assessing the antitumor 
activity of immunotherapies. 
1.2.4.2. 
Secondary Endpoints 
In Phase 1 and Phase 2, each antitumor activity endpoint (DCR, DOR, and PFS) will be assessed 
by 
 RECIST v1.1 
 
 
 
In Phase 2, the secondary safety endpoint will assess AEs, clinical laboratory assessments, 
physical examination results, and 12-lead ECG results at the RP2D of INCB001158 in 
combination with each of 3 chemotherapy regimens. 
The PK of INCB001158 given in combination with chemotherapy will be assessed using 
standard PK parameters. 
1.3. 
Potential Risks and Benefits of the Treatment Regimen 
1.3.1. 
Risks From INCB001158 
INCB001158 is a potent and selective inhibitor of arginase 1 and arginase 2.  Arginase 1 is 
primarily expressed in granulocytic myeloid cell granules, where it is excreted extracellularly 
and depletes extracellular arginine levels, and in liver hepatocytes, where it functions 
intracellularly as part of the urea cycle.  It has been shown that INCB001158 is approximately 
1000-fold more potent at inhibition of extracellular arginase 1 than intracellular arginase 1 that is 
engaged in the urea cycle, primarily due to poor penetration of INCB001158 across cell 
membranes (refer to the IB).  Arginase 2 is primarily expressed in the mitochondria of many 
other tissues, including the gut and the kidney.  The functions of arginase 2 in these tissues 
include regulation of systemic arginine concentration, regulation of the production of 
downstream products (eg, proline, polyamines), and regulation of arginine availability for nitric 
oxide synthesis.  Inhibition of arginase 2 is thought to result in elevations in systemic arginine 


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levels, which may contribute to the therapeutic effect.  Elevated arginine (up to approximately 
100-fold above baseline) has been well-tolerated in humans following intravenous 
administration.  A ten-fold elevation in plasma arginine (to a mean concentration of 822 μM) 
were associated with no change in systolic or diastolic blood pressure, and a 100-fold increase in 
arginine was associated with mild reductions in systolic and diastolic blood pressure (~9 mmHg 
for each; Mehta et al 1996, Bode-Böger et al 1998). 
The results of the GLP-compliant rat and monkey toxicity studies are described in the 
INCB001158 IB (refer to the IB).  The low- and mid-dose levels were well-tolerated with no 
adverse findings, and the mid-dose level was considered the no-observed-adverse-effect level in 
both species.  INCB001158 exposures at the mid-dose level were > 16-fold above the projected 
human efficacious exposure and were associated with robust pharmacodynamic effects 
(eg, elevated plasma arginine) with no significant toxicities noted. 
There are no preclinical data available to date on the potential phototoxicity of INCB001158. 
Therefore, subjects enrolled in this study should be instructed by the investigator to minimize 
their exposure to the sun/ultraviolet light for the duration of the study and for 2 weeks after the 
last dose of study drug. 
1.3.1.1. 
Potential Urea Cycle Toxicity 
As detailed in the INCB001158 IB, high doses of INCB001158 that resulted in significant 
morbidity and mortality in mice, rats, and monkeys achieved exposures over 19-fold above the 
projected human efficacious exposure.  In the nonclinical animal studies, the toxicity at the high 
doses was associated with evidence of hepatic urea cycle inhibition, including an elevation in 
liver arginine concentration, an increase in plasma ammonia concentration, a decrease in BUN 
concentration, and an increase in urinary orotic acid levels.  Of particular interest, urinary orotic 
acid was elevated by > 1000-fold in rats at the high dose following a single dose administration 
prior to any signs of toxicity.  Smaller elevations in urinary orotic acid were also measured in 
some animals at the well-tolerated mid-dose level.  Elevations of urinary orotic acid have also 
been observed in cancer patients dosed at the highest tested dose of 150 mg BID in the 
first-in-human INCB 01158-101 study, although these patients were asymptomatic without signs 
of clinically significant urea cycle inhibition.  Refer to the INCB001158 IB for the latest data and 
the rationale for the thresholds of OA (see Section 5.4.2) to be used in this study. 
Several measures of potential toxicity related to urea cycle inhibition will be evaluated in this 
study (see Table 16 and Table 17).  In particular, urinary orotic acid, plasma (venous) ammonia, 
and BUN will be measured on Day 1 and at regular intervals in the dose-escalation portion of the 
study (Phase 1). 
Orotic acid - When the urea cycle is disrupted, the urea cycle substrate carbamoyl phosphate 
accumulates and is diverted into the pyrimidine synthesis pathway, producing substantial 
quantities of the pyrimidine precursor orotic acid.  The elevated orotic acid is rapidly cleared in 
the urine and is used as a sensitive assay to identify defects in the urea cycle either due to inborn 
errors or toxic or therapeutic inhibition. 
Ammonia - Urea cycle inhibition can result in large elevations in ammonia, which can lead to 
CNS toxicity.  Inhibition of arginase, the last step in the urea cycle, does not tend to cause 
dramatic elevations in ammonia, but such elevations are possible and will be evaluated, as 


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ammonia is the primary mechanism of acute toxicity associated with urea cycle inhibition.  Since 
plasma ammonia can be quite variable, elevations in plasma ammonia should be confirmed, 
particularly in asymptomatic patients. 
BUN - Blood urea nitrogen is a measure of plasma urea and can be reduced in the setting of urea 
cycle inhibition.  Since it is also affected by other factors (eg, protein consumption, fluid 
status/dehydration), it is not an ideal biomarker of urea cycle function.  However, clear evidence 
of significant reduction in plasma BUN would be consistent with sustained inhibition of the 
hepatic urea cycle and should be avoided. 
1.3.1.2. 
Immune-Related Adverse Events 
It is not known to what extent arginine depletion is operative in normal tissues or in noncancer 
inflammatory states.  However, since arginase-mediated depletion of arginine is an 
immunosuppressive mechanism, irAEs may be associated with the restoration of local arginine 
by INCB001158 treatment.  Although preclinical toxicity studies have not demonstrated any 
evidence of increased inflammation or autoimmunity, these models tend to be poor predictors of 
the safety profile of immuno-oncology agents in humans.  Experience with other 
immuno-oncology agents that target endogenous immunosuppressive mechanisms has 
demonstrated that irAEs can affect any organ or tissue but most frequently occur in the skin 
(rash), gastrointestinal system (diarrhea/colitis), liver (hepatitis), lungs (pneumonitis), endocrine 
system (endocrinopathies due to inflammation of the pituitary, thyroid, and adrenals), and 
kidneys (nephritis).  
Documentation of the immune-mediated nature of toxicities (eg, through demonstration of 
immune infiltration in biopsy tissue) will be of great value, and an effort should be made in cases 
of severe or prolonged potential irAEs to provide evidence of the role of the immune system.  
Management of irAEs will follow the general approach that has been used for other 
immuno-oncology agents, including 1) withholding study drug for events of moderate or worse 
severity (≥ Grade 2) and 2) the use of immunosuppressive corticosteroids for more severe irAEs 
(≥ Grade 3) or prolonged irAEs (lasting > 2 weeks with minimal or no improvement, despite 
withholding study drug).  High-dose steroids may be used for particularly severe irAEs or irAEs 
that fail to respond to initial oral steroids within 3 to 4 days.  Nonsteroidal immunosuppressive 
agents may also be employed for steroid-refractory irAEs. 
1.3.1.3. 
Alterations in Hemodynamic Status 
Although preclinical toxicity studies have not identified this as a toxicity signal, reductions in 
blood pressure leading to orthostatic hypotension, presyncope, or syncope are possible due to 
increased production of nitric oxide (NO) in response to the increased availability of circulating 
arginine, a key substrate for the NO-producing NO synthase enzymes.  This is considered an 
unlikely toxicity for INCB001158 based on the absence of preclinical evidence of hypotension 
and the tolerability of very high levels of arginine when administered intravenously to humans, 
including the absence of an effect on blood pressure in individuals with a 10-fold mean increase 
of plasma arginine (Mehta et al 1996, Bode-Böger et al 1998).  There has been no preclinical 
evidence of altered hemodynamic status in any preclinical studies of INCB001158.  In order to 
identify modest changes in hemodynamic status, blood pressure and careful assessment of 


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orthostatic hypotension will be monitored in this study as part of the standard monitoring of vital 
signs. 
1.3.1.4. 
Clinical Experience 
The INCB 01158-101 first-in-human study is ongoing.  See Section 1.1.3.1 for early data from 
this study and the INCB001158 IB for more recent data.  Urinary orotic acid will continue to be 
monitored in all clinical trials to understand the role of food and extended exposure to 
INCB001158 and to combinations of INCB001158 with other molecules. 
1.3.2. 
Risks From mFOLFOX6 
Oxaliplatin, a platinum-containing alkylating agent used in combination with infusional 
5-fluorouracil and leucovorin, is indicated for the adjuvant treatment of Stage III colon cancer in 
patients who have undergone complete resection of the primary tumor and treatment of advanced 
CRC. 
The most common adverse reactions (incidence ≥ 40%) of oxaliplatin are peripheral sensory 
neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and ALP, 
diarrhea, emesis, fatigue, and stomatitis.  Serious adverse reactions including anaphylaxis and 
allergic reactions, neuropathy, pulmonary toxicities, and hepatotoxicity can occur.  Anaphylactic 
reactions to oxaliplatin may occur within minutes of administration. 
In clinical trials of oxaliplatin, the most common adverse reactions in previously untreated and 
treated patients with advanced CRC were peripheral sensory neuropathies, fatigue, neutropenia, 
nausea, emesis, and diarrhea.  Both 5-fluorouracil and oxaliplatin are associated with 
gastrointestinal and hematologic adverse reactions.  When oxaliplatin is administered in 
combination with 5-fluorouracil, the incidence of these events is increased.  Allergic 
sensitization, including anaphylactoid reactions and urticaria, has been reported following the 
administration of both oral and parenteral leucovorin. 
Investigators should advise male patients to consider conservation of sperm before enrolling in 
the study because of the possibility of irreversible infertility after treatment with mFOLFOX6. 
1.3.3. 
Risks From Gemcitabine/Cisplatin 
Gemcitabine is a nucleoside analog with structural similarity to cytarabine, which is approved to 
treat breast cancer, NSCLC, OC, and pancreatic cancer either alone or in combination with other 
chemotherapy agents. 
Cisplatin is a platinum-containing alkylating agent and is currently approved to treat ovarian 
germ cell cancer, invasive bladder cancer, OC, and testicular germ cell cancer either alone or in 
combination with other chemotherapy agents. 
The combination of gemcitabine and cisplatin is indicated for use in the treatment of BTC, 
bladder cancer, cervical cancer, malignant mesothelioma, NSCLC, and OC. 
Risks associated with use of gemcitabine include myelosuppression, which is the principal DLT.  
Gemcitabine can suppress bone marrow function as manifested by leukopenia, 
thrombocytopenia, and anemia.  The most common adverse reactions as a monotherapy are 


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nausea; vomiting; anemia; increased ALT, AST, and ALP; neutropenia; leukopenia; proteinuria; 
fever; hematuria; rash; thrombocytopenia; and dyspnea. 
The following cisplatin side effects are common (occurring in > 30%):  nausea, vomiting, kidney 
toxicity (dose-related and typically reversible), neutropenia, leukopenia, and anemia.  Less 
common side effects (occurring in 10%-29%) include the following:  peripheral neuropathy; 
paresthesia; sensory loss; numbness and tingling; difficulty walking (some effects may be 
irreversible); tinnitus; anorexia; dysgeusia; increased ALT, AST, and ALP; and alopecia.  
Although peripheral neurotoxicity is infrequent, its incidence is increased in patients older than 
65 years and in patients previously treated with cisplatin.  A relationship was found between the 
gemcitabine dose or cisplatin frequency and the incidence of the most common hematologic 
(ie, anemia, neutropenia, thrombocytopenia) and nonhematologic (ie, nausea, vomiting) 
toxicities. 
Investigators should advise male patients to consider conservation of sperm before enrolling in 
the study because of the possibility of irreversible infertility after treatment with gemcitabine and 
cisplatin. 
1.3.4. 
Risks From Paclitaxel 
Paclitaxel is a microtubule-stabilizing drug approved for the treatment of OC, breast cancer, 
NSCLC, pancreatic cancer, and cervical cancer and Kaposi's sarcoma and is also used in 
combination with other chemotherapy agents for the treatment of gastroesophageal, endometrial, 
prostate, and HNSCC. 
Myelosuppression and neurotoxicity are common side effects of paclitaxel.  Neutropenia, the 
most important hematologic toxicity, was dose- and schedule-dependent and was generally 
rapidly reversible.  Peripheral neuropathy has been demonstrated to be dependent upon the dose 
administered, the duration of the infusion, and the schedule of administration.  Nausea/vomiting, 
diarrhea, and mucositis were reported by 52%, 38%, and 31% of all patients, respectively.  In the 
Phase 3 second-line OC study, infectious episodes were reported in 20% and 26% of the patients 
treated with a dose of 135 mg/m2 or 175 mg/m2 given as 3-hour infusions, respectively.  
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension 
requiring treatment, angioedema, and generalized urticaria have occurred in 2% to 4% of 
subjects receiving paclitaxel in clinical studies.  Fatal reactions have occurred in subjects despite 
premedication.  Weekly paclitaxel at a dose of 67 mg/m2 was found to have a better safety 
profile and seemed to be as effective as the equivalently dose administration schedule of every 
3 weeks in subjects with OC (Rosenberg et al 2002).  Reduced toxicity (6% hematological, 4% 
neuropathy, 8% fatigue Grade III/IV AEs) was observed in the weekly paclitaxel GOG study 
(GOG 2006). 
Investigators should advise male patients to consider conservation of sperm before enrolling in 
the study because of the possibility of irreversible infertility after treatment with paclitaxel. 
1.3.5. 
Risks From the Combination of INCB001158 and Chemotherapy 
The effects of concomitant INCB001158 with mFOLFOX6, gemcitabine/cisplatin, and 
paclitaxel, are being assessed in this Protocol. 


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As described in Sections 1.3.2, 1.3.3, and 1.3.4, the most common AEs associated with these 
medications are neutropenia/leukopenia, thrombocytopenia, anemia, and peripheral neuropathy.  
As described in Section 1.3.1, INCB001158 has been well-tolerated at the first 3 doses tested 
(50, 100, and 150 mg BID) in the INCB 01158-101 first-in-human study.  In addition, given its 
mechanism of action of inhibiting arginase 1, there is not an expected overlap or interaction 
between these profiles.  Hematology, blood chemistry, and urine parameters will be closely 
monitored in all study subjects.  In addition, all AEs will be monitored to identify occurrences of 
new safety signals or potentiation of any mFOLFOX6-related, gemcitabine-related, 
cisplatin-related, and paclitaxel-related side effects. 
1.3.6. 
Benefits of the Combination of INCB001158 and Chemotherapy 
As described in Section 1.2.1, inhibition of arginase 1 using INCB001158 could further deepen 
the responses observed in multiple solid tumors with each of the 3 chemotherapy regimen used 
in the study by providing broader inhibition of the immunosuppressive environment driven by 
MDSCs, Tregs, and other immune cells and factors.  It is hypothesized that this additional 
benefit will not come at the cost of additional toxicity (see Section 1.3.5). 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
The study objectives and endpoints are presented in Table 1. 
Table 1: 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• Phase 1:  To assess the safety and tolerability and 
determine the RP2D of INCB001158 in 
combination with chemotherapy. 
• Safety, tolerability, DLTs, and RP2D of INCB001158 in 
combination with chemotherapy, as assessed by AEs, 
clinical laboratory tests, physical examination results, 
and 12-lead ECG results. 
• Phase 2:  To evaluate the ORR of INCB001158 in 
combination with chemotherapy. 
• ORR, defined as the percentage of subjects having a CR 
or PR, as determined by investigator assessment of 
radiographic disease as per RECIST v1.1. 
Secondary 
• Phase 2:  To assess the safety, tolerability, and 
RP2D of INCB001158 in combination with 
chemotherapy. 
• Safety, tolerability, and RP2D of INCB001158 in 
combination with chemotherapy, as assessed by AEs, 
clinical laboratory tests, physical examination results, 
and 12-lead ECG results. 
• To evaluate the antitumor effect of INCB001158 
in combination with chemotherapy. 
• ORR, defined as the percentage of subjects having a CR 
or PR, as determined by investigator assessment of 
radiographic disease as per RECIST v1.1 (Phase 1 
only).  
• DOR, defined as the time from earliest date of CR or 
PR (as determined by investigator assessment of 
radiographic disease assessment per RECIST v1.1) 
until the earliest date of disease progression or death 
due to any cause, if occurring sooner than disease 
progression. 
• DCR, defined as the percentage of subjects having CR, 
PR, or SD for at least 8 weeks, as determined by 
investigator assessment of radiographic disease as per 
RECIST v1.1. 
• PFS, defined as the time from date of first dose of study 
drug until the earliest date of disease progression (as 
determined by investigator assessment of radiographic 
disease assessment per RECIST v1.1), or death due to 
any cause, if occurring sooner than progression. 
• To determine the PK of INCB001158 in subjects 
treated with INCB001158 in combination with 
chemotherapy. 
• PK of INCB001158 will be assessed by summarizing 
Cmin, Cmax, tmax, AUC0-t, and AUC0-τ. 


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Table 1: 
Study Objectives and Endpoints (Continued) 
Objectives 
Endpoints 


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3. 
SUBJECT ELIGIBILITY 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or subject safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential. 
3.1. 
Subject Inclusion Criteria 
A subject who meets all of the following criteria may be included in the study (see Overall Study 
Design in Section 4.1 for the definition of the cohorts):  
1. Men or women aged 18 years or older. 
2. Presence of measurable disease per RECIST v1.1.  
Note:  If subjects have only 1 measurable lesion per RECIST v1.1, this lesion should not 
have been in the field of prior irradiation unless there is documented progression of the 
lesion(s). 
3. ECOG performance status 0 to 1.  
4. Life expectancy > 12 weeks. 
5. Willing to avoid pregnancy or fathering children based on the criteria below:  
a. Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 51 years of age). 
b. Woman of childbearing potential who has a negative serum pregnancy test at 
screening and before the first dose on Day 1 and who agrees to take appropriate 
precautions to avoid pregnancy (with at least 99% certainty) from screening until 
6 months after the last dose of the last component of study treatment.  Permitted 
methods that are at least 99% effective in preventing pregnancy (see Appendix A) 
should be communicated to the subject and their understanding confirmed.  
c. Man who agrees to take appropriate precautions to avoid fathering children (with at 
least 99% certainty) from screening until 6 months after the last dose of the last 
component of study treatment.  Permitted methods that are at least 99% effective in 
preventing pregnancy (see Appendix A) should be communicated to the subject and 
their understanding confirmed. 
6. 
 
 
  
7. Willingness to undergo pretreatment and on-treatment tumor biopsies, until at least 
5 evaluable paired specimens are collected in each cohort. 
8. Have resolution of all toxicities and any toxic effect(s) of the most recent prior therapy to 
Grade 1 or less (except alopecia).  
9. Adequate renal, hepatic, and hematologic functions as defined by laboratory parameters 
within ≤ 7 days before treatment initiation. 
a. Absolute neutrophil count ≥ 1.5 × 109/L. 
b. Platelets ≥ 100 × 109/L. 


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c. Hemoglobin ≥ 9 g/dL. 
d. Measured or calculated CrCl (glomerular filtration rate can also be used in place of 
creatinine or CrCl) ≥ 50 mL/min. 
Note:  Creatinine clearance should be calculated per institutional standard. 
e. Total bilirubin ≤ 1.5 × ULN OR direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 × ULN. 
i. If there is no institutional normal range available for the direct bilirubin, then the 
direct bilirubin should be < 40% of the total bilirubin. 
ii. In no case can total bilirubin exceed 3.0 × ULN. 
f. AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN.  
g. INR or PT ≤ 1.5 × ULN unless subject is receiving anticoagulant therapy, as long as 
PT or INR is within therapeutic range of intended use of anticoagulants. 
h. Activated partial thromboplastin time ≤ 1.5 × ULN unless subject is receiving 
anticoagulant therapy, as long as aPTT is within therapeutic range of intended use of 
anticoagulants. 
10. Albumin > 3.0 g/dL. 
11. Phase 1 dose escalation only 
a. Subjects with histologically or cytologically confirmed advanced or metastatic solid 
tumors that have failed prior standard therapy (disease progression, subject refusal, or 
intolerance is also allowable). 
Note:  There is no limit to the number of prior treatment regimens. 
b. Locally advanced disease must not be amenable to resection with curative intent. 
12. Phase 2 Expansion Cohort A1:  MSS-CRC subjects only 
a. Subjects with histologically or cytologically confirmed advanced or metastatic 
adenocarcinoma of the colon or rectum.  
Note:  Should have documented MSS status, or consent to local institutional MSI 
testing during the screening period. 
Note:  Must have received at least 1, but not more than 2, prior chemotherapy 
regimen for locally advanced/metastatic CRC, including fluoropyrimidine-, 
oxaliplatin-, or irinotecan-based chemotherapy with or without anti-VEGF therapy (if 
no contraindication). 
Note:  Subjects who completed a fluoropyrimidine-, irinotecan-, or oxaliplatin-based 
chemotherapy regimen as adjuvant, neoadjuvant, or part of a course of 
chemoradiation therapy and progressed ≥ 6 months after completing therapy will be 
eligible.  If progression occurred < 6 months after completing therapy, then the 
subject will not be eligible. 
13. Phase 2 Expansion Cohort B1:  BTC subjects only 
a. Subjects with histologically or cytologically confirmed nonresectable advanced or 
metastatic biliary tract carcinoma (intra- or extrahepatic cholangiocarcinoma, 
gallbladder cancer, or ampullary carcinoma). 
Note:  Should not have received prior systemic chemotherapy for metastatic or 
inoperable locally advanced BTC (not including adjuvant therapy completed at least 
6 months prior to enrollment). 


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14. Phase 2 Expansion Cohort B2:  OC subjects only 
a. Subjects with histologically confirmed recurrent epithelial ovarian, peritoneal, or 
fallopian tube carcinoma and carcinosarcomas (Sertoli-Leydig or germ cell cancers 
are excluded) that have progressed within 6 months of prior cytotoxic chemotherapy. 
Note:  Should have received at least 1 and no more than 4 prior therapies, and failed 
at least 1 standard line of chemotherapy. 
Note:  Adjuvant regimens given within 6 months of screening would be counted as 
first-line therapy. 
15. Phase 2 Expansion Cohort C1:  GC subjects only 
a. Subjects with histologically or cytologically confirmed advanced or metastatic 
adenocarcinoma of the stomach, esophagus, or GEJ. 
Note:  Should have received only 1 prior chemotherapy regimen for advanced or 
metastatic disease (not including neoadjuvant and/or adjuvant therapy).  Adjuvant 
regimens given within 6 months of screening would be counted as first-line therapy.  
16. Phase 2 Expansion Cohort C2:  EC subjects only 
a. Subjects with histologically or cytologically confirmed advanced or metastatic 
endometrial carcinoma. 
Note:  Should have documented MSI status (eg, MSI-H, MSI-low, MSS), or consent 
to local institutional MSI testing during the screening period.  
Note:  Should have received at least 1, but not more than 2, prior chemotherapy 
regimens for advanced or metastatic disease (not including neoadjuvant and/or 
adjuvant therapy).  Adjuvant regimens given within 6 months of screening would be 
counted as first-line therapy. 
Note:  May have received prior hormonal and/or biological therapy in addition to 
prior systemic chemotherapy, which will not count as prior therapy. 
17. Phase 2 Expansion Cohort C3:  OC subjects only 
a. Subjects with histologically confirmed recurrent epithelial ovarian, peritoneal or 
fallopian tube carcinoma and carcinosarcomas that have progressed within 6 months 
of prior cytotoxic chemotherapy (Sertoli-Leydig or germ cell cancers are excluded). 
Note:  Should have received no more than 5 prior therapies and failed at least 
1 standard (platinum-containing) chemotherapy regimen and be considered platinum-
resistant. 
Note:  Adjuvant regimens given within 6 months of screening would be counted as 
first-line therapy. 


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3.2. 
Subject Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Participation in any other study in which receipt of an investigational study drug or 
device occurred within 28 days or 5 half-lives (whichever is longer) before first dose.  
For investigational agents with long half-lives (eg, 5 days), enrollment before the fifth 
half-life requires medical monitor approval. 
2. Has received a prior monoclonal antibody within 4 weeks or 5 half-lives (whichever is 
shorter) before administration of study drug.  
a. Exception:  Washout of immune checkpoint inhibitor therapy is NOT required. 
b. Exception:  Denosumab may be used. 
3. Has had prior chemotherapy or targeted small molecule therapy within 2 weeks before 
administration of study treatment. 
4. Has received prior approved radiotherapy within 14 days of study therapy (exception for 
radiation to CNS, which requires ≥ 28-day washout as described below). 
Note:  Subjects must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis.  A 1-week washout is permitted 
for palliative radiation (≤ 2 weeks of RT) to non-CNS disease. 
5. Subjects must not have received therapy with an arginase inhibitor. 
Note:  Prior immunotherapy treatment with an anti–PD-1, anti–PD-L1, anti–PD-L2,  
anti–CTLA-4, anti-CD137, or any other antibody or drug specifically targeting immune 
checkpoint pathways is allowed. 
6. Has had major surgery within 4 weeks before enrollment (C1D1). 
7. Has had known additional malignancy that is progressing or requires active treatment, or 
history of other malignancy within 2 years of study entry with the exception of cured 
basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, prostate 
intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent 
malignancy, or cancers from which the subject has been disease-free for > 1 year, after 
treatment with curative intent. 
8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(exceeding 10 mg daily of prednisone equivalent in dose) or any other form of 
immunosuppressive therapy within 7 days before the first dose of study treatment. 
9. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).  
Note:  Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment. 
10. Has a known history of HIV infection.  HIV testing is not required unless mandated by 
the local health authority. 


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11. Has a known history of or is positive for hepatitis B (HBsAg reactive) or hepatitis C.  
Note:  Testing must be performed to determine eligibility.  
a. HBV DNA must be undetectable and HBsAg negative at screening visit. 
b. Hepatitis C antibody testing is allowed for screening purposes in countries where 
HCV RNA is not part of standard-of-care treatment.  In these cases, HCV antibody–
positive patients will be excluded. 
c. Subjects who have had definitive treatment for HCV are permitted if HCV RNA is 
undetectable at screening visit.  
12. Has known active CNS metastases and/or carcinomatous meningitis. 
Note:  Subjects with previously treated brain metastases may participate provided that 
they are stable (without evidence of progression by imaging for at least 28 days before 
the first dose of study drug and any neurologic symptoms have returned to baseline), 
have no evidence of new or enlarging brain metastases or cerebral edema, and have not 
required steroids for at least 14 days before the first dose of study drug.  
Note:  Subjects with evidence of cerebral edema or those with < 28 days since RT to the 
CNS will be excluded from study. 
13. Has not recovered to ≤ Grade 1 from toxic effects of previous therapy and/or 
complications from previous surgical intervention before starting study therapy. 
Note:  Subjects with stable chronic AEs (≤ Grade 2) not expected to resolve (eg, 
alopecia) are exceptions and may enroll. 
Note:  Subjects with a history of peripheral neuropathy ≥ Grade 2 will be excluded. 
14. Has a known or suspected defect in the function of the urea cycle, including a known 
deficiency of carbamoyl phosphate synthetase I, ornithine transcarbamylase, 
argininosuccinate synthetase, argininosuccinate lyase, N-acetyl glutamate synthetase, or 
arginase. 
15. Has had a significant cardiac event within 6 months before Cycle 1 Day 1, including 
myocardial infarction (including severe/unstable angina), coronary/peripheral artery 
bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient 
ischemic attack, or pulmonary embolism.  Medically controlled arrhythmia is permitted. 
16. Has a history or presence of an abnormal ECG that, in the investigator's opinion, is 
clinically meaningful.  Screening QTc interval > 480 ms is excluded (corrected by 
Fridericia formula).  In the event that a single QTc is > 480 ms, the screening ECG may 
be repeated in triplicate, and the subject may enroll if the average QTc is < 480 ms. 
17. Concomitant therapy with valproic acid/valproate-containing therapies.  
18. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, chicken pox/zoster, yellow fever, rabies, Bacillus Calmette-Guérin, and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines are live-attenuated 
vaccines and are not allowed. 


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19. Current use of any prohibited medication as described in Section 5.6.3. 
20. Evidence of interstitial lung disease or active, noninfectious pneumonitis. 
21. Inability to swallow food or any condition of the upper gastrointestinal tract that 
precludes administration of oral medications. 
22. Active infection requiring systemic therapy. 
23. Has known hypersensitivity to any of the active substances or any of their excipients, 
including mannitol. 
24. Women who are pregnant or breastfeeding. 
25. Subjects with bleeding associated with tumors in proximity to major blood vessels are 
excluded except with medical monitor approval. 
26. Has a history of a gastrointestinal condition (eg, inflammatory bowel disease, Crohn's 
disease, ulcerative colitis) that may affect drug absorption. 
27. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject's participation for 
the full duration of the study, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is an open-label, nonrandomized, Phase 1/2 study to evaluate the safety, tolerability, and 
antitumor activity of INCB001158 in combination with 3 different chemotherapy regimens 
(Figure 2).  Phase 1 will consist of dose-escalation using a BOIN design (Liu and Yuan 2015) 
and will determine the RP2D of INCB001158 when given in combination with each 
chemotherapy regimen; efficacy will also be explored.  Subjects with advanced or metastatic 
solid tumors for whom treatment with one of the chemotherapy regimens is appropriate will be 
enrolled in Phase 1. 
Phase 2 will evaluate ORRs using a Simon 2-stage design to determine whether the combinations 
have sufficient antitumor activity to warrant further testing in subsequent clinical studies and will 
further evaluate the safety and tolerability of the RP2D of INCB001158 when given in 
combination with chemotherapy.  Subjects with advanced or metastatic CRC, BTC, OC, GC, and 
EC will be enrolled in the Phase 2 expansion cohorts.  
See Section 4.1.1 for full details of the Phase 1 dose escalation, Section 4.1.2, for full details of 
Phase 2 tumor expansion, and Section 5.2 for full study drug administration information. 
The definition of DLTs is provided in Section 5.4.2. 


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Figure 2: 
Study Design 
 
4.1.1. 
Phase 1:  Dose Escalation of INCB001158 + Chemotherapy  
In Phase 1, a BOIN design will be used to determine the RP2D of the combination of 
INCB001158 and chemotherapy in 21-day (for gemcitabine/cisplatin) or 28-day (for 
mFOLFOX6 or paclitaxel) treatment cycles in subjects with advanced or metastatic solid tumors.  
The RP2D will then be further assessed in tumor expansion cohorts in Phase 2. 
Subjects with advanced or metastatic solid tumors will be assigned to 1 of the treatment groups 
summarized in Table 2 based on the chemotherapy regimen most appropriate for the subject's 
tumor type. 


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Table 2: 
Treatment Groups for Subjects Enrolled in Phase 1 Dose Escalation  
Treatment Group A 
INCB001158  
mFOLFOX6 
25-150 mg PO BID 
continuous daily dosing 
Oxaliplatin 85 mg/m2 IV on Day 1 and Day 15 of 
a 28-day cycle 
Leucovorin 400 mg/m2 IV on Day 1 and Day 15 
of a 28-day cycle 
5-Fluorouracil 400 mg/m2 IV bolus on Day 1 and 
Day 15, then 1200 mg/m2 per day IV infusion 
over 46 hours for a total dose of 2400 mg/m2 on 
Day 1 and Day 15 of a 28-day cycle 
Treatment Group B 
INCB001158  
Gemcitabine and Cisplatin 
25-150 mg PO BID 
continuous daily dosing 
Gemcitabine 1000 mg/m2 IV infusion on Days 1 
and 8 of a 21-day cycle 
Cisplatin 30 mg/m2 IV infusion on Days 1 and 8 
of a 21-day cycle 
Treatment Group C 
INCB001158  
Paclitaxel 
25-150 mg PO BID 
continuous daily dosing 
Paclitaxel 80 mg/m2 IV infusion on Days 1, 8, 
and 15 of a 28-day cycle 
BID = twice daily; IV = intravenous; PO = orally. 
Dose escalation will begin with starting doses of INCB001158 at least 2 dose levels below the 
maximum tolerated and tested dose from the INCB 01158-101 study (likely to be 50 mg BID or 
75 mg BID) – see Table 3, Column A and B, respectively.  
Table 3: 
INCB001158 Dose Cohorts 
INCB001158 Dose Cohort 
INCB001158 Dose Levels for Phase 1 
A.  Starting Dose of 50 mg BID 
B.  Starting Dose of 75 mg BID 
-1 
25 mg BID 
50 mg BID 
1 (starting dose) 
50 mg BIDa 
75 mg BIDb 
2 
75 mg BID 
100 mg BID 
3 
100 mg BID 
150 mg BID 
4 
150 mg BID 
N/A 
BID = twice daily. 
a If INCB001158 50 mg BID is not tolerated within a treatment group, INCB001158 25 mg BID may be evaluated. 
b If INCB001158 75 mg BID is not tolerated within a treatment group, INCB001158 50 mg BID may be evaluated. 
If the starting dose is not 1 of those 2 dose levels, dose escalation will follow the same pattern, 
and the exact dose escalation table will be provided to sites.  The INCB001158 dose will be 
escalated using an open-label BOIN design in each chemotherapy regimen, and a PAD or the 
MTD will be determined, or the maximum dose of INCB001158 (150 mg BID) will be reached.  
A PAD of INCB001158 is defined as a dose that achieves a trough (Cmin) plasma concentration 
of INCB001158 at steady state of ≥ 1 μM that is equivalent to the IC90 for arginase 1.  This 
definition may be modified based on emerging data from the INCB 01158-101 first-in-human 
study, upon agreement between the medical monitor and the study investigators.  The MTD is 
the maximum tolerated or tested dose of INCB001158, such that fewer than 33% of the subjects 


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receiving the combination experience a DLT during the first 28 days on study drug.  After the 
dose escalation is completed, one of the INCB001158 dose levels that is pharmacologically 
active and tolerable in combination with each chemotherapy regimen (ie, MTD or lower) will be 
the RP2D. 
Dose interruptions and/or modifications may be implemented based on toxicity.  Dose 
modifications should not be made during the DLT observation period without discussion with 
the medical monitor.  Intrasubject dose escalation is not permitted. 
Dose escalation and de-escalation in Phase 1 will follow the BOIN design algorithm.  Given the 
target DLT rate of 33% for the INCB001158 in combination with chemotherapy, the dose 
escalation and de-escalation rules are shown in Table 4.  The BOIN design also includes an 
elimination rule.  When  3 subjects have been treated, if the probability that the estimated 
toxicity rate that is above the target DLT rate is > 95% at a certain dose level, then this dose level 
and higher dose levels are assumed to be too toxic and will be eliminated.  If the lowest dose 
level is eliminated, then the whole dose escalation will be terminated.  Table 4 (in the bottom 
row) provides the elimination rules.  Based on this algorithm, a minimum of 3 evaluable subjects 
and a maximum of 9 evaluable subjects will be enrolled at each tested dose level.  The dose 
escalation will continue, based on the rules in Table 4, until at least 1 of the following occurs: 
• Enrollment of additional subjects in a dose cohort that already has 9 evaluable 
subjects, or 
• Dose escalation to a dose level that has already been eliminated, or 
• Dose escalation above the maximum allowable dose level identified in the 
INCB 01158-101 study (see Section 1.2.3).  
At that point, the dose escalation will be stopped. 
Table 4: 
Dose Escalation, De-Escalation, and Elimination Boundaries for Target DLT 
Rate of 33% in Phase 1 
Action 
Number of Subjects Treated at the Current Dose 
1 
2 
3 
4 
5 
6 
7 
8 
9a 
Escalate if # of 
DLTs ≤ 
0 
0 
0 
1 
1 
1 
1 
2 
2 
De-escalate if # 
of DLTs ≥ 
1 
1 
2 
2 
2 
3 
3 
4 
4 
Elimination if # 
of DLTs ≥ 
N/A 
N/A 
3 
3 
4 
4 
5 
5 
6 
DLT = dose-limiting toxicity. 
a If 9 evaluable subjects are enrolled in a dose cohort and 3 of those subjects experience a DLT, the medical monitor 
and the investigators will review the entirety of the data and decide whether to escalate the dose level, de-escalate 
the dose level, or stop at that dose level. 
When applying the BOIN design, a maximum of 9 evaluable subjects will be used at each dose 
level for initially identifying the MTD; however, the MTD of INCB001158 for one of the 
chemotherapy combinations may be a dose level below the other MTDs.  After the PADs or 
MTDs are selected for each of the 3 combinations, the cohort may be expanded to 12 (and then 


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to 15) in one of the chemotherapy combinations, and an MTD will be redetermined if all the 
following conditions are satisfied.  
• If and only if a single one of the chemotherapy combinations has a lower MTD than 
the others. 
• The Incyte medical monitor and the investigators review the entirety of the safety 
data and agree that the dose with the lower MTD needs to be re-challenged.  
• The de-escalation and elimination boundaries are not crossed during the dose 
rechallenge and dose levels are retested.  (Neither the de-escalation nor the 
elimination boundaries are touched.)  
For expanding the cohorts, the decisions rules are presented in Table 5. 
Table 5: 
Dose Escalation, De-Escalation, and Elimination Boundaries for Target DLT 
Rate of 33% for Cohort Expansion in Phase 1 
Action 
Number of Subjects Treated at the Current Dose 
10 
11 
12 
13 
14 
15 
Escalate if # of 
DLTs ≤ 
2 
2 
3 
3 
3 
3 
De-escalate if # 
of DLTs ≥ 
4 
5 
5 
6 
6 
6 
Elimination if # 
of DLTs ≥ 
6 
7 
7 
8 
8 
8 
At the discretion of the sponsor, up to a total of 6 additional "backfill" subjects may be enrolled 
at any tolerable dose level to further investigate safety 
.  
 
 
 
4.1.2. 
Phase 2:  Tumor Expansion Cohorts of INCB001158 + Chemotherapy  
To determine whether the combinations result in adequate ORRs to warrant further testing in 
subsequent clinical studies, a Simon 2-stage design will be used for each tumor expansion cohort 
to evaluate the ORR of the RP2D of INCB001158 determined in Phase 1 in combination with 
chemotherapy and further evaluate the safety and tolerability of the combination.  If, at the time 
of completion of enrollment in Stage 1, it is not known whether the target ORR to proceed to 
Stage 2 will be met, then enrollment will be paused until and unless the ORR to proceed has 
been met. 
Enrollment in a specific expansion cohort will begin when the RP2D of INCB001158 for the 
corresponding treatment group in Phase 1 has been determined. 


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The expansion cohorts will be limited to the following advanced/metastatic or recurrent tumor 
types:  
• Cohort A1:  MSS-CRC (INCB001158 + mFOLFOX6) 
• Cohort B1:  BTC (INCB001158 + gemcitabine/cisplatin) 
• Cohort B2:  OC (INCB001158 + gemcitabine/cisplatin) 
• Cohort C1:  GC (INCB001158 + paclitaxel) 
• Cohort C2:  EC (INCB001158 + paclitaxel) 
• Cohort C3:  OC (INCB001158 + paclitaxel) 
Subjects will be assigned to the expansion cohorts summarized in Table 6. 
Table 6: 
Expansion Cohorts for Subjects Enrolled in Phase 2 Tumor Expansion 
Expansion Cohort A1 
INCB001158 
mFOLFOX6 
PO BID continuous 
daily dosing 
Oxaliplatin 85 mg/m2 IV on Day 1 and Day 15 of 
a 28-day cycle 
Leucovorin 400 mg/m2 IV on Day 1 and Day 15 
of a 28-day cycle 
5-Fluorouracil 400 mg/m2 IV bolus on Day 1 and 
Day 15, then 1200 mg/m2 per day IV infusion 
over 46 hours for a total dose of 2400 mg/m2 on 
Day 1 and Day 15 of a 28-day cycle 
Expansion Cohort B1 
INCB001158 
Gemcitabine and Cisplatin 
PO BID continuous 
daily dosing 
Gemcitabine 1000 mg/m2 IV infusion on Days 1 
and 8 of a 21-day cycle 
Cisplatin 25 mg/m2 IV infusion on Days 1 and 8 
of a 21-day cycle 
Expansion Cohort B2 
INCB001158 
Gemcitabine and Cisplatin 
PO BID continuous 
daily dosing 
Gemcitabine 750 mg/m2 IV infusion on Days 1 
and 8 of a 21-day cycle 
Cisplatin 30 mg/m2 IV infusion on Days 1 and 8 
of a 21-day cycle 
Expansion Cohorts 
C1, C2, and C3 
INCB001158  
Paclitaxel 
PO BID continuous 
daily dosing 
Paclitaxel 80 mg/m2 IV infusion on Days 1, 8, and 
15 of a 28-day cycle 
BID = twice daily; IV = intravenous; PO = orally. 
Continuous evaluation of toxicity events will be performed in the expansion cohorts.  If the 
cumulative incidence of ≥ Grade 3 INCB001158-related AEs or ≥ Grade 3 chemotherapy-related 
AEs is > 40% after 10 subjects are enrolled in a specific expansion cohort within Phase 2, then 
further enrollment in that cohort will be interrupted until the sponsor and investigators determine 
the appropriate course of action.  If an expansion cohort is discontinued due to toxicity, a new 
cohort may be initiated at a previously tested lower dose level. 


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Regular meetings such as teleconferences will be scheduled by the sponsor with study 
investigators in order to review cohort-specific data and overall safety data, to agree on dose 
escalation/de-escalation, to adjudicate individual high-grade AEs as potentially dose-limiting, 
and to guide other major study decisions. 
In each cohort, a Simon 2-stage design will be used to assess the antitumor activity of the 
INCB001158 + chemotherapy combination (see Table 7), to determine whether the combination 
results in sufficient antitumor activity to warrant further testing in subsequent clinical studies.  
Table 7: 
Phase 2:  Simon 2-Stage Design 
Cohort 
(Tumor Type) 
Background 
ORR 
Target 
ORR 
Alpha 
Power 
N for 
Stage 1 
ORR to 
Proceed 
N for 
Stage 2 
ORR for 
Positive 
Cohort 
A1 (MSS-CRC) 
10% 
30% 
0.1 
80 
7 
≥ 1/7 
11 
≥ 4/18 
B1 (BTC) 
20% 
40% 
0.1 
80 
12 
≥ 3/12 
13 
≥ 8/25 
B2 (OC) 
15% 
35% 
0.1 
80 
9 
≥ 2/9 
14 
≥ 6/23 
C1 (GC) 
15% 
35% 
0.1 
80 
9 
≥ 2/9 
14 
≥ 6/23 
C2 (EC)  
15% 
35% 
0.1 
80 
9 
≥ 2/9 
14 
≥ 6/23 
C3 (OC)  
15% 
35% 
0.1 
80 
9 
≥ 2/9 
14 
≥ 6/23 
Note:  See Sections 1.1 and 1.2 for background and target ORRs rationale for each cohort. 
At certain prespecified study sites, mandatory paired predose and on-treatment tumor biopsies 
will be collected from subjects (unless it is not considered to be safe or otherwise is not feasible), 
until approximately 5 evaluable paired specimens are collected in each treatment cohort.  
Collection of paired biopsies is optional in subjects subsequently enrolled at those sites and for 
all subjects enrolled at other sites. 
If either cohort completes enrollment, based on the Simon 2-stage design, before sufficient 
evaluable paired biopsies have been collected, then enrollment may continue at the prespecified, 
investigative sites until approximately 5 evaluable paired specimens have been collected in each 
cohort. 
4.2. 
Measures Taken to Avoid Bias 
This is an open-label study.  Assessment of safety using CTCAE v4.03 and efficacy using 
RECIST v1.1 are objective measurements, and only comparisons to pretreatment conditions will 
be made. 


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4.3. 
Number of Subjects 
4.3.1. 
Planned Number of Subjects 
Up to a total of 222 subjects (if starting dose level is 75 mg in Phase 1) or up to a total of 249 (if 
starting dose level is 50 mg in Phase 1) are planned for enrollment.  This may vary due to the 
number of subjects required to determine the target dose. 
• Phase 1 dose escalation – Up to 87 (if starting dose level is 75 mg in Phase 1) or up to 
114 (if starting dose level is 50 mg in Phase 1) evaluable subjects. 
• Phase 2 tumor expansion (Simon 2-stage) – Approximately 55 to 135 evaluable 
subjects 
It is planned to have 4 to 5 sites during Phase 1 dose escalation and approximately 11 to 
16 additional sites during Phase 2 tumor expansion. 
4.3.2. 
Replacement of Subjects 
During dose escalation in Phase 1, up to 4 subjects per dose cohort will be enrolled at a time, 
with the aim of having at least 3 subjects who are evaluable for DLTs (see Section 5.4.2 for 
definition).  If fewer than 3 subjects are evaluable, additional subjects will be enrolled until 
3 evaluable subjects are available. 
In the tumor expansion in Phase 2, enrollment will continue in each expansion cohort until there 
are sufficient subjects who are evaluable for each stage of the Simon 2-Stage design (see 
Section 4.1.2 for definition).  
 
 
 
4.4. 
Duration of Treatment and Subject Participation 
After signing the ICF, subject study participation, including screening and post-treatment 
follow-up, is expected to average approximately 12 to 18 months per individual subject, as long 
as subjects are deriving benefit, tolerating the regimen and do not meet any of the withdrawal 
criteria. 
4.5. 
Overall Study Duration 
The study begins when the first subject signs the ICF.  The end of the study will occur when all 
subjects have completed applicable follow-up assessments or when the sponsor terminates the 
study. 
If there have been ≤ 5 subjects on study for more than 6 months, then a database lock of the 
study may occur to allow the analysis of the study data.  Any remaining subjects may continue to 
receive study treatment and be seen by the investigator per usual standard of care for this subject 
population.  In addition, the investigator will be expected to monitor for and report any SAEs, 
AESIs, and pregnancies per the study assessments in Section 8.  The remaining subjects are 
considered to be on study until a discontinuation criterion is met and written notification is 
provided to the sponsor. 


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4.6. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the institutional review board 
(IRB)/independent ethics committee (IEC) in writing of the study's completion or early 
termination, send a copy of the notification to the sponsor or sponsor's designee, and retain 
1 copy for the site study regulatory file. 
The sponsor may terminate the study electively if, for example, required by regulatory decision 
or upon review of emerging data.  If the study is terminated prematurely, the sponsor will notify 
the investigators, the IRBs and IECs, and regulatory bodies of the decision and reason for 
termination of the study. 
5. 
TREATMENT 
5.1. 
Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
Each subject will be identified in the study by a subject ID number, which is a combination of 
the site ID and subject number.  Site staff should contact the IRT to obtain the subject ID number 
during screening.  This subject ID number will be maintained throughout the study and will not 
be reassigned.  Subjects who fail screening and are repeating the screening process due to a 
change in eligibility status will be assigned a new subject ID number.  For subjects who signed 
an ICF but are not treated, refer to the eCRF Completion Guidelines for instructions on which 
eCRFs to complete. 
Site staff will contact the IRT to obtain the initial study drug assignment.  The investigator or 
designee will select the assigned study drug from their stock that corresponds to the number 
provided by the IRT, record the unique identifiers in the eCRF, and dispense the study drug to 
the subject.  All subsequent dispensing of study drug should follow this process.  Full details will 
be provided in the IRT manual. 
If a subject is mistakenly given a bottle of study drug that is not the bottle assigned by the IRT, 
then the IRT help desk must be notified immediately.  The reason for the misallocation of the 
study drug must be documented by the study site. 
5.1.2. 
Randomization and Blinding 
Not applicable, as this is an open-label study. 
5.2. 
Study Drug and Other Study Treatments 
Study treatment is defined as any investigational treatment(s) or marketed product(s) intended to 
be administered to a study subject according to the Study Protocol.  There are 4 investigational 
study treatments in this study – INCB001158, mFOLFOX6, gemcitabine/cisplatin, and 
paclitaxel.  INCB001158 is also referred to as the study drug in this Protocol. 


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5.2.1. 
INCB001158 
5.2.1.1. 
Description and Administration 
INCB001158 will be administered PO BID using a tablet (25 mg or 100 mg per tablet) 
formulation.  Doses will be taken in the morning and evening, approximately 12 hours apart.  
INCB001158 will be administered on Days 1 through 28 of each 28-day cycle (mFOLFOX6 and 
paclitaxel treatment groups) or on Days 1 through 21 of each 21-day cycle (gemcitabine/cisplatin 
treatment group) and should be taken PO using the number of tablets directed in the Pharmacy 
Manual.  The starting dose will depend on which phase and cohort of the study that the subject is 
in.  In Phase 1, the starting dose will be based on which dose level cohort that the subject is in; in 
Phase 2, the starting dose will be the RP2D identified in Phase 1.  INCB001158 dose regimens 
will not be adjusted for body weight or surface area. 
INCB001158 will be administered beginning on Cycle 1 Day 1 and continuously thereafter.  On 
days when INCB001158 is administered in the clinic, INCB001158 should be taken before 
beginning the infusion of the applicable chemotherapy regimen (mFOLFOX6, 
gemcitabine/cisplatin, or paclitaxel).  
INCB001158 will be given daily for as long as disease progression has not occurred and criteria 
for treatment discontinuation have not been met. 
5.2.1.2. 
Supply, Packaging, and Labeling 
INCB001158 will be provided to sites by Incyte.  
Study drug will be supplied as INCB001158 25 mg or 100 mg tablets packaged in bottles.  No 
preparation is required.  All tablet excipients comply with the requirements of the applicable 
compendial monographs (Ph Eur, USP/NF; refer to the IB). 
All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each country.  
5.2.1.3. 
Storage 
Bottles of INCB001158 tablets should be stored at room temperature, 15°C to 30°C (59°F to 
86°F).  Subjects will be requested to store the study drug at the recommended storage conditions 
noted on the label and out of the reach of children or other cohabitants. 
5.2.1.4. 
Instruction to Subjects for Handling Study Drug (INCB001158) 
The subject must be instructed in the handling of study drug as follows: 
• To store the study drug at room temperature. 
• To only remove from the study drug bottle the number of tablets needed at the time of 
administration. 
• Not to remove doses in advance of the next scheduled administration. 
• Not to split or crush tablets. 
• To make every effort to take doses on schedule. 


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• To report any missed doses. 
• To take study drug at approximately the same times each day without respect to food 
(except on Protocol-defined clinic days, when the subject should fast for at least 
8 hours before taking study drug) and with a full glass of water.  The second dose on 
any given day should be taken approximately 12 hours after the first dose. 
• Subjects who vomit their INCB001158 dose should be instructed NOT to make up 
that dose and to report the frequency of vomiting occurrences associated with study 
drug administration to the site.  Subjects who report ≥ 3 incidences of vomiting 
associated with study drug administration will have a blood sample drawn for an 
unscheduled PK analysis. 
• To bring all used and unused study drug bottles to the site at each visit. 
• Missed doses of INCB001158 should be skipped.  If a subject forgets to take a dose 
of study drug and he/she is outside of the allotted window period (± 6 h), he/she 
should be instructed to skip that dose and NOT take extra study drug at their next 
administration. 
On Protocol-defined clinic days (see Table 11, Table 12, Table 13, and Table 14; see Table 15 
for all subjects as of Protocol Amendment 4) subjects should be instructed NOT to take their 
morning dose of INCB001158 at home.  The morning dose must be administered at the clinical 
site after all predose procedures have been performed.  The time of dose administration will be 
recorded in the clinic.  The evening doses will be self-administered by the subject after all 
postdose activities have been completed. 
5.2.2. 
mFOLFOX6 
5.2.2.1. 
Description and Administration 
Subjects will receive oxaliplatin 85 mg/m2 IV given concurrently with leucovorin 400 mg/m2 IV 
over 2 hours ± 15 minutes (or equivalent dose and schedule based on institutional practice), 
followed by a 5-fluorouracil 400 mg/m2 IV bolus (administration time per institutional practice), 
then a 5-fluorouracil 1200 mg/m2 per day IV continuous infusion over 46 hours for a total dose 
of 2400 mg/m2.  These 3 agents will be administered on Day 1 and Day 15 of each 28-day cycle 
after administration of INCB001158.  Investigators may reduce or discontinue oxaliplatin for 
peripheral neuropathy; if discontinued, investigators have the option to discontinue 
5-fluorouracil and leucovorin.  Subjects must meet minimum criteria for the start of each 
chemotherapy cycle as outlined in Appendix C, Section C.1.  
The Pharmacy Manual provides additional information and instructions for preparation and 
infusion of 5-fluorouracil, leucovorin, and oxaliplatin.  
Subjects may receive prophylactic G-CSF support with filgrastim.  Granulocyte-colony 
stimulating factor should not be given in the first cycle.  If chemotherapy is held for toxicity, 
then prophylactic G-CSF support should also be held.  Additionally, if chemotherapy is held 
because of neutropenia, then G-CSF may be administered to treat neutropenia per institutional 
guidelines.  Granulocyte-colony stimulating factor support can be held for ANC levels 
≥ 4.0 × 109/L at the investigator's discretion.  


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5.2.2.2. 
Supply, Packaging, Labeling, and Storage 
In countries where 5-fluorouracil, leucovorin, oxaliplatin, filgrastim, or their generic equivalents 
are commercially available, investigators are responsible for ensuring that subjects receive 
commercially available supplies of these therapies for the entire duration of study participation.  
Incyte may provide certain reference therapies where required by applicable law or regulation or 
under other limited circumstances when a subject may not otherwise have access to these 
therapies. 
5.2.3. 
Gemcitabine/Cisplatin 
5.2.3.1. 
Description and Administration 
For Phase 1 dose escalation, subjects with advanced or metastatic disease will receive 
gemcitabine 1000 mg/m2 IV over 30 minutes (± 5 min) and cisplatin 30 mg/m2 IV over 
30 minutes (± 5 min) on Days 1 and 8 of each 21-day cycle. 
For Phase 2 tumor expansion, subjects will receive the gemcitabine/cisplatin regimen that is the 
standard dose and schedule used for the corresponding tumor type patients: 
• In Cohort B1 (BTC), subjects will receive gemcitabine 1000 mg/m2 IV over 
30 minutes (± 5 min) and cisplatin 25 mg/m2 IV over 30 minutes (± 5 min) on Days 1 
and 8 of each 21-day cycle. 
• In Cohort B2 (OC), subjects will receive gemcitabine 750 mg/m2 IV over 30 minutes 
(± 5 min) and cisplatin 30 mg/m2 IV over 30 minutes (± 5 min) on Days 1 and 8 of 
each 21-day cycle. 
Subjects must meet minimum criteria for the start of each chemotherapy cycle as outlined in 
Appendix D, Section D.1. 
The Pharmacy Manual provides additional information and instructions for preparation and 
infusion of gemcitabine and cisplatin. 
Subjects may receive prophylactic G-CSF support with filgrastim.  Granulocyte-colony 
stimulating factor should not be given in the first cycle.  If chemotherapy is held for toxicity, 
then prophylactic G-CSF support should also be held.  Additionally, if chemotherapy is held 
because of neutropenia, then G-CSF may be administered to treat neutropenia per institutional 
guidelines.  Granulocyte-colony stimulating factor support can be held for ANC levels 
≥ 4.0 × 109/L at the investigator's discretion. 
5.2.3.2. 
Supply, Packaging, Labeling, and Storage 
In countries where gemcitabine and cisplatin (or its generic equivalents) are commercially 
available, investigators are responsible for ensuring that subjects receive commercially available 
supplies of these therapies for the entire duration of study participation.  Incyte may provide 
certain reference therapies where required by applicable law or regulation or under other limited 
circumstances when a subject may not otherwise have access to these therapies. 


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5.2.4. 
Paclitaxel 
5.2.4.1. 
Description and Administration 
Subjects will receive weekly paclitaxel 80 mg/m2 IV infusion over 1 hour (± 10 min) on Days 1, 
8, and 15 of each 28-day cycle. 
Subjects must meet minimum criteria for start of each chemotherapy cycle as outlined in 
Appendix E, Section E.1.  
The Pharmacy Manual provides additional information and instructions for preparation and 
infusion of paclitaxel. 
Subjects must receive premedication; for example, see Table 8.  Alternative institutional 
premedications are allowed. 
Table 8: 
Recommended Premedication Schedule 
Drug 
Dose 
Route 
Administration 
Dexamethasone 
8 mg 
IV 
30-60 minutes before paclitaxel infusion 
Chlorphenamine 
10 mg 
IV 
30-60 minutes before paclitaxel infusion over at least 1 minute 
Ranitidine 
50 mg 
IV 
30-60 minutes before paclitaxel infusion over at least 2 minute 
It may not be necessary to stop treatment for minor hypersensitivity (eg, reactions, flushing, 
localized rash).  Infusions must be stopped for major reactions (eg, hypotension, dyspnea, 
angioedema, or generalized urticarial). 
Subjects may receive prophylactic G-CSF support with filgrastim.  Granulocyte-colony 
stimulating factor should not be given in the first cycle.  If chemotherapy is held for toxicity, 
then prophylactic G-CSF support should also be held.  Additionally, if chemotherapy is held 
because of neutropenia, then G-CSF may be administered to treat neutropenia per institutional 
guidelines.  Granulocyte-colony stimulating factor support can be held for ANC levels 
≥ 4.0 × 109/L at the investigator's discretion. 
5.2.4.2. 
Supply, Packaging, Labeling, and Storage 
In countries where paclitaxel or generic equivalent is commercially available, investigators are 
responsible for ensuring that subjects receive commercially available supplies of these therapies 
for the entire duration of study participation.  Incyte may provide certain reference therapies 
where required by applicable law or regulation or under other limited circumstances when a 
subject may not otherwise have access to these therapies. 
5.3. 
Treatment Compliance 
Compliance with all study-related treatments should be emphasized to the subject by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study.  
Compliance with INCB001158 will be calculated by the sponsor based on the drug 
accountability documented by the site staff and monitored by the sponsor/designee (tablet 
counts).  Subjects will be instructed to bring INCB001158 tablets with them to the study visits in 
order for site personnel to conduct tablet counts to assess study drug accountability.  The drug 
accountability documentation will be used by the sponsor to calculate treatment compliance. 


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5-Fluorouracil, leucovorin, oxaliplatin, gemcitabine, cisplatin, and paclitaxel are administered 
intravenously by site personnel.  Receipt of infusions will be documented by the site staff and 
monitored by the sponsor or designee. 
5.4. 
Treatment Interruptions and Adjustments 
5.4.1. 
Dose Modifications 
Selections and modifications to the study drug regimen are planned for the Phase 1 
dose-escalation cohorts.  Dose interruptions and modifications also may occur for individual 
study subjects.  The identification of DLTs will define the doses used in planned dose cohorts 
(see Section 4.1.1).  Dose modifications in the form of reductions, interruption, or 
discontinuation for any of the study treatments (INCB001158 or chemotherapy regimen) may 
also be needed for individual subjects in the event of a DLT or AE (related or unrelated to study 
treatment).  Intrasubject dose escalation for any study drug is not permitted. 
5.4.1.1. 
INCB001158 
For subjects in Phase 1, dose reductions of INCB001158 will be permitted during the first 
28 days only if a subject experiences a DLT or a toxicity that may herald a DLT.  If a subject 
experiences a DLT, treatment continuation at a lower dose of INCB001158 will be permitted as 
long as the toxicity has returned to ≤ Grade 1 or baseline within 28 days.  When INCB001158 is 
held or discontinued, chemotherapy may be continued, at the investigator's discretion.  Upon 
recovery, subjects may restart at 1 INCB001158 dose level lower.  Subjects who do not recover 
within 28 days will not be eligible for resumption of study treatment without approval from the 
medical monitor.  See also Table 10. 
5.4.2. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose in 
Phase 1 
Dose-limiting toxicity will be defined as the occurrence of any of the toxicities in Table 9 
occurring up to and including Day 28, except those with a clear alternative explanation 
(eg, disease progression) or transient (≤ 72 hours) abnormal laboratory values without associated 
clinically significant signs or symptoms based on investigator determination.  All DLTs will be 
assessed by the investigator using CTCAE v4.03 criteria.  For INCB001158 at the dose level 
assigned, subjects who receive at least 32 of 42 doses for 21-day cycle regimens and at least 
42 of 56 doses for 28-day cycle regimens (both representing ≥ 75% of the dose planned), or 
subjects who have a DLT will be considered evaluable for determining tolerability of the dose.  
Subjects who do not meet these criteria may be replaced to obtain sufficient evaluable subjects to 
be able to assess that dose level using the BOIN design, as outlined in Table 4. 
Clear evidence of urea cycle inhibition (eg, an increase in fasting urinary orotic acid to 
> 10 × ULN, any OA value of > 40 × ULN, or symptomatic hyperammonemia) would be 
considered a dose-limiting event and will be treated the same as a DLT with regard to the 
dose-escalation rules and definition of the MTD described in Section 4.1.1.  See the 
INCB001158 IB for an explanation.  
Individual subject dose reductions for INCB001158 may be made based on events observed at 
any time during treatment; however, for the purposes of dose cohort escalation/de-escalation, 


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expanding a dose cohort, and determining the MTD of INCB001158, decisions will be made 
based on events that are observed from the first day of study drug administration through and 
including Day 28.  A lower MTD may subsequently be determined based on relevant toxicities 
that become evident after Day 28. 
Table 9: 
Definition of Dose-Limiting Toxicity 
Toxicity 
Nonhematologic 
• Any ≥ Grade 3 nonhematologic toxicity EXCEPT: 
− Transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs or symptoms. 
− Nausea, vomiting, and diarrhea adequately controlled with medical therapy within 48 hours. 
− Changes in cholesterol and triglycerides. 
− An event clearly associated with the underlying disease, disease progression, a concomitant medication, or 
comorbidity. 
− Asymptomatic changes in lipid profiles. 
− Singular or nonfasting elevations in blood glucose (ie, blood glucose excursions will be considered toxicities if 
fasting blood glucose is elevated on 2 separate occasions). 
Hematologic 
• Grade 3 thrombocytopenia with bleeding. 
• Grade 4 thrombocytopenia. 
• Any grade febrile neutropenia (ANC < 1.0 × 109/L and fever > 101°F/38.5°C). 
• Grade 4 neutropenia that does not recover to ≤ Grade 2 in ≤ 7 days after interrupting study drug. 
• Grade 4 anemia not explained by underlying disease or some other concomitant disorder. 
Immune-related toxicity 
• ≥ Grade 2 ocular irAEs will be considered a DLT. 
• Grade 3 irAEs that do not improve to baseline or at least Grade 1 in < 5 days with appropriate care or with 
corticosteroid therapy will be considered a DLT.   
Exception:  Grade 3 rash in the absence of desquamation, with no mucosal involvement, that does not require 
systemic steroids, and that resolves to Grade 1 within 14 days. 
• Grade 4 irAEs will be considered a DLT regardless of duration.  
• ≥ Grade 2 pneumonitis. 
General 
• The inability to receive ≥ 75% of INCB001158 doses during the DLT-evaluation period (28 days) due to a 
drug-related AE will be considered a DLT. 
• Any other AE that is felt to be treatment-limiting in the medical opinions of the principal investigator and the 
medical monitor may be considered a DLT. 
AE = adverse event; ANC = absolute neutrophil count; DLT = dose-limiting toxicity; irAE = immune-related adverse event. 
Note:  Transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs or symptoms based on 
investigator determination will not be considered a dose-limiting toxicity. 
5.4.3. 
Management of Dose-Limiting Toxicities or Other Urgent Situations 
In all cases, investigators may employ any measures or concomitant medications, after 
discussion with the sponsor (whenever possible), necessary to optimally treat the subject. 


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5.4.4. 
Follow-Up of Dose-Limiting Toxicities 
Any DLT should be followed until it resolves to baseline or appears to have stabilized for a 
minimum of 4 weeks, unless the subject discontinues study treatment, in which case, the subject 
will be followed for 90 days after last dose of study treatment (see Section 8).  During follow-up, 
subjects should be seen as often as medically indicated to assure safety. 
5.4.5. 
Procedures for Cohort Review and Dose Escalation 
Regular meeting such as teleconferences will be scheduled by the sponsor with study 
investigators in order to review cohort-specific data and overall safety data, to agree on dose 
escalation, adjudicate individual high-grade AEs as potentially dose-limiting, and guide other 
major study decisions. 
5.4.6. 
Dose Modifications for Immune-Related Adverse Events and Adverse Events 
Related to Urea-Cycle Inhibition 
As described in Section 1.3.1, INCB001158 has the potential to cause toxicity related to the 
inhibition of arginase 1 in the hepatic urea cycle.  
Table 10 provides guidance for INCB001158 dose modifications and subject management if 
there is evidence of urea cycle inhibition. 
Dose modification and toxicity management for irAEs associated with INCB001158 should be 
managed as follows. 
Adverse events (both nonserious and serious) associated with INCB001158 exposure may 
represent an immunologic etiology.  These irAEs may occur shortly after the first dose or several 
months after the last dose of treatment and may affect more than 1 body system simultaneously.  
Therefore, early recognition and initiation of treatment is critical to reduce complications.  For 
suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes.  
Additional procedures or tests such as bronchoscopy, endoscopy, or skin biopsy may be included 
as part of the evaluation.  Based on the severity of irAEs, withhold or permanently discontinue 
INCB001158 and administer corticosteroids. 
Table 10 summarizes the AE dose modification actions for INCB001158.  Of note, when 
indicated by Table 10 to mitigate irAEs, the dose of INCB001158 must be reduced using the 
dosing levels outlined in Table 4.  Once reduced, re-escalation of INCB001158 is not permitted. 


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Table 10: 
Dose Modification and Toxicity Management Guidelines for Adverse Events Related to INCB001158 
Adverse Event 
Toxicity Grade or 
Conditions (CTCAEv4.03) 
Action Taken 
AE Management With 
Corticosteroid and/or 
Other Therapies 
Monitor and Follow-Up 
Evidence of urea 
cycle inhibition 
• Fasting urinary orotic acid 
> 2 × and ≤ 10 × ULN 
• Any urinary orotic acid 
> 2 × and ≤ 40 × ULN 
• Continue. 
• None. 
• Retest fasting urinary orotic acid 
1 week later. 
• Ammonia 2 × ULN and 
2 × baseline (repeated 
measurements or with 
symptoms) 
• Fasting urinary orotic acid 
> 10 × ULN 
• Any urinary orotic acid 
> 40 × ULN 
• BUN < 50% LLN 
• Withhold. 
• Consider restarting (at a lower dose) 
in consultation with medical 
monitor. 
• See Section 5.4.8 for management 
of hyperammonemia. 
 
Pneumonitis 
Grade 2 
• Withhold until Grade 0-1.  Restart 
at full dose. 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg/day prednisone 
or equivalent) followed by taper. 
• Monitor subjects for signs and 
symptoms of pneumonitis. 
• Evaluate subjects with suspected 
pneumonitis with radiographic 
imaging and initiate corticosteroid 
treatment. 
• Add prophylactic antibiotics for 
opportunistic infections. 
Grade 3 or 4, or recurrent 
Grade 2 
• Withhold until Grade 0-1.  Consider 
rechallenge at next dose level lower. 
Diarrhea/colitis 
Grade 2 or 3 
• Withhold until Grade 0-1. 
• Grade 2:  Restart at same dose level. 
• Grade 3:  Restart at next dose level 
lower. 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg/day prednisone 
or equivalent) followed by taper. 
• Monitor subjects for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood 
or mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
• Subjects with ≥ Grade 2 diarrhea 
suspecting colitis should consider 
GI consultation and performing 
endoscopy to rule out colitis.  
• Subjects with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids.  If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion. 
Grade 4 
• Withhold until Grade 0-1.  Consider 
rechallenge at next dose level lower. 


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Table 10: 
Dose Modification and Toxicity Management Guidelines for Adverse Events Related to INCB001158 
(Continued) 
Adverse Event 
Toxicity Grade or 
Conditions (CTCAEv4.03) 
Action Taken 
AE Management With 
Corticosteroid and/or 
Other Therapies 
Monitor and Follow-Up 
AST/ALT elevation or 
increased bilirubina 
Grade 2 
• Withhold until Grade 0-1.  Restart 
at same dose level. 
• Administer corticosteroids (initial 
dose of 0.5-1mg/kg prednisone or 
equivalent) followed by taper. 
• Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme 
value returns to baseline or is 
stable. 
Grade 3 or 4  
• Withhold until Grade 0-1.  Consider 
rechallenge at next dose level lower. 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper. 
T1DM or 
hyperglycemiab 
Newly onset T1DM or 
Grade 3 or 4 hyperglycemia 
associated with evidence of 
-cell failure 
• Withhold until Grade 0-1. 
• Grade 2:  Restart at same dose level. 
• Grade 3:  Restart at next dose level 
lower. 
• Initiate insulin replacement therapy 
for subjects with T1DM. 
• Administer antihyperglycemic in 
subjects with hyperglycemia. 
• Monitor subjects for 
hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
• Withhold until Grade 0-1.  Restart 
at same dose level. 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated. 
• Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency). 
Grade 3 or 4 
• Withhold until Grade 0-1. 
• Grade 3:  Restart at same dose level. 
• Grade 4:  Consider rechallenge at 
next dose level lower. 
Hyperthyroidismb 
Grade 2 
• Continue. 
• Treat with nonselective β-blockers 
(eg, propranolol) or thionamides as 
appropriate. 
• Monitor for signs and symptoms 
of thyroid disorders. 
Grade 3 or 4 
• Withhold until Grade 0-1.  Consider 
rechallenge at next dose level lower. 
Hypothyroidismb 
Grade 2-4 
• Continue. 
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care. 
• Monitor for signs and symptoms 
of thyroid disorders. 
Nephritis and renal 
dysfunction 
Grade 2 
• Withhold until Grade 0-1.  Restart 
at same dose level. 
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• Monitor changes of renal 
function. 
Grade 3 or 4  
• Withhold until Grade 0-1. 
• Grade 3:  Restart at same dose level. 
• Grade 4:  Consider rechallenge at 
next dose level lower. 


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Table 10: 
Dose Modification and Toxicity Management Guidelines for Adverse Events Related to INCB001158 
(Continued) 
Adverse Event 
Toxicity Grade or 
Conditions (CTCAEv4.03) 
Action Taken 
AE Management With 
Corticosteroid and/or 
Other Therapies 
Monitor and Follow-Up 
Rash 
Grade 1 or 2 
• Continue. 
• Manage with topical steroids with 
or without drug interruption. 
 
Grade 3c 
• Withhold until Grade 0-1. 
• Restart at same dose level. 
• Consider dermatology consultation 
and biopsy for confirmation of 
diagnosis. 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper. 
• If toxicity does not resolve within 
12 weeks of last dose, or cannot 
taper below 10 mg or less of 
prednisone or equivalent within 
12 weeks, must permanently 
discontinue. 
Grade 4 
• Withhold until Grade 0-1.  Consider 
rechallenge at next dose level lower. 
• Dermatology consultation and 
consideration of biopsy and 
clinical dermatology photograph. 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper. 
 
Asymptomaticd 
amylase or lipase 
increased 
Grade 3 
• May continue treatment with 
medical monitor approval. 
 
• Permanently discontinue if 
clinical signs and symptoms of 
pancreatitis develop (abdominal 
pain, nausea, vomiting). 
• If toxicity does not resolve within 
12 weeks of last dose after an 
interruption, must permanently 
discontinue unless approved by 
the medical monitor to continue. 
• If Grade 4 lipase/amylase 
elevation is asymptomatic and 
abdominal imaging suggests no 
pathology, study drug 
administration dosing may 
continue with medical monitor 
approval. 
Grade 4 
• Withhold until Grade 0-1.  Restart 
at same dose level. 
 
All other irAEs 
Grade 3, or 
intolerable/persistent Grade 2 
• Withhold until Grade 0-1.  Consider 
rechallenge at next dose level lower. 
• Based on severity of AE 
administer corticosteroids. 
• Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Grade 4 or recurrent Grade 3  
• Withhold until Grade 0-1.  Consider 
rechallenge at next dose level lower. 


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Table 10: 
Dose Modification and Toxicity Management Guidelines for Adverse Events Related to INCB001158 
(Continued) 
Adverse Event 
Toxicity Grade or 
Conditions (CTCAEv4.03) 
Action Taken 
AE Management With 
Corticosteroid and/or 
Other Therapies 
Monitor and Follow-Up 
General Instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where INCB001158 has been withheld, INCB001158 can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered.  
INCB001158 should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤ 10 mg prednisone or 
equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid.  Other immunosuppressive treatment should be initiated if irAEs 
cannot be controlled by corticosteroids. 
AE = adverse event; ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase); CTCAE = Common Terminology Criteria for Adverse Events; DKA = diabetic ketoacidosis; IV = intravenous; irAE = infusion-related adverse events; 
T1DM = Type 1 diabetes mellitus. 
a Subjects with radiographically documented liver metastases should withhold at > 5 × ULN. 
b For subjects with Grade 3 or 4 immune-related endocrinopathy where withholding of INCB001158 is required, INCB001158 may be resumed when AE resolves to ≤ Grade 2 
and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM). 
c Subjects with Grade 3 rash in the absence of desquamation, with no mucosal involvement, that does not require systemic steroids, and that resolves to Grade 1 within 14 days do 
not have to hold study medication and may be treated similar as Grade 1 events. 
d If Grade 4 lipase/amylase elevation is asymptomatic and abdominal imaging suggests no pathology, then study drug administration dosing may continue (with or without dose 
reduction) with medical monitor approval. 


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5.4.7. 
Management of Chemotherapy-Related Adverse Events 
Dose modifications for hematologic and nonhematologic AEs related to chemotherapy may be 
managed per institutional guidelines.  In the absence of these, recommendations for dose 
modifications for chemotherapy regimen in the event of hematologic and nonhematologic AEs 
are provided in the Protocol appendices: 
• Appendix C for subjects who receive mFOLFOX6  
• Appendix D for subjects who receive gemcitabine/cisplatin 
• Appendix E for subjects who receive paclitaxel 
It is important to note that some AEs will overlap with potential irAEs.  In these cases, both the 
AE and irAE guidance should be reviewed to determine the most appropriate management of 
study medications. 
5.4.8. 
Supportive Care Guidelines for Management of Hyperammonemia 
Subjects should be monitored for elevated venous plasma ammonia.  Asymptomatic clinically 
significant drug-related elevations in ammonia (eg, a repeatable elevation in ammonia 
> 2 × ULN AND > 2 × baseline) should be managed by interrupting INCB001158 and 
monitoring to resolution.  For symptomatic elevations (ie, significant ammonia elevation 
associated with nausea, vomiting, severe anorexia, mental status changes, seizure, or other 
symptoms associated with hyperammonemia), subjects should be admitted for management 
according to the local institutional protocol for hyperammonemia, including 1) sending 
appropriate labs (ammonia [on ice, measured immediately], plasma amino acid profile, LFTs, 
electrolytes, bicarb, BUN, creatinine, glucose, and urine orotic acid), 2) IV hydration with 
dextrose-containing fluids, 3) discontinuation of protein intake, 4) implementing therapy to 
reduce ammonia levels (oral lactulose/lactitol, IV Ammonul®), and 5) identifying and treating 
any potential triggers (eg, discontinue corticosteroids, treat infections, etc). 
5.4.9. 
Criteria for Permanent Discontinuation of Study Drug 
The occurrence of unacceptable toxicity not caused by the underlying malignancy will be 
presumed to be related to study treatment administration and will require that the study treatment 
be permanently discontinued.  Unacceptable toxicity is defined as follows: 
• Occurrence of an AE that is related to treatment with the study treatment that, in the 
judgment of the investigator or the sponsor's medical monitor, compromises the 
subject's ability to continue study-specific procedures or is considered to not be in the 
subject's best interest. 
• An AE requiring more than 2 dose reductions of INCB001158. 
• Persistent AE requiring a delay of therapy for more than 12 weeks unless a greater 
delay has been approved by the sponsor. 


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5.5. 
Withdrawal of Subjects From Study Treatment 
5.5.1. 
Withdrawal Criteria 
Subjects must be withdrawn from study treatment for the following reasons: 
• The subject becomes pregnant. 
• Consent is withdrawn.  Subjects may choose to withdraw from the study at any time 
without penalty of jeopardizing their health care or loss of benefits to which the 
subject is otherwise entitled. 
Note:  Consent withdrawn means that the subject can no longer be followed and no 
additional data can be collected.  Subjects may choose to discontinue study treatment 
and remain in the study to be followed for progression 
. 
Note:  As of Protocol Amendment 4, subjects who withdraw consent will no longer 
be followed for progression 
 beyond the last safety follow-up visit. 
• Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
• Unacceptable toxicity (see Sections 5.4.6 and 5.4.9).  Subjects with unacceptable 
toxicities must be withdrawn from study treatment but will continue in the follow-up 
period of the study (see Section 6.4). 
• The subject has an unacceptable toxicity or a toxicity that does not recover in 
6 weeks.  Investigators who wish to continue treatment after a treatment delay of 
4 weeks should consult with the sponsor's medical monitor for approval. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A subject may be discontinued from study treatment as follows: 
• Confirmed radiographic progression of disease per RECIST v1.1 (see 
Section 7.7.1.2).  A subject may be granted an exception to continue on treatment 
with confirmed radiographic progression if clinically stable or clinically improved 
(see Section 7.7.1.2 and 7.7.1.5). 
Note:  For unconfirmed progression, see Section 7.7.1.2. 
If, during the course of the study, a subject is found not to have met eligibility criteria 
(see Section 3), then the medical monitor, in collaboration with the investigator, will 
determine whether the subject should be withdrawn from the study. 
• If a subject is noncompliant with study procedures or study drug administration in the 
investigator's opinion, then the sponsor should be consulted for instruction on 
handling the subject. 


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5.5.2. 
Withdrawal Procedures 
In the event that the decision is made to permanently discontinue the study drug, the subject will 
be withdrawn from the study, and the end-of-treatment visit should be conducted.  Reasonable 
efforts should be made to have the subject return for a follow-up visit.  These visits are described 
in Section 6.  The last date of the last dose of study drug and the reason for subject withdrawal 
will be recorded in the eCRF. 
If a subject is withdrawn from the study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the subject's medical record and 
in the eCRF. 
• The EOT visit should be performed. 
• The date of the EOT visit should be recorded in the eCRF and IRT. 
• Subjects must be followed for safety until the time of the follow-up visit or until 
study drug–related toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longest. 
• Subjects who discontinue for reasons other than disease progression will continue to 
be followed for disease status as outlined in Section 6.4.2. 
 
 
If the subject discontinues study treatment and actively withdraws consent for collection of 
follow-up data (safety follow-up or disease assessment), then no additional data collection 
should occur; however, subjects will have the option of withdrawing consent for study treatment 
but continuing in the follow-up period of the study for safety/efficacy assessments. 
5.6. 
Concomitant Medications 
All prior and concomitant medications and treatments must be recorded in the eCRF.  Any 
medication received up to 21 days before the first dose of study treatment and within 90 days 
after the last dose of study treatment, or until the subject begins a new anticancer therapy, 
whichever occurs first, will be recorded in the eCRF.  Any addition, deletion, or change in the 
dose of these medications will also be recorded.  Concomitant medications administered after 
90 days after the last dose of study treatment should be recorded for SAEs as defined in 
Section 8.3.  Concomitant treatments/procedures that are required to manage a subject's medical 
condition during the study will also be recorded in the eCRF. 
NOTE:  As of Protocol Amendment 4, use of concomitant medications should be monitored for 
subjects to verify that they are not taking any concomitant medication prohibited per protocol; 
however, concomitant medications no longer need to be collected in the eCRF, except for 
concomitant medications in relation with SAEs or AESIs. 


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5.6.1. 
Permitted Medications 
All treatments that the investigator considers necessary for a subject's welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the eCRF including all 
prescription, over-the-counter, herbal supplements, and IV medications and fluids.  If changes 
occur during the study period, documentation of drug dosage frequency, route, and date will also 
be included on the eCRF. 
Palliative and supportive care is permitted during the course of the study for underlying medical 
conditions and management of symptoms.  Surgery for tumor control is not permitted during the 
study.  Palliative radiotherapy is permitted to a limited number of lesions if considered medically 
necessary by the treating physician as long as the lesions are NOT a RECIST v1.1–defined target 
lesion.  Study therapy should be held during the course of palliative radiotherapy and should be 
resumed no earlier than the next scheduled administration of study therapy.  The specifics of the 
radiation treatment, including the location, will be recorded. 
Xanthine oxidase inhibitors (eg, allopurinol) cause an accumulation of orotic acid in the urine, 
which would confound the assessment of safety in these subjects.  Since there is no expected 
toxicity associated with this accumulation, subjects receiving xanthine oxidase inhibitors may be 
enrolled.  The sponsor should be informed of any subject that is receiving a xanthine oxidase 
inhibitor as a concomitant therapy, and the evaluation of urinary orotic acid should not be 
performed, as the results will be uninterpretable and may incorrectly suggest urea cycle 
inhibition. 
Note:  The use of bisphosphonates and denosumab are permitted in this study. 
5.6.2. 
Restricted Medications 
Caution should be exercised when paclitaxel is administered with concomitant medications that 
are inhibitors of CYP2C8 and/or CYP3A4, to avoid excess toxicity due to higher paclitaxel 
exposure. 
Caution should be exercised when cisplatin is administered with concomitant medications that 
are nephrotoxic or ototoxic to avoid additive toxicity with cisplatin. 
5.6.3. 
Prohibited Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy may be required.  
The investigator should discuss any questions regarding this with the medical monitor.  The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the subject's 
primary physician.  However, the decision to continue the subject on study treatment requires the 
mutual agreement of the investigator, the medical monitor, and the subject. 


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Subjects are prohibited from receiving the following therapies during the screening and treatment 
of this study: 
• Antineoplastic systemic chemotherapy or biological therapy not specified in this 
Protocol. 
• Immunotherapy not specified in this Protocol. 
• Investigational agents other than INCB001158 and chemotherapy used in the study. 
• Oncologic surgery for tumor control. 
• Radiation therapy for disease control. 
Note:  Radiation therapy to symptomatic lesions or to the brain may be allowed at the 
investigator's discretion, provided the lesions were not previously defined by the site 
as target lesions. 
• Live vaccines within 30 days before the first dose of study treatment, while 
participating in the study, and until 3 months after the last dose of any component of 
study treatment. 
− Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, chickenpox, yellow fever, nasal seasonal flu, nasal H1N1 flu, 
rabies, Bacillus Calmette-Guérin, and typhoid. 
• Except for erythropoietin or darbepoetin alpha (Aranesp®), use of growth factors 
(G-CSF, GM-CSF, etc) is not permitted in the first treatment cycle unless the subject 
experiences a hematologic DLT. 
• Concomitant treatment with valproic acid/valproate-containing therapies is not 
permitted, as hyperammonemia is a well-described toxicity of valproic acid, 
particularly at high exposures, potentially through inhibition of the urea cycle 
(Verrotti et al 2002, Wadzinski et al 2007). 
• Concomitant administration of inducers of CYP2C8 or CYP3A4 is prohibited with 
paclitaxel treatment.  See Appendix F for a list of inducers and inhibitors of CYP2C8 
and CYP3A4. 
• Prolonged therapy with systemic glucocorticoids (> 7 days) for any purpose other 
than to modulate symptoms from an AE, SAE, or event of clinical interest, or for use 
as a premedication for chemotherapy or in participants with a known history of an IV 
contrast allergy administered as part of CT radiography.  Brief, limited use of 
systemic corticosteroids (≤ 7 days) are permitted where such use is considered 
standard of care (eg, for chronic obstructive pulmonary disease exacerbation).  
− Replacement doses of steroids (for example, prednisone 5 to 7.5 mg daily) are 
permitted while on study, as is the use of local steroids. 


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Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from treatment but should continue in the 
study for assessment of disease status 
. 
NOTE:  As of Protocol Amendment 4, subjects who require the use of a prohibited medication 
and are removed from treatment will no longer be followed for progression 
 
. 
The exclusion criteria describe other medications that are prohibited in this study. 
There are no prohibited therapies during the post-treatment follow-up period. 
6. 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in the schedule of assessments (see 
Table 11, Table 12, Table 13, and Table 14) and all laboratory assessments will be performed as 
indicated in Table 16.  The order of assessments is suggested by the order of mention within the 
schedule.  See Section 7 for instructions on each assessment.  Further details of study procedures 
and assessments can be found in the study reference manual. 
NOTE:  As of Protocol Amendment 4, please refer to Table 15 for the schedule of assessments 
for all subjects. 


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Table 11: 
Schedule of Assessments for Subjects Treated With INCB001158 + mFOLFOX6 or INCB001158 + Paclitaxel 
Procedure 
Protocol 
Section 
Screening 
Treatment (28-Day Cycles) 
EOT  
Follow-Up 
Notes 
Cycle 1 
Other Cycles 
Q8W 
± 7d 
Safety 
Disease 
Status 
 
Days 
-21 to -1 
D1 
D8  
± 3d 
D15  
± 3d 
D1  
± 3d 
D8  
± 3d 
D15  
± 3d 
+ 7d 
30 d 
After 
EOT 
± 7d 
90 d 
After 
EOT 
± 7d 
Q8W 
After 
EOT  
± 7d 
 
 
Administrative procedures 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion and 
exclusion criteria 
3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography and 
medical history 
7.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
7.4 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
 
Dispensing 
INCB001158 study 
drug 
5.1.1  
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Study treatment administration 
Administer 
INCB001158 at site 
5.2.1 
 
X 
X 
X 
X 
X* 
X 
 
 
 
 
 
 
Subject to withhold AM dose 
of INCB001158 study drug. 
* D8 of Cycle 2 and beyond 
only for subjects receiving 
paclitaxel. 
Administer 
mFOLFOX6 at site 
5.2.2 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
Should be administered after 
INCB001158. 
Administer paclitaxel at 
site 
5.2.4 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Should be administered after 
INCB001158. 
Assess study drug 
compliance 
5.3 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Distribute reminders 
7.11.1 
X 
X 
X 
X 
X 
X* 
X 
 
X 
 
 
 
 
* D8 of Cycle 2 and beyond for 
subjects receiving paclitaxel. 
Clinical procedures and assessments 
Comprehensive 
physical examination  
7.6.2.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical 
examination 
7.6.2.2 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
 


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Table 11: 
Schedule of Assessments for Subjects Treated With INCB001158 + mFOLFOX6 or INCB001158 + Paclitaxel 
(Continued) 
Procedure 
Protocol 
Section 
Screening 
Treatment (28-Day Cycles) 
EOT  
Follow-Up 
Notes 
Cycle 1 
Other Cycles 
Q8W 
± 7d 
Safety 
Disease 
Status 
 
Days 
-21 to -1 
D1 
D8  
± 3d 
D15  
± 3d 
D1  
± 3d 
D8  
± 3d 
D15  
± 3d 
+ 7d 
30 d 
After 
EOT 
± 7d 
90 d 
After 
EOT 
± 7d 
Q8W 
After 
EOT  
± 7d 
 
 
Vital signs 
7.6.3 
X 
X* 
X 
X* 
X 
 
X 
 
X 
X 
X 
X 
 
* Orthostatic blood 
pressure monitoring at 
predose and 4 hours 
postdose. 
12-lead ECG 
7.6.4 
X 
X* 
X* 
 
 
 
 
 
X 
 
 
 
 
* Timed triplicate ECGs 
(separated by 5 minutes  ± 
1 minute) at predose and 
2 to 4 hours postdose. 
ECOG status 
7.8.1 
X 
X 
X 
X 
X 
X* 
X 
 
X 
X 
 
X 
 
* D8 of Cycle 2 and 
beyond only for subjects 
receiving paclitaxel. 
Radiographic tumor 
assessments (CT or 
MRI) 
7.7.1 
X 
 
 
 
 
 
 
X* 
X** 
 
 
X 
 
* Baseline and then every 
8 weeks ± 7 days. 
** ± 4 weeks. 
Review AEs 
8.1 
X 
X 
X 
X 
X 
X* 
X 
 
X 
X 
X 
X 
 
* D8 of Cycle 2 and 
beyond only for subjects 
receiving paclitaxel. 
Post-treatment 
anticancer therapy 
status  
7.5 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 12: 
Schedule of Laboratory Assessments for Subjects Treated With INCB001158 + mFOLFOX6 or INCB001158 + 
Paclitaxel 
Procedure 
Protocol 
Section 
Screening 
Treatment (28-Day Cycles) 
EOT 
Safety 
Follow-Up 
Notes 
Cycle 1 
Other Cycles 
Q8W 
± 7d 
30 d 
After 
EOT 
± 7d 
90 d 
After 
EOT 
± 7d 
Days 
-21 to -1 
D1 
D8  
± 3d 
D15  
± 3d 
D1  
± 3d 
D8  
± 3d 
D15  
± 3d 
+ 7d 
Local laboratory tests 
Chemistries  
7.6.5.1 
X 
X* 
X 
X 
X 
X** 
X 
 
X 
X 
X 
* Does not need to be repeated if the screening 
sample was obtained within 3 days before C1D1, 
unless a clinically significant change is suspected. 
** D8 of Cycle 2 and beyond only for subjects 
receiving paclitaxel. 
Hematology 
7.6.5 
X 
X* 
X 
X 
X 
X** 
X 
 
X 
X 
X 
Coagulation panel 
7.6.5.7 
X 
 
 
 
 
 
 
 
 
X 
 
 
Hepatitis and HIV 
screening 
7.6.5.6  
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
7.6.5.2 
X 
X* 
 
 
X 
 
 
 
 
X 
 
* Does not need to be repeated if the screening 
sample was obtained within 3 days before C1D1, 
unless a clinically significant change is suspected. 
Blood sample for 
plasma ammonia 
levels 
7.6.5.3 
X 
 
 
 
 
 
 
 
 
 
 
Collect during screening.  If plasma ammonia is 
above ULN, repeat screening sample to confirm 
value.  If the subject experiences an elevation in 
urine orotic acid (> 10 × ULN fasted or 
> 40 × ULN of any value) while on study 
treatment or during the follow-up period, monitor 
plasma ammonia levels each time the urine orotic 
acid is tested, at least until orotic acid levels have 
returned to normal, at the investigator's and 
medical monitor's discretion. 
CA 125 testing (OC 
only) 
7.6.5.5 
X 
X 
 
 
X* 
 
 
X 
X 
 
 
*Collect at C2D1 and C4D1.  If available, the 
most recent measurement before screening should 
be recorded. 
Pregnancy test 
7.6.5.4 
X 
X* 
 
 
X* 
 
 
 
 
X 
 
All female subjects of childbearing potential. 
*Day 1 of each cycle.  


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Table 12: 
Schedule of Laboratory Assessments for Subjects Treated With INCB001158 + mFOLFOX6 or INCB001158 + 
Paclitaxel (Continued) 
Procedure 
Protocol 
Section 
Screening 
Treatment (28-Day Cycles) 
EOT 
Safety 
Follow-Up 
Notes 
Cycle 1 
Other Cycles 
Q8W 
± 7d 
30 d 
After 
EOT 
± 7d 
90 d 
After 
EOT 
± 7d 
Days 
-21 to -1 
D1 
D8  
± 3d 
D15  
± 3d 
D1  
± 3d 
D8  
± 3d 
D15  
± 3d 
+ 7d 
Central laboratory samples 
Urine sample for orotic 
acid  
7.6.5.2 
 
X* 
X* 
X* 
X* 
 
 
 
 
 
 
* See Table 17 for sample timings.  Additional 
samples may be collected as clinically 
indicated. 
Blood sample for 
INCB001158 PK 
7.9.1 
 
X* 
 
 
X* 
 
 
 
 
 
 
* See Table 20 and Table 21 for detailed for 
extensive and sparse sample timings.  Samples 
will be drawn on C1D1 and C2D1 only. 


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Table 12: 
Schedule of Laboratory Assessments for Subjects Treated With INCB001158 + mFOLFOX6 or INCB001158 + 
Paclitaxel (Continued) 
Procedure 
Protocol 
Section 
Screening 
Treatment (28-Day Cycles) 
EOT 
Safety 
Follow-Up 
Notes 
Cycle 1 
Other Cycles 
Q8W 
± 7d 
30 d 
After 
EOT 
± 7d 
90 d 
After 
EOT 
± 7d 
Days 
-21 to -1 
D1 
D8  
± 3d 
D15  
± 3d 
D1  
± 3d 
D8  
± 3d 
D15  
± 3d 
+ 7d 


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Table 13: 
Schedule of Assessments for Subjects Treated With INCB001158 + Gemcitabine and Cisplatin 
Procedure 
Protocol 
Section 
Screening 
Treatment (21-Day Cycles) 
EOT 
+ 7d 
Follow-Up 
Notes 
Cycle 1 
Other Cycles 
Q8W 
± 7d 
Safety 
Disease 
Status 
 
Days 
-21 to -1 
D1 
D8  
± 3d 
D15  
± 3d 
D1  
± 3d 
D8  
± 3d 
30 d 
After 
EOT 
± 7d 
90 d 
After 
EOT 
± 7d 
Q8W 
After 
EOT  
± 7d 
 
 
Administrative procedures 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review inclusion and 
exclusion criteria 
3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography and medical 
history 
7.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
7.4 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
Dispensing INCB001158 
study drug 
5.1.1  
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Study treatment administration 
Administer INCB001158 at 
site 
5.2.1 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Subject to withhold AM dose 
of INCB001158 study drug. 
Administer cisplatin/ 
gemcitabine at site  
5.2.3 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
Should be administered after 
INCB001158. 
Assess study drug 
compliance 
5.3 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
Distribute reminders 
7.11.1 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
Clinical procedures and assessments 
Comprehensive physical 
examination 
7.6.2.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical 
examination 
7.6.2.2 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
Vital signs 
7.6.3 
X 
X* 
X 
X* 
X 
 
 
X 
X 
X 
X 
 
* Orthostatic blood pressure 
monitoring at predose and 
4 hours postdose. 


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Table 13: 
Schedule of Assessments for Subjects Treated With INCB001158 + Gemcitabine and Cisplatin (Continued) 
Procedure 
Protocol 
Section 
Screening 
Treatment (21-Day Cycles) 
EOT 
+ 7d 
Follow-Up 
Notes 
Cycle 1 
Other Cycles 
Q8W 
± 7d 
Safety 
Disease 
Status 
 
Days 
-21 to -1 
D1 
D8  
± 3d 
D15  
± 3d 
D1  
± 3d 
D8  
± 3d 
30 d 
After 
EOT 
± 7d 
90 d 
After 
EOT 
± 7d 
Q8W 
After 
EOT  
± 7d 
 
 
12-lead ECG 
7.6.4 
X 
X* 
X* 
 
 
 
 
X 
 
 
 
 
* Timed triplicate ECGs 
(separated by 5 minutes ± 1 
minute) at predose and 2 to 
4 hours postdose. 
ECOG status 
7.8.1 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
 
Radiographic tumor 
assessments (CT or MRI) 
7.7.1 
X 
 
 
 
 
 
X* 
X** 
 
 
X 
 
* Baseline and then every 
8 weeks ± 7 days. 
** ± 4 weeks. 
Review AEs 
8.1 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Post-treatment anticancer 
therapy status  
7.5 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 14: 
Schedule of Laboratory Assessments for Subjects Treated With INCB001158 + Gemcitabine and Cisplatin 
Procedure 
Protocol 
Section 
Screening 
Treatment (21-Day Cycles) 
EOT 
Safety 
Follow-Up 
Notes 
Cycle 1 
Other Cycles 
Q8W 
± 7d 
30 d 
After 
EOT 
± 7d 
90 d 
After 
EOT 
± 7d 
Days 
-21 to -1 
D1 
D8  
± 3d 
D15  
± 3d 
D1  
± 3d 
D8  
± 3d 
+ 7d 
Local laboratory tests 
Chemistries 
7.6.5.1 
X 
X* 
X 
X 
X 
X 
 
X 
X 
X 
* Does not need to be repeated if the screening 
sample was obtained within 3 days before 
C1D1, unless a clinically significant change is 
suspected. 
Hematology 
7.6.5 
X 
X* 
X 
X 
X 
X 
 
X 
X 
X 
Coagulation panel 
7.6.5.7 
X 
 
 
 
 
 
 
 
X 
 
 
Hepatitis and HIV screening 
7.6.5.6  
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
7.6.5.2 
X 
X* 
 
 
X 
 
 
 
X 
 
* Does not need to be repeated if the screening 
sample was obtained within 3 days before 
C1D1, unless a clinically significant change is 
suspected. 
Blood sample for plasma 
ammonia levels 
7.6.5.3 
X 
 
 
 
 
 
 
 
 
 
Collect during screening.  If plasma ammonia is 
above ULN, repeat screening sample to confirm 
value.  If the subject experiences an elevation in 
urine orotic acid (> 10 × ULN fasted or 
> 40 × ULN of any value) while on study 
treatment or during the follow-up period, 
monitor plasma ammonia levels each time the 
urine orotic acid is tested, at least until orotic 
acid levels have returned to normal, at the 
investigator's and medical monitor's discretion. 
CA 125 testing (OC only) 
7.6.5.5 
X 
X 
 
 
X* 
 
X 
X 
 
 
*Collect at C2D1 and C4D1.  If available, the 
most recent measure before screening should be 
recorded. 
Pregnancy test 
7.6.5.4 
X 
X* 
 
 
X* 
 
 
 
X 
 
All female subjects of childbearing potential. 
*Day 1 of each cycle. 


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Table 14: 
Schedule of Laboratory Assessments for Subjects Treated With INCB001158 + Gemcitabine and Cisplatin 
(Continued) 
Procedure 
Protocol 
Section 
Screening 
Treatment (21-Day Cycles) 
EOT 
Safety 
Follow-Up 
Notes 
Cycle 1 
Other Cycles 
Q8W 
± 7d 
30 d 
After 
EOT 
± 7d 
90 d 
After 
EOT 
± 7d 
Days 
-21 to -1 
D1 
D8  
± 3d 
D15  
± 3d 
D1  
± 3d 
D8  
± 3d 
+ 7d 
Central laboratory samples 
Urine sample for orotic acid 
7.6.5.2 
 
X* 
X* 
X* 
X* 
 
 
 
 
 
* See Table 17 for sample timings.  Additional 
samples may be collected as clinically 
indicated. 
Blood sample for 
INCB001158 PK 
7.9.1 
 
X* 
 
 
X* 
 
 
 
 
 
* See Table 20 and Table 21 for detailed for 
extensive and sparse sample timings.  Samples 
will be drawn on C1D1 and C2D1 only. 


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Table 14: 
Schedule of Laboratory Assessments for Subjects Treated With INCB001158 + Gemcitabine and Cisplatin 
(Continued) 
Procedure 
Protocol 
Section 
Screening 
Treatment (21-Day Cycles) 
EOT 
Safety 
Follow-Up 
Notes 
Cycle 1 
Other Cycles 
Q8W 
± 7d 
30 d 
After 
EOT 
± 7d 
90 d 
After 
EOT 
± 7d 
Days 
-21 to -1 
D1 
D8  
± 3d 
D15  
± 3d 
D1  
± 3d 
D8  
± 3d 
+ 7d 


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Table 15: 
Schedule of Assessments for All Subjects (as of Protocol Amendment 4) 
Procedure 
Protocol 
Section 
Treatment 
Period 
EOT 
Safety 
Follow-Up 
Notes 
(21- or 28-
Day Cycle) 
+ 7d 
30 d 
After 
EOT 
± 7d 
90 d 
After 
EOT 
± 7d 
Informed consent 
7.1 
X 
 
 
 
Subjects will sign a new ICF as per Protocol Amendment 4. 
Concomitant 
medications 
7.4 
X 
X 
X 
X 
Review to ensure no prohibited medications are being used. 
Provide data to sponsor about medications used for SAEs and AESIs only. 
Dispense/Administer 
INCB001158 
5.2.1 
X 
 
 
 
On clinic days when subjects are receiving chemotherapy at the site, INCB001158 
should be administered before beginning the infusion of the chemotherapy. 
Administer 
chemotherapy 
regimen at site 
5.2.2 
5.2.3 
5.2.4 
X* 
 
 
 
Should be administered after INCB001158. 
*Refer to the applicable chemotherapy administration as per the subject’s 
treatment assignment (Section 5.1.1). 
Assess study drug 
compliance 
5.3 
X* 
X 
 
 
*Day 1 of each cycle. 
Distribute reminders 
7.11.1 
X* 
X 
 
 
*On the clinic days for the next visit. 
AE assessment 
8.1 
X 
X 
X 
X 
All SAEs and AESIs must be recorded in the eCRFs, regardless of the causal 
relationship. 
Radiographic tumor 
assessments 
(CT/MRI) 
7.7 
X* 
X 
 
 
*Every 8 weeks ± 7 days.  After Week 96, the radiographic tumor assessments are 
only required to be performed as per standard of care guidelines for the subject's 
condition and monitoring. 
Pregnancy test 
7.6.5.4 
X* 
 
X 
 
All female subjects of childbearing potential. 
*Day 1 of each cycle. 
Post-treatment 
anticancer therapy 
status 
7.5 
 
 
X 
X 
If a subject is scheduled to begin a post-treatment anticancer therapy before the 
end of the safety follow-up period, then the safety follow-up visit should be 
performed before post-treatment anticancer therapy is started. 
 


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Table 16: 
Laboratory Tests:  Required Analytes 
Chemistries 
Hematology 
Urinalysis With 
Microscopic 
Examination 
Hepatitis and HIV 
Screening 
Albumin 
Alkaline phosphatase 
ALT 
Amino acid panela 
Ammonia 
Amylase 
Arginasea 
AST  
Bicarbonate or CO2 
Blood urea nitrogen or urea 
Calcium 
Chloride  
Creatinine 
Glucose 
Lactate dehydrogenase 
Lipase 
Ornithinea 
Phosphate 
Potassium 
Sodium 
Thyroid panel:  TSH, FT4, 
FT3/T3 
Total bilirubin 
Direct bilirubin (if total 
bilirubin is elevated above 
ULN) 
Total protein 
Uric acid 
Complete blood count, 
including: 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
White blood cell count 
 
Differential count, 
including: 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
 
Absolute values must be 
provided for:  
WBC differential 
laboratory results: 
Lymphocytes 
Neutrophils 
 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Orotic acida 
Protein 
Urobilinogen 
Hepatitis B surface 
antigen 
Hepatitis B surface 
antigen antibody 
Hepatitis B core 
antibody 
HBV-DNA 
HCV antibody 
HCV-RNA 
HIV-RNA (if required 
by local regulations) 
Lipid Panel 
Pregnancy Testing 
Total cholesterol 
Triglycerides 
LDL 
HDL 
Female subjects of 
childbearing potential 
require a serum 
pregnancy test at 
screening and a urine 
pregnancy test before the 
first dose on Cycle 1 
Day 1 and on Day 1 of 
every cycle.  A serum 
pregnancy test will be 
performed at 30-day 
safety follow up visit. 
Pregnancy tests (serum 
or urine) should be 
repeated if required by 
local regulations. 
Coagulation 
PT 
aPTT 
INR 
CA 125 testing 
(subjects with OC 
only) 
Note:  Additional tests may be required, as agreed upon by investigator and sponsor, based on emerging safety data. 
a Tests to be conducted by central laboratory.  All other tests will be conducted by a local laboratory where possible. 
6.1. 
Screening 
Screening is the interval between signing the ICF and the day the subject is enrolled in the study 
(Cycle 1 Day 1).  Screening may not exceed 21 days.  Assessments that are required to 
demonstrate eligibility may be performed over the course of 1 or more days during the screening 
process. 
Procedures conducted as part of the subject's routine clinical management (eg, blood count, 
imaging study) and obtained before signing of informed consent may be used for screening or 
baseline purposes provided that the procedure meets the Protocol-defined criteria and has been 
performed in the timeframe of the study (ie, within 21 days of Cycle 1 Day 1).  All information 
associated with eligibility requirements must be entered into the appropriate eCRF pages. 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
enrollment or the administration of study drug.  Tests with results that fail eligibility 
requirements may be repeated once during screening if the investigator believes the results to be 


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in error.  For screening assessments that are repeated, the most recent available result before 
treatment assignment will be used to determine subject eligibility.  Additionally, a subject who 
fails screening may repeat the screening process 1 time if the investigator believes there has been 
a change in eligibility status (eg, after recovery from an infection). 
6.2. 
Treatment 
The treatment period begins on the day the subject receives the first dose of study treatment 
(Cycle 1 Day 1), as assigned in the IRT system, through the point at which the investigator 
determines the subject will be permanently discontinued from study treatment.  Cycle 1 Day 1 
must be no more than 21 days after the subject has signed the ICF.  Dates for subsequent study 
visits will be determined based on this day and should occur within 3 days (±) of the scheduled 
date unless delayed for safety reasons.  At Cycle 1 Day 1, results from screening visit evaluations 
should be reviewed to determine whether the subject continues to meet the eligibility 
requirements, as specified in the Protocol. 
Subjects will have regularly scheduled study visits as outlined in Table 11, Table 12, Table 13, 
and Table 14 (see Table 15 for all subjects as of Protocol Amendment 4), and toxicities will be 
monitored continuously and will be graded using the NCI CTCAE v4.03 criteria. 
6.3. 
End of Treatment 
When the subject permanently discontinues treatment, as outlined in Section 5.5, the EOT visit 
should be conducted.  If the EOT visit coincides with a regular study visit, the EOT evaluations 
will supersede those of that scheduled visit, and the data should be entered in the EOT visit in the 
eCRF.  The EOT visit may occur up to 7 days after the subject receives the final dose of study 
treatment.  The subject should be encouraged to return for the safety follow-up visit.  When the 
subject permanently discontinues study drug, the EOT visit should be conducted.  If the EOT 
visit coincides with a regular study visit, the EOT evaluations will supersede those of that 
scheduled visit, and the data should be entered in the EOT visit in the eCRF.  The subject should 
be encouraged to return for the follow-up visit. 
6.4. 
Follow-Up 
6.4.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-up 
visit, which should occur 30 days and 90 days after the EOT visit (or after the last dose of study 
drug if the EOT visit was not performed).  Adverse events and SAEs must be reported up until at 
least 90 days after the last dose of study drug, the date of the second safety follow-up visit, or 
until toxicities resolve, return to baseline, or are deemed irreversible, whichever is longer.  
Reasonable efforts should be made to have the subject return for the follow-up visits and report 
any AEs that may occur during this period.  If the subject cannot return to the site for the safety 
follow-up visits, the subject should be contacted by telephone for assessment of AEs and SAEs, 
and this should be documented in the eCRF. 
Adverse events and SAEs before the start of the new anticancer therapy must be reported.  If a 
subject begins a new anticancer therapy before the end of the 30-day or 90-day safety follow-up 


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period, the safety follow-up visit should be performed before the new anticancer therapy is 
started. 
 
 
NOTE:  As of Protocol Amendment 4, data will only be collected for SAEs, AESIs, and 
pregnancy.  
 
 
6.4.2. 
Disease Status Follow-Up 
Subjects who discontinue study treatment for a reason other than disease progression will move 
into the disease status follow-up period and should be assessed every 8 weeks (± 7 days) by 
radiologic imaging to monitor disease status.  Every effort should be made to collect information 
regarding disease status until: 
• The start of new antineoplastic therapy. 
• Disease progression. 
• Death. 
• The end of the study. 
• Withdrawal of consent. 
Information regarding post-treatment anticancer therapy will be collected if it is initiated. 
NOTE:  As of Protocol Amendment 4, disease status follow-up visits for subjects who 
discontinue study treatment for a reason other than disease progression are no longer required 
beyond the last safety follow-up visit.  The last disease status follow-up data will be recorded in 
the eCRF at the time of the last safety follow-up visit.  The last study visit will be the safety 
follow-up visit. 
 
 
 
 
 
 
 
 
 
 


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6.5. 
End of Study 
Subjects will be considered as having completed the study if they meet any of the following 
criteria: 
• Subject dies and a date of death is available. 
• Subject is known to have died; however, the date of death cannot be obtained.  
(NOTE:  Every effort must be made to obtain the date of death.) 
• Consent is withdrawn for any further contact related to this study. 
− Subjects may choose to withdraw from the study at any time without penalty of 
jeopardizing their health care or loss of benefits to which the subject is otherwise 
entitled.  Every reasonable effort should be made to determine the reason a 
subject withdraws prematurely, and this information should be recorded in the 
eCRF. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority or IRB or IEC. 
6.6. 
Unscheduled Visits 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments performed 
at those visits should be recorded in the eCRF.  


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7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the study subject before conducting any 
study-specific procedures using an ICF approved by the local IRB/IEC that contains all elements 
required by ICH E6, and describes the nature, scope, and possible consequences of the study in a 
form understandable to the study subject.  Local and institutional guidelines for ICF content and 
administration must be followed; the original signed ICF must be retained by the investigator, 
and a copy of the signed ICF must be provided to the study subject.  The informed consent 
process for each subject must be documented in writing within the subject source documentation.  
Subjects of childbearing potential must agree to take appropriate measures to avoid pregnancy in 
order to participate in the study (see Appendix A). 
7.2. 
Interactive Response Technology Procedure 
The IRT will be contacted to obtain a subject identification number when a subject enters 
screening.  Upon determining that the subject is eligible for study entry, the IRT will be 
contacted to obtain the treatment assignment.  Additionally, the IRT will be contacted at each 
regular study visit to update the study drug supply. 
7.3. 
Demography and Medical History 
7.3.1. 
Demographics and General Medical History 
Demographic data and a complete medical and medication history will be collected at screening 
by the investigator or qualified designee and will include date of birth, race, ethnicity, medical 
and surgical history, and current illnesses.  Medical history will include relevant medical or 
surgical treatment within the last 10 years that are considered to be clinically significant by the 
investigator. 
7.3.2. 
Disease Characteristics and Treatment History 
A disease-targeted medical and medication history will be collected at screening.  In addition, 
disease-relevant biomarker information is required where available (eg, CRC:  MSI status, 
carcinoembryonic antigen level; gastric cancer:  Epstein Barr virus status, H. pylori status, CA 
19-9 level; OC:  BRCA1 and BRCA2 status, CA 125 level; EC:  MSI status).  These items will 
be recorded separately and not listed in medical history. 
7.4. 
Prior and Concomitant Medications and Procedures 
Prior and concomitant medications and procedures will be reviewed to determine subject 
eligibility.  All concomitant medications and measures must be recorded in the eCRF, and any 
medication received or procedure performed within 21 days before enrollment and up to the end 
of study will be recorded in the eCRF.  The medication record will be maintained after signing 
the ICF to document concomitant medications, including any changes to the dose or regimen.  
Concomitant medications include any prescription, over-the-counter, or natural/herbal 
preparations taken or administered during the study period.  Concomitant treatments and/or 
procedures that are required to manage a subject's medical condition during the study will also be 


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recorded in the eCRF.  See Section 5.6 for details regarding restricted and prohibited 
medications. 
NOTE:  As of Protocol Amendment 4, use of concomitant medications should be monitored for 
subjects to verify that they are not taking any concomitant medication prohibited per protocol; 
however, concomitant medications no longer need to be collected in the eCRF, except for 
concomitant medications in relation with SAEs or AESIs. 
7.5. 
Post-Treatment Anticancer Therapy Status  
The investigator or qualified designee will review all new antineoplastic therapy initiated after 
the last dose of study treatment.  If a subject initiates a new anticancer therapy within 30 days 
after the last dose of study treatment, then the 30-day safety follow-up visit should occur before 
the first dose of the new anticancer therapy. 
7.6. 
Safety Assessments 
The chemotherapy agents used in this study are approved therapies; therefore, the investigator 
should refer to and follow the safety management guidelines as appropriate within the 
prescribing information for the chemotherapy agents. 
NOTE:  As of Protocol Amendment 4, safety assessments are only required to be performed as 
per the site standard of care guidelines for the subject's condition and monitoring.  Only SAEs, 
AESIs, and pregnancy will be collected in the eCRF. 
7.6.1. 
Adverse Events 
Adverse events will be monitored from the time the subject signs the ICF.  Subjects will be 
instructed to report all AEs during the study and will be assessed for the occurrence of AEs 
throughout the study.  In order to avoid bias in eliciting AEs, subjects will be asked general, 
nonleading questions such as "How are you feeling?"  All AEs (serious and nonserious) must be 
recorded on the source documents and eCRFs regardless of the assumption of a causal 
relationship with the study drug.  The definition, reporting, and recording requirements for AEs 
are described in Section 8. 
7.6.2. 
Physical Examinations 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits. 
Clinically notable abnormalities that are considered clinically significant in the judgement of the 
investigator are to be reported as AEs. 
7.6.2.1. 
Comprehensive Physical Examination 
The comprehensive physical examination will include height and body weight, and assessment(s) 
of the following organ or body systems:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; 
cardiovascular system; abdomen (liver, spleen); extremities; and lymph nodes; as well as a brief 
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7.6.2.2. 
Targeted Physical Examination 
The targeted physical examination will be a symptom-directed evaluation.  The targeted physical 
examination will include body weight and assessment(s) of the body systems or organs, as 
indicated by subject symptoms, AEs, or other findings. 
7.6.3. 
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiratory rate, and body temperature.  
Blood pressure and pulse will be taken with the subject in the recumbent, semirecumbent, or 
sitting position after 5 minutes of rest.  In addition, orthostatic blood pressure monitoring will be 
performed on the days indicated in Table 11 and Table 13.  Clinically notable abnormalities that 
are considered clinically significant in the judgment of the investigator are to be reported as AEs. 
7.6.4. 
Electrocardiograms 
All 12-lead ECGs will be performed with the subject in a recumbent or semirecumbent position 
after 5 minutes of rest. 
The 12-lead ECGs will be interpreted by the investigator at the site to be used for immediate 
subject management.  The decision to include or exclude a subject or withdraw a subject from 
the study based on an ECG flagged as "Abnormal, Clinically Significant" is the responsibility of 
the investigator, in consultation with the sponsor's medical monitor, as appropriate.  Clinically 
notable abnormalities that are considered clinically significant in the judgment of the investigator 
are to be reported as AEs. 
7.6.5. 
Laboratory Assessments 
A certified laboratory local to the study site and subject will perform most of the clinical 
laboratory assessments for safety (ie, chemistries, hematology assessments, coagulation panel, 
thyroid panel, lipid panel, and urinalysis).  The investigative site will enter the laboratory results 
and laboratory normal ranges into the eCRF.  All local laboratory assessments should be 
performed using standard procedures on the days indicated in Table 12 and Table 14.  Table 16 
lists the specific laboratory analytes required for each test.  Some additional tests (ie, plasma 
arginase, amino acid panel, including ornithine, plus urinary orotic acid – see Table 17) will be 
conducted by 1 or more central laboratories, on the days indicated in Table 12 and Table 14. 
Additional testing may be required by the sponsor based on emerging safety data.  Additional 
tests may also be performed if clinically indicated. 
Screening laboratory assessments must be performed within 7 days of Cycle 1 Day 1.  If 
performed more than 7 days before Cycle 1 Day 1, then the tests must be repeated and eligibility 
confirmed before study drug administration on Cycle 1 Day 1.  Laboratory samples collected on 
study Day 1 must be performed before study drug administration.  After Cycle 1, predose 
laboratory procedures can be conducted up to 72 hours before study drug administration (within 
the 3-day study window), and results should be reviewed by the investigator or qualified 
designee and found to be acceptable before a new cycle of treatment is initiated. 
NOTE:  As of Protocol Amendment 4, laboratory assessments should be performed in 
accordance with the standard of care of the investigational site for the subject's condition.  
Laboratory results do not need to be reported in the eCRF, but all laboratory results 


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corresponding with an SAE or an AESI will be reported on the SAE form.  In addition, 
pregnancy testing will continue to be performed for all subjects as per the schedule of 
assessments in Table 15. 
7.6.5.1. 
Chemistries 
In addition to the standard serum chemistry analytes,
 as outlined in Table 16.  
See Table 12 and Table 14 for sampling timepoints and the Laboratory Manual for details of how 
to process, store, and ship the samples to the certified central laboratory or laboratories for 
sample analysis. 
7.6.5.2. 
Urinalysis 
Standard urinalysis as outlined in Table 16, and urinary orotic acid, which is a marker of urea 
cycle inhibition that is a potential side effect of INCB001158 (see Section 1.3.1), will be 
assessed (Table 16).  Subjects must fast at least 8 hours before each clinic visit and void their 
bladder in the morning before providing the predose urine sample at the clinic, as outlined in 
Table 17. 
Table 17: 
Sample Collection Time Windows for Urine Assessments of Orotic Acid 
Study Visit 
Time 
C1D1 
Predose and 6 h postdose 
C1D8 
Predose 
C1D15 
Predose and 6 h postdose 
C2D1 and D1 of all subsequent cycles 
Predose 
Note:  Additional samples may be collected as clinically indicated. 
7.6.5.3. 
Plasma Ammonia 
Plasma ammonia levels are to be tested during screening (Table 12 and Table 14).  If above the 
ULN, repeat the sample to confirm the value.  If the subject experiences an elevation in urine 
orotic acid (> 10 × ULN fasted or > 40 × ULN of any value) while on study treatment or during 
the follow-up period, monitor plasma ammonia levels each time the urine orotic acid is tested, at 
least until orotic acid levels have returned to normal, at the investigator's and medical monitor's 
discretion. 
7.6.5.4. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential during 
screening.  A urine pregnancy test will be required on Cycle 1 Day 1 (before the first dose of 
study drug) and Day 1 of each subsequent cycle (Table 12 and Table 14; Table 15 for all subjects 
as of Protocol Amendment 4).  A serum pregnancy test should also be repeated at the 30-day 


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safety follow-up visit.  Pregnancy testing is not required if a subject is going to hospice.  Urine 
pregnancy tests will be conducted as medically indicated, or per country-specific requirement.  
Urine pregnancy tests will be performed locally.  If a urine pregnancy test is positive, then the 
results should be confirmed with a serum pregnancy test. 
If the serum pregnancy test is negative after a urine test was positive, then the investigator will 
assess the potential benefit/risk to the subject and determine whether it is in the subject's best 
interest to resume study treatment and continue participation in the study. 
7.6.5.5. 
CA 125 Monitoring 
CA 125 monitoring will be performed locally for subjects with OC as indicated in Table 12 and 
Table 14.  If available, the most recent measure before screening will also be recorded. 
7.6.5.6. 
Hepatitis and HIV Screening Tests 
Hepatitis and HIV screening assessments will be performed at the screening visit (Table 12 and 
Table 14) to rule out hepatitis and HIV infection, respectively; required analytes are shown in 
Table 16.  Generally, hepatitis and HIV tests should be performed early in the screening process 
due to the length of time needed to obtain the results.  Additional tests may be performed if 
clinically indicated. 
Note:  HIV testing is not required unless mandated by the local health authority. 
7.6.5.7. 
Coagulation Panel 
A coagulation panel will be performed as indicated in Table 12 and Table 14; required analytes 
for this panel are listed in Table 16.  The coagulation panel will be analyzed by the site's local 
laboratory. 
7.7. 
Efficacy Assessments 
NOTE:  As of Protocol Amendment 4, no further efficacy assessment will be required beyond 
Week 96.  After Week 96, the radiographic tumor assessments are only required to be performed 
as per the site standard of care guidelines for the subject's condition and monitoring.  Subjects 
must be withdrawn from the study if, in the opinion of the investigator, the disease has 
progressed and the subject is no longer having clinical benefit from the study treatment. 
7.7.1. 
Tumor Imaging and Assessment of Disease 
Tumor imaging is strongly preferred to be acquired by CT.  For the abdomen and pelvis, MRI 
may be used when CT with iodinated contrast is contraindicated or when local practice mandates 
it.  Magnetic resonance imaging is the strongly preferred modality for imaging the brain.  The 
same imaging modality (ideally the same scanner) and the use of contrast should be used in a 
subject throughout the study to optimize the reproducibility of the assessment of existing and 
new tumor burden and improve the accuracy of the assessment of response or progression based 
on imaging. 
Subject eligibility will be determined using local assessment (investigator assessment) based on 
RECIST v1.1.  All scheduled images for all study subjects will be assessed by the investigator.  


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The sponsor may request that images from scans obtained during the study be sent to a central 
reader for independent image analysis. 
7.7.1.1. 
Initial Tumor Imaging 
Initial tumor imaging at screening must be performed within 21 days prior to the date of 
enrollment.  The site study team must review screening images to confirm the subject has 
measurable disease per RECIST v1.1.  
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 21 days prior to the 
date of enrollment. 
Subjects with previously treated brain metastases may participate provided that they have stable 
brain metastases, that is, without evidence of progression by imaging (confirmed by MRI or CT 
imaging, whichever was used at prior imaging) for at least 4 weeks before the first dose of study 
treatment.  Any neurologic symptoms must have returned to baseline, subjects must have no 
evidence of new or enlarging brain metastases, and subjects must not have used steroids for brain 
metastases for at least 14 days before initiating study treatment as per investigator assessment.  
This exception does not include carcinomatous meningitis, as subjects with carcinomatous 
meningitis are excluded regardless of clinical stability.  Subjects with evidence of cerebral edema 
will also be excluded from participation.  In addition, subjects will be excluded from 
participation in the study if it has been < 4 weeks since RT was delivered to the CNS. 
7.7.1.2. 
Tumor Imaging During the Study 
The first on study imaging assessment should be performed at 8 weeks (56 days ± 7 days) from 
the date of enrollment.  Imaging then continues every 8 weeks (56 days ±7 days).  This equates 
to an imaging schedule occurring after Weeks 8, 16, 24, 32, 40, etc.  Imaging timing should 
follow calendar days and should not be adjusted for delays in cycle dosing.  
Imaging should continue to be performed until PD is identified by the investigator, the start of 
new anticancer treatment, withdrawal of consent for imaging, or death, whichever occurs first.   
Partial response and CR should be confirmed by a repeat imaging assessment.  The imaging for 
confirmation of response may be performed no earlier than 4 weeks after the first indication of a 
response, or at the next scheduled scan (ie, 8 weeks later), whichever is clinically indicated.  
Subjects will then return to the regular imaging schedule, starting with the next scheduled 
imaging timepoint.  Subjects who receive additional imaging for confirmation do not need to 
undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may 
resume at the subsequent scheduled imaging timepoint. 


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7.7.1.3. 
End-of-Treatment and Follow-Up Imaging 
In subjects who discontinue study treatment, tumor imaging should be performed at the time of 
treatment discontinuation (± 4 week window).  If a previous imaging was obtained within 
4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not 
mandatory.  
 
 
 
In subjects who discontinue study treatment without documented disease progression, every 
effort should be made to continue monitoring disease status by tumor imaging using the same 
imaging schedule used while on treatment until the start of new anti-cancer treatment, disease 
progression, death, withdrawal of consent, or the end of the study, whichever occurs first.  For 
these subjects, the next imaging would occur at the discontinuation visit.  If previous imaging 
was obtained within 4 weeks before the date of discontinuation, then imaging at treatment 
discontinuation is not mandatory.  The next imaging would then occur every 8 weeks (± 7 days) 
subsequently.  
 
 
NOTE:  As of Protocol Amendment 4, follow-up imaging to monitor disease status for subjects 
who discontinue study treatment for any of the aforementioned reasons is no longer required 
beyond the last safety follow-up visit (see Section 6.4.2). 
7.7.1.4. 
RECIST v1.1 Assessment of Disease 
RECIST v1.1 will be the primary measure for assessment of tumor response and as a basis for 
Protocol guidelines related to disease status (eg, discontinuation of study therapy).  


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7.8. 
Performance and Quality-of-Life Assessments 
7.8.1. 
Eastern Cooperative Oncology Group Performance Status 
The ECOG performance status will be assessed as shown in Table 11 and Table 13 according to 
the criteria in Table 19. 
Table 19: 
Eastern Cooperative Oncology Group Performance Status Scoring 
Grade 
ECOG Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Source:  Oken et al 1982. 
7.9. 
Pharmacokinetic Assessments 
7.9.1. 
Blood Sample Collection 
Subjects will arrive at the clinic having fasted at least 8 hours and having withheld their morning 
dose of INCB001158.  Pharmacokinetic samples will be obtained at the visits indicated in 
Table 12 and Table 14.  Predose is defined as within 24 hours before administration of the 
morning dose of INCB001158 and before administration of chemotherapy (if drugs are 
given on PK assessment days).  After the predose PK sample is drawn, subjects will take 
INCB001158 and then chemotherapy. 
  The exact date and time of the PK blood draws will be 
recorded in the eCRF along with the date and time of the last dose of study drug and details of 
the last meal preceding the blood draw.  Instructions for sample preparation and shipping will be 
provided in the Laboratory Manual.  Sample collection times and windows for INCB001158 are 
shown in Table 20 and Table 21. 
Table 20: 
Extensive Sample Collection Time Windows for Pharmacokinetic 
Assessments for INCB001158 in the First 12 Subjects Enrolled in Each 
Chemotherapy Regimen in Phase 2 
Study Visit 
Timing of Sample Relative to INCB001158 Administration 
C1D1 
Predose 
0.5 h 
± 10 min 
1 h 
 ± 10 min 
2 h 
± 30 min 
4 h 
± 30 min 
6 h 
± 30 min 
8-10 h 
± 30 min 
C2D1 
Predose 
0.5 h 
 ± 10 min 
1 h 
± 10 min 
2 h 
± 30 min 
4 h 
± 30 min 
6 h 
± 30 min 
8-10 h 
± 30 min 


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Table 21: 
Sparse Sample Collection Time Windows for Pharmacokinetic Assessments 
for INCB001158 in Phase 1 and in the Thirteenth Subject Onwards Enrolled 
in Phase 2 
Study Visit 
Timing of Sample Relative to INCB001158 Administration 
C1D1 
Predose 
1 h 
± 10 min 
4 h 
± 30 min 
C2D1 
Predose 
2 h 
± 30 min 
6-10 h 
± 30 min 
7.9.2. 
Bioanalytical Methodology and Analysis 
The plasma samples will be analyzed for INCB001158 by using a validated liquid 
chromatography tandem mass spectrometry assay.  These samples will be analyzed by the 
sponsor or its designee. 


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7.11. 
Other Study Procedures 
7.11.1. 
Distribution of Subject Reminder Cards and/or Subject Diaries 
Subjects will be provided with a reminder card at each visit, containing the following reminders: 
• The date/time of the next visit; 
• Not to take their morning doses of INCB001158 before visiting the clinic on those 
days, as they will take them after blood draws for safety evaluation have been 
completed; 
• To fast for at least 8 hours before the next clinic visit and to void their bladder in the 
morning before providing the predose urine sample at the clinic, as outlined in 
Table 17. 
Subjects will also be provided with diaries to record dates, times, and doses of INCB001158 that 
they take between clinic visits. 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
8. 
SAFETY MONITORING AND REPORTING 
NOTE:  As of Protocol Amendment 4, the only safety data that will be collected will be related 
to SAEs, AESIs, and pregnancy.  The safety follow-up visits may be completed remotely (such 
as by televisit). 
8.1. 
Adverse Events 
8.1.1. 
Definitions 
For the purposes of this Protocol, an adverse event (AE) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related, 
that occurs after a subject provides informed consent.  Abnormal laboratory values or test results 
occurring after informed consent constitute AEs only if they induce clinical signs or symptoms, 
are considered clinically meaningful, require therapy (eg, hematologic abnormality that requires 
transfusion), or require changes in the study drug(s). 
8.1.2. 
Reporting 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events form of the eCRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History form in the eCRF.  Monitoring for the occurrence of 
new AEs should be continued for at least 90 days after the last dose of study drug.  Adverse 
events (including laboratory abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible rather than by individual underlying signs and symptoms.  When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate AE. 
The term "disease progression" should be recorded as an AE/SAE only if there are no other 
identifiable AEs/SAEs associated with the disease progression at the time of reporting.  For 
events associated with disease progression, the relevant signs and symptoms should be reported 
using a diagnosis whenever possible rather than individual underlying signs and symptoms.  
When a clear diagnosis cannot be identified, each sign or symptom should be reported as a 
separate AE.  If the events resulting from disease progression meet the criteria for an SAE 
(eg, resulted in hospitalization, a life-threatening event, or death), the specific event(s) should be 
reported as an SAE(s) as described in Section 8.3.2.  In both cases (ie, AEs or SAEs related to 
disease progression), it should be indicated that each event (reported as a diagnosis or as signs 
and symptoms) is related to disease progression on the Adverse Events form of the eCRF. 


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The severity of AEs will be assessed using CTCAE v4.03 Grades 1 through 5.  If an event is not 
classified by CTCAE, the severity of the AE will be graded according to the scale below to 
estimate the grade of severity: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate activities of daily living. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death due to AE 
The occurrence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit during the study.  Adverse events may 
also be detected when they are volunteered by the subject during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments.  To the 
extent possible, each AE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 5). 
• Whether there is at least a reasonable possibility that the AE is related to the study 
treatment:  suspected (yes) or not suspected (no).  Relatedness will be assessed for 
INCB001158 and chemotherapy. 
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study drug. 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per serious adverse event (SAE) definition provided in 
Section 8.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see Section 8.3.2). 
All AEs should be treated appropriately.  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event form and the treatment should 
be specified on the Prior/Concomitant Medications or Procedures and Non-Drug Therapy form 
in the eCRF. 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to 
treat the event, and the outcome. 
When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE until the event resolves.  For example, 


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2 separate AEs will be reported if a subject has Grade 1 diarrhea, meeting the definition of an 
AE, that lasts for 3 days before worsening to a Grade 3 severity.  The Grade 1 event will be 
reported as an AE with a start date equal to the day the event met the Grade 1 AE definition and 
a stop date equal to the day that the event increased in severity from Grade 1 to Grade 3.  The 
Grade 3 event will also be reported as an AE, with the start date equal to the day the event 
changed in intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event 
either changed severity again or resolved. 
NOTE:  As of Protocol Amendment 4, all AESIs will continue to be reported in the eCRF. 
8.2. 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug) should be recorded on the Adverse Event form in the eCRF.  Whenever possible, a 
diagnosis rather than a symptom should be provided (eg, "anemia" instead of "low hemoglobin").  
Laboratory abnormalities that meet the criteria for AEs should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found.  When an abnormal 
laboratory test result corresponds to a sign or symptom of a previously reported AE, it is not 
necessary to separately record the laboratory test result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs.  
A Grade 3 or 4 AE does not automatically indicate an SAE unless it meets the definition of 
serious, as defined in Section 8.3.1.  A dose modification for the laboratory abnormality may be 
required (see Section 5.5) and should not contribute to the designation of a laboratory test 
abnormality as an SAE. 
NOTE:  As of Protocol Amendment 4, laboratory assessments should be performed in 
accordance with the standard of care of the investigational site for the subject's condition.  
Laboratory results do not need to be reported in the eCRF, but all laboratory results 
corresponding with an SAE or AESI will be reported on the SAE form. 
8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
An SAE is defined as an event that meets at least 1 of the following criteria: 
• Is fatal or life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− A routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition.  
− An elective surgery or preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since signing the 
ICF. 
− A treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE and not resulting in hospital admission. 
− Any social reasons and respite care, in the absence of any deterioration in the 
subject's general condition. 


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• Results in persistent or significant disability, incapacity, or a substantial disruption of 
a person's ability to conduct normal life functions. 
• Constitutes a congenital anomaly or birth defect. 
• Is considered to be an important medical event or a medically significant event that 
may not result in death, be immediately life-threatening, or require hospitalization but 
may be considered serious when, based on appropriate medical judgment, the event 
may jeopardize the subject or may require medical or surgical intervention to prevent 
1 of the outcomes listed above. 
8.3.2. 
Reporting 
Every SAE, regardless of suspected causality (eg, relationship to study drug(s) or study 
procedure or disease progression), occurring after the subject has signed the ICF through the last 
study visit (or 90 days after the last dose of study drug, whichever is later) must be reported to 
the sponsor (or designee) within 24 hours of learning of its occurrence, unless otherwise 
specified by the Protocol.  Any SAEs occurring more than 90 days after the last dose of study 
drug should be reported to the sponsor or its designee only if the investigator suspects a causal 
relationship to the study drug.  
Information about all SAEs is collected and recorded on the Adverse Event form of the eCRF.  
The investigator must assess and record the causal relationship of each SAE to the study 
treatment.  Relatedness will be assessed for INCB001158 and chemotherapy. 
The investigator must also complete the Incyte Serious Adverse Event Report Form, in English, 
and send the completed and signed form to the sponsor or designee within 24 hours of becoming 
aware of the SAE.  The investigator must provide a causality assessment, that is, assess whether 
there is at least a reasonable possibility that the SAE is related to the study treatment:  suspected 
(yes) or not suspected (no).  Refer to the Incyte Reference Guide for Completing the Serious 
Adverse Event Report Form. 
The contact information of the sponsor's study-specific representatives is listed in the 
investigator manual provided to each site.  The original copy of the SAE Report Form and the 
confirmation sheet must be kept at the study site. 
Investigational site personnel must report any new information regarding the SAE within 
24 hours of becoming aware of the information in the same manner that the initial SAE Report 
Form was sent.  Follow-up information is recorded on an amended or new SAE Report Form, 
with an indication that it is follow-up to the previously reported SAE and the date of the original 
report.  The follow-up report should include information that was not provided on the previous 
SAE Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment 
provided, action taken with study drug because of the SAE (eg, dose reduced, interrupted, or 
discontinued), or subject disposition (eg, continued or withdrew from study participation).  Each 
recurrence, complication, or progression of the original event should be reported as follow-up to 
that event, regardless of when it occurs. 
If the SAE is not documented in the IB for the study drug (new occurrence) and is thought to be 
related to the sponsor's study drug, the sponsor or its designee may urgently require further 
information from the investigator for reporting to health authorities.  The sponsor or its designee 
may need to issue an Investigator Notification (IN) to inform all investigators involved in any 


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study with the same drug that this SAE has been reported.  Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC, or as per national 
regulatory requirements in participating countries. 
NOTE:  As of Protocol Amendment 4, all SAEs regardless of causality relationship will continue 
to be reported in the eCRF. 
8.4. 
Emergency Unblinding of Treatment Assignment 
Not applicable. 
8.5. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a subject during maternal or paternal exposure to study drug, 
the following procedures should be followed in order to ensure subject safety: 
• The study drug must be discontinued immediately (female subjects only). 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
• A serum pregnancy test must be performed to confirm the urine pregnancy test result.  
If a negative serum test does not confirm the urine pregnancy result, then:  
− The investigator will use his or her expert judgment, based on an assessment of 
the potential benefit/risk to the subject, to determine whether it is in the subject's 
best interest to resume study treatment and continue participation in the study.  
• The EOT visit evaluations must be performed. 
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation.  Follow-up should be conducted for each pregnancy to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications, by following 
until the first well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy form 
and reported by the investigator to the sponsor or its designee.  Pregnancy follow-up information 
should be recorded on the same form and should include an assessment of the possible causal 
relationship to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the 
first well-baby visit or the duration specified in local regulations, whichever is later.  Refer to the 
Incyte Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy must be recorded on the SAE report form and 
submitted to the sponsor or designee. 
NOTE:  As of Protocol Amendment 4, pregnancy will continue to be reported in the eCRF. 


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8.6. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the IB.  Additional safety information collected 
between IB updates will be communicated in the form of Investigator Notifications (INs).  Any 
important new safety information should be discussed with the subject during the study, as 
necessary.  If new significant risks are identified, they will be added to the ICF. 
8.7. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be reported as described in Section 8.1.2 of this Protocol. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 


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9. 
STATISTICS 
9.1. 
Study Populations 
The full analysis set includes all subjects enrolled in the study who received at least 1 dose of 
study treatment (INCB001158, mFOLFOX6, gemcitabine/cisplatin, or paclitaxel).  This 
population will be used in the analyses of demographic, baseline, safety, study treatment 
administration, and efficacy data. 
The DLT evaluable population is defined in Section 5.4.2 and includes subjects who receive at 
least 32 of 42 doses for 21-day cycle regimens and at least 42 of 56 doses for 28-day cycle 
regimens (both representing ≥ 75% of the dose planned) of INCB001158 at the level assigned or 
have a DLT.  This population will be used for determining tolerability of the dose. 
The PK evaluable population includes subjects who received at least 1 dose of study treatment 
(INCB001158, mFOLFOX6, gemcitabine/cisplatin, or paclitaxel) and had at least 1 postdose PK 
sample collected and analyzed.  
 
 
 
9.2. 
Selection of Sample Size  
9.2.1. 
Sample Size for Phase 1 
In Phase 1, the BOIN design will be used to determine the RP2D of INCB001158 when given in 
combination with chemotherapy in subjects with advanced or metastatic solid tumors.  The 
details of the dose escalation, de-escalation, and elimination rules according to the BOIN design 
are provided in Section 4.1.1. 
9.2.2. 
Sample Size for Phase 2 
Phase 2 will further evaluate the safety, tolerability, preliminary efficacy, PK, and pharmacologic 
activity of the recommended dose of INCB001158 in combination with chemotherapy.  A Simon 
2-stage design will be run for each tumor type within a given expansion cohort. 
The sample size for each tumor type within a given expansion cohort will be guided by the 
Simon 2-stage design.  The planned Simon 2-stage designs are summarized in Table 7.  Each 
Simon 2-stage design will have a stopping rule to allow early termination of a particular tumor 
type within the given cohort at the end of Stage 1 if there is insufficient response observed, while 
enrolling enough subjects to predict possible target responses worthy of cohort expansion and 
potentially further evaluation in future studies.  The individual Simon 2-stage designs run for 
each tumor type within each cohort will have design parameters that are determined by historical 
response rates.  
In order to determine whether the target response rate (p1%) is likely, an initial number of 
evaluable subjects (n1 subjects) will be treated at the RP2D of INCB001158 in combination with 
each chemotherapy (Stage 1).  If there are r1 or fewer responses in the expansion cohort, then it 
will be concluded that the true response rate is unlikely to be ≥ the target rate, and no more 
subjects will be enrolled in that tumor type for that cohort in Stage 2.  In the cohorts in which 
> r1 responses are observed among the Stage 1 subjects, n2 additional evaluable subjects will be 


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treated in Stage 2 to estimate the response rate.  At the end of Stage 2, if ≤ r subjects have 
responded among the n evaluable subjects, then the drug will be declared nonpromising for that 
cohort.  The detailed calculations for each tumor type–specific cohort are based on a 1-sided 
Type I error of 0.1 and power of 80%. 
9.3. 
Level of Significance 
For the primary efficacy endpoints, the 1-sided Type I error will be controlled at 0.1 for each 
individual cohort expansion.  Note that this level of significance does not account for the 
multiple expansion cohorts.  For other endpoints, confidence intervals will be reported at a 
95% confidence level. 
9.4. 
Statistical Analyses 
9.4.1. 
Efficacy Analyses 
9.4.1.1. 
Primary Efficacy Analyses 
Objective response rate, defined as the percentage of subjects enrolled in Phase 2 (plus subjects 
enrolled in Phase 1 who meet all of the inclusion and exclusion criteria for Phase 2) having a CR 
or PR, as determined by investigator assessment of radiographic disease as per RECIST v1.1 will 
be summarized by expansion cohort. 
9.4.1.2. 
Secondary Efficacy Analyses 
The following efficacy analyses will be assessed for all subjects in each treatment combination: 
• ORR, defined as the percentage of subjects having a CR or PR, as determined by 
investigator assessment of radiographic disease as per RECIST v1.1 (Phase 1 only).  
• DOR, defined as the time from earliest date of CR or PR (as determined by 
investigator assessment of radiographic disease assessment per RECIST v1.1) until 
the earliest date of disease progression or death due to any cause, if occurring sooner 
than disease progression. 
• DCR, defined as the percentage of subjects having CR, PR, or SD for at least 
8 weeks, as determined by investigator assessment of radiographic disease as per 
RECIST v1.1. 
• PFS, defined as the time from date of first dose of study drug until the earliest date of 
disease progression (as determined by investigator assessment of radiographic disease 
assessment per RECIST v1.1), or death due to any cause, if occurring sooner than 
progression. 


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9.4.2. 
Safety Analyses 
9.4.2.1. 
Adverse Events 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first dose of study drug.  Analysis of AEs will be limited to TEAEs, but data listings will include 
all AEs regardless of their timing to study drug administration.  Adverse events will be tabulated 
by the MedDRA preferred term and system organ class for all events and AESIs, including 
irAEs.  Severity of AEs will be based on the NCI CTCAE v4.03 using Grades 1 through 5. 
The subset of AEs considered by the investigator to have a relationship to study drug will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study drug, then the AE will be considered treatment-related.  The incidence of AEs 
and treatment-related AEs will be tabulated. 
9.4.2.2. 
Clinical Laboratory Tests 
Laboratory test values outside the normal range will be assessed for severity based on the normal 
ranges for the clinical reference laboratory.  The incidence of abnormal laboratory values and 
shift tables relative to baseline will be tabulated. 
Laboratory data will be classified into Grades 1 through 5 using CTCAE v4.03.  The following 
summaries will be produced for the laboratory data: 
• Number and percentage of subjects with worst postbaseline CTCAE grade (regardless 
of baseline value).  Each subject will be counted only for the worst grade observed 
postbaseline. 
• Shift tables from baseline to the worst postbaseline value using CTCAE grade. 


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• For laboratory parameters where CTCAE grades are not defined, shift tables to the 
worst postbaseline value using the low/normal/high classifications based on 
laboratory reference ranges. 
9.4.2.3. 
Vital Signs 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time.  Vital sign 
results will be reviewed for clinically notable abnormalities (see Table 22), and subjects 
exhibiting clinically notable vital sign abnormalities will be listed.  A value will be considered an 
"alert" value if it is outside the established range and shows a > 25% change from baseline. 
Table 22: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24/min 
< 8/min 
9.4.2.4. 
Electrocardiograms 
Descriptive statistics and mean change from baseline will be determined for each ECG parameter 
at each assessment time.  Electrocardiogram results will be reviewed for clinically notable 
abnormalities according to predefined criteria (Table 23).  Subjects exhibiting clinically notable 
ECG abnormalities will be listed. 
Table 23: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF 
> 480 ms 
< 295 ms 
PR 
> 220 ms 
< 75 ms 
QRS 
> 120 ms 
< 50 ms 
QT 
> 500 ms 
< 300 ms 
RR 
> 1330 ms 
< 600 ms 
QTcF = Fridericia correction. 
9.4.2.5. 
Adverse Events of Special Interest 
Adverse events of special interest include irAEs that are seen with immunotherapy and any other 
observed autoimmune phenomenon.  
An overall summary of irAEs will include number (%) of subjects reporting any irAEs, any 
Grade 3 or higher irAEs, any treatment-related irAEs, any fatal irAEs, and any irAEs leading to 
treatment interruption/dose reduction/discontinuation. 


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9.4.3. 
Pharmacokinetic Analysis 
The PK parameters of Cmax, tmax, Cmin, AUC0-t, and AUC0-τ (INCB001158) for first 12 subjects 
enrolled in Phase 2 will be calculated from the blood plasma concentrations of INCB001158 
using standard noncompartmental (model-independent) PK methods.  Pharmacokinetic 
calculations will be performed, if appropriate, using commercial software such as WinNonlin®.  
Nominal times will be used in all cases, except when the difference between the actual time and 
nominal time is greater than 15 minutes for samples collected up to 4 hours after administration 
and greater than 30 minutes for samples collected more than 4 hours after administration; in 
these cases, actual time will be used for PK analysis.  See Appendix B for a detailed list and 
description of the PK parameters. 
If there is a sufficient amount of plasma concentration data from this study, the data will be 
analyzed by standard population PK methods using appropriate software (eg, NONMEM). 
9.5. 
Interim Analyses 
9.5.1. 
Interim Analysis for the BOIN Design 
In Phase 1, the BOIN design will be used to determine the RP2D of INCB001158 in combination 
with each chemotherapy regimen.  For the design parameters, let ϕ denote the target DLT rate, 
ϕ1 denote the highest toxicity probability below the MTD so that dose escalation is required, and 
ϕ2 denote the lowest toxicity probability deemed overly toxic so that dose de-escalation is 
required.  We assume that ϕ1 = 0.6ϕ and ϕ2 = 1.4ϕ.  Also, to avoid assigning too many subjects to 
an overly toxic dose, we use the dose elimination rule when implementing the BOIN design.  If 
pr (pj > ϕ│mj,nj) > 0.95 and nj ≥ 3, then dose levels 𝑗 and higher are eliminated from the study, 
and the study is terminated if the first dose level is eliminated, where pj represents the toxicity 
rate, ϕ represents the target DLT rate, nj represents the total subjects who have been treated, and 
mj represents the subjects who have experienced toxicity at dose level j.  Table 4 (in the bottom 
row) provides the elimination boundaries for the target DLT rate of 33%, respectively.  For 
example, for the target DLT rate 33%, when the number of subjects treated at the current dose 
nj = 4, we will eliminate that dose and higher doses if 3 or more subjects experience toxicity.  
Based on the algorithm of the BOIN design, a minimum of 3 evaluable subjects will be enrolled 
in each dose level with a maximum of 9 evaluable subjects in each dose level. 
9.5.2. 
Interim Analysis for the Simon 2-Stage Design 
In Phase 2, there will be a planned interim analysis for futility in each of the 6 expansion cohorts.  
The Simon 2-stage design will be applied for each expansion cohort independently.  During 
Stage 1, n1 evaluable subjects treated at the recommended dose and schedule will be enrolled 
(see Table 7), and if r1 or fewer responses are observed, then the cohort will be discontinued.  As 
discussed in Section 9.2.2, the Simon 2-stage designs for each tumor type have design 
parameters determined by historical response rates and will have different sample sizes and 


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different futility rules, depending on the historical response rate.  Based on this early termination 
rule, the probabilities of early termination under the assumption of treatment interruption 
response rates (H0) and desired response rates (HA) are summarized in Table 24.  
Table 24: 
Probability of Early Termination for Simon 2-Stage Design 
Cohort (Tumor Type) 
p0 
p1 
Probability of Early Termination 
Under H0 
Under HA 
A1 (MSS-CRC) 
10% 
30% 
0.5995 
0.1211 
B1 (BTC) 
20% 
40% 
0.5583 
0.0834 
B2 (OC) 
15% 
35% 
0.5995 
0.1211 
C1 (GC) 
15% 
35% 
0.5995 
0.1211 
C2 (EC) 
15% 
35% 
0.5995 
0.1211 
C3 (OC) 
15% 
35% 
0.5995 
0.1211 


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10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
10.1. 
Investigator Responsibilities 
This study will be performed in accordance with ethical principles that originate in the 
Declaration of Helsinki and conducted in adherence to the study Protocol; GCPs as defined in 
Title 21 of the US CFR Parts 11, 50, 54, 56, and 312; ICH E6 GCP consolidated guidelines; and 
local regulatory requirements as applicable to the study locations. 
The investigator will be responsible for: 
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
subject records at each monitoring visit. 
− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all subjects. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents.  The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
• Obtaining informed consent and ensuring that the study subjects' questions have been 
answered and the subjects fully understand study procedures: 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the subject.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template.  The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
direct access to subject records. 


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• Obtaining approval from the IRB/IEC before the start of the study and for any 
changes to the clinical study Protocol, important Protocol deviations, routine updates, 
and safety information in accordance with institutional requirements and local law. 
− The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements 
and with the policies and procedures established by the IRB/IEC. 
• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling subjects who have met the 
specified eligibility criteria. 
• Retaining records in accordance with all local, national, and regulatory laws, but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records.  If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 
− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail.  
10.1.1. 
Identification of the Coordinating Principal Investigator 
A coordinating principal investigator will be appointed by the sponsor before the end of the 
study.  As part of his or her responsibilities, the coordinating principal investigator will review 
the final CSR.  Agreement with the final CSR will be documented by the dated signature of the 
coordinating principal investigator. 
10.2. 
Accountability, Handling, and Disposal of Study Drug 
The investigator is responsible for drug accountability at the study site; however, some of the 
drug accountability duties may be assigned to an appropriate pharmacist or other designee.  
Inventory and accountability records must be maintained and readily available for inspection by 
the study monitor and are open to inspection at any time by any applicable regulatory authorities.  
The investigator or designee must maintain records that document: 
• Delivery of study drug to the study site. 
• Inventory of study drug at the site. 


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• Subject use of the study drug including pill or unit counts from each supply 
dispensed. 
• Return of study drug to the investigator or designee by subjects. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the subjects were provided the specified 
study drug.  These records should include dates, quantities, and any available batch or serial 
numbers or unique code numbers assigned to the investigational product and study subjects. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study drug 
until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
study drug back to the sponsor or its designee for destruction according to institutional standard 
operating procedures.  If local procedures mandate on-site destruction of investigational supply, 
the site should (where local procedures allow) maintain the investigational supply until the study 
monitor inspects the accountability records in order to evaluate compliance and accuracy of 
accountability by the investigative site.  At sites where the study drug is destroyed before 
monitor inspection, the monitors rely on documentation of destruction per the site SOP. 
10.3. 
Data Management 
Data management will be performed in a validated database via an Electronic Data Capture 
(EDC) system.  All data entry, verification, and validation will be performed in accordance with 
the current standard operating procedures of the Data Management Department at the sponsor or 
its designee.  The database will be authorized for lock once all defined procedures are completed. 
The investigator will be provided with access to an EDC system so that an eCRF can be 
completed for each subject.  Entries made in the eCRF must be verifiable against source 
documents; if updates to the database are not possible, any discrepancies should be explained 
and documented.  The investigator will be responsible for reviewing all data and eCRF entries, 
and will sign and date the designated forms in each subject's eCRF, verifying that the 
information is true and correct.  The investigator is responsible for the review and approval of all 
query responses. 
Protocol deviations will be identified and recorded in the Protocol Deviation form of the eCRF.  
The study monitor will reference the Monitoring Plan in order to ensure that each issue identified 
is appropriately documented, reported, and resolved in a timely manner in accordance with the 
plan's requirements. 
10.4. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor or its designee are responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 


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Subject names will not be supplied to the sponsor or its designee, if applicable.  Only the subject 
number and subject's initials (subject's initials will only be recorded if allowable by local 
regulations) will be recorded in the eCRF, where permitted; if the subject's name appears on any 
other document (eg, laboratory report), it must be obliterated on the copy of the document to be 
supplied to the sponsor or its designee.  Study findings stored on a computer will be stored in 
accordance with local data protection laws.  The subjects will be informed that representatives of 
the sponsor or its designee, IRB or IEC, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
10.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 Code of Federal Regulations (CFR) Part 54 – Financial Disclosure by 
Clinical Investigators (ie, "covered studies") are required to submit a completed Clinical 
Investigator Financial Disclosure form that sufficiently details any financial interests and 
arrangements that apply.  For the purpose of this regulation, "clinical investigator" is defined as 
any investigator or subinvestigator who is directly involved in the treatment or evaluation of 
research subjects, including the spouse and each dependent child of the clinical investigator or 
subinvestigator.  These requirements apply to both US and foreign clinical investigators 
conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
10.6. 
Publication Policy 
By signing the study Protocol, the investigator and his or her institution agree that the results of 
the study may be used by the sponsor, Incyte Corporation (Incyte), for the purposes of national 
and international registration, publication, and information for medical and pharmaceutical 
professionals.  Study results will be published in accordance with applicable local and national 
regulations.  If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee.  A signed agreement will 
be retained by the sponsor or its designee. 
The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission.  
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 


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multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined in line with International Committee of Medical Journal Editors 
authorship requirements. 
10.7. 
Study and Site Closure 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
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 health authorities, the sponsor's procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the investigator. 
• Discontinuation of further study treatment development. 


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11. 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For Subjects Participating in the Study: 
The following methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective birth control methods.  
Such methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1 
− oral 
− injectable 
− implantable2 
• Intrauterine device (IUD)2 
• Intrauterine hormone-releasing system (IUS)2 
• Bilateral tubal occlusion2 
• Vasectomised partner2,3 
• Sexual abstinence4 
For Male Subjects Participating in the Study:  
In addition to the aforementioned contraceptive methods, male subjects must also use a condom 
during intercourse from the time of first dose of study treatment and through at least 6 months 
+ 93 days after last dose of study treatment.  Males who have had a vasectomy qualify as having 
met the requirement for a highly effective birth control method. 
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2 Contraception methods that in the context of this guidance are considered to have low user dependency. 
3 Vasectomised partner is a highly effective method of avoiding pregnancy provided that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the 
surgical success.  
4 In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
Source:  CTFG 2014. 


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APPENDIX B. PHARMACOKINETIC ANALYTICAL PARAMETERS  
Cave 
Average steady-state plasma concentration (AUC0-12h/12h or 
AUC0-24h/24h) 
Cmax 
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration during the dosing interval 
Tmax 
Time to maximum plasma concentration 
AUC0-t 
Area under the single-dose plasma concentration-time curve from 
Hour 0 to the last quantifiable measurable plasma concentration, 
calculated by the linear trapezoidal rule for increasing concentrations 
and the log trapezoidal rule for decreasing concentrations 
AUC0- (ie, 
AUC0-12h or 
AUC0-24h) 
Area under the steady-state plasma concentration-time curve over 
1 dosing interval (ie, from Hour 0 to 12 for BID administration or from 
Hour 0 to 24 for QD administration), calculated by the linear trapezoidal 
rule for increasing concentrations and the log trapezoidal rule for 
decreasing concentrations 
λz 
Apparent terminal phase disposition rate constant, where λz is the 
magnitude of the slope of the linear regression of the log concentration 
versus time profile during the terminal phase 
t½ 
Apparent plasma terminal phase disposition half-life (whenever 
possible), where t½ = (ln2) / λz 
Cl/F 
Oral dose clearance 
Vz/F 
Apparent oral dose volume of distribution 
Fluctuation 
Steady-state fluctuation ([Cmax – Cmin]/Cave) 


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APPENDIX C. DOSE MODIFICATIONS FOR MFOLFOX6 
C.1. 
Criteria for Start of Cycle (Criteria for Administration on Day 1 of Each Cycle) 
After confirmation that each subject meets criteria for the start of each cycle described in 
Table C-1, mFOLFOX6 will be administered.  If any criteria are not met, administration of 
therapy will be postponed.  From the second cycle onwards, study treatment will be discontinued 
if therapy has not been initiated by 14 days after the estimated Day 1. 
Table C-1: 
Criteria for Administration of mFOLFOX6 on Day 1 of Each Cycle or 
Within a Cycle 
Parameter 
Criterion for Start 
White blood cell count 
≥ 3 × 109/L 
Neutrophil count  
≥ 1.5 × 109/L 
Platelet count  
≥ 75 × 109/L 
Infection 
No fever (> 38.0°C or 100.4°F) suspect for infection 
Nonhematologic toxicities  
Diarrhea 
≤ No water diarrhea 
Others 
< Grade 2 (except for nausea, vomiting, anorexia, and fatigue) 
If mFOLFOX6 is held for any of the reasons noted in Table C-1, INCB001158 may be continued 
at the discretion of the investigator with the approval of the medical monitor, and the subject will 
be evaluated at least weekly until the toxicity has resolved.  The guidelines shown in Table C-2 
and Table C-3 for hematologic toxicities will determine the dose selected for use in the new 
cycle, and the investigator will take tolerability of the most recent dose into account. 
C.2. 
Dose Modifications for Hematologic Toxicities 
Table C-2 provides guidance for dose reductions for the first appearance of the hematologic 
toxicities.  Toxicities must be resolved to Grade 0 or 1 before resuming study treatment.  When 
the dose of 5-fluoroucil (5FU) is reduced, the dose of leucovorin will remain the same. 
Table C-2: 
Criteria for Dose Reductions for the First Appearance of Hematologic 
Toxicities 
Criteria 
INCB001158 
Oxaliplatin 
5FU Bolus 
5FU Continuous 
Grade 3 leukopenia 
or neutropenia 
Resume at same dose. 
20% dose 
reduction 
Stop treatment 
No dose reduction 
Grade 4 leukopenia 
or neutropenia 
Reduce 1 dose level. 
Grade 2 or 3 
thrombocytopenia 
Resume at same dose. 
Grade 4 
thrombocytopenia 
Reduce 1 dose level. 
Note:  The dose of leucovorin remains the same. 
Table C-3 provides guidance for dose reductions for the second appearance of the specified 
hematologic toxicities.  Based on the most severe toxicity experienced since the last treatment, 
the following dose modifications will also be used for nonhematologic toxicities.  When the dose 
of 5FU is reduced, the dose of leucovorin will remain the same.  If oxaliplatin is discontinued for 


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peripheral neuropathy, then 5FU, leucovorin, and/or INCB001158 may be continued until 
additional discontinuation criteria are met. 
Table C-3: 
Criteria for Dose Reductions for Recurrent Hematologic Toxicities 
Criteria 
INCB001158 
Oxaliplatin 
5FU Bolus 
5FU Continuous 
Grade 3 leukopenia or 
neutropenia 
Resume at same 
dose. 
20% dose 
reduction 
N/A 
No dose reduction 
Grade 4 leukopenia or 
neutropenia 
Reduce 1 dose 
level. 
Grade 2 or 3 
thrombocytopenia 
Resume at same 
dose. 
Grade 4 
thrombocytopenia 
Reduce 1 dose 
level. 
Note:  The dose of leucovorin remains the same. 
After a second dose reduction, if any hematologic toxicities reoccur (third occurrence) and are 
clearly associated with chemotherapy, then chemotherapy may be discontinued, and 
INCB001158 may be continued at the same dose at the discretion of the investigator and with the 
approval of the medical monitor. 
C.3. 
Management Guidelines for Nonhematologic Toxicities 
Table C-4 provides guidance for dose reductions for the appearance of nonhematologic 
toxicities.  Toxicities must be resolved to Grade 0 or 1 before resuming study treatment.  When 
the dose of 5FU is reduced, the dose of leucovorin will remain the same.  Some adverse events 
(AEs) will overlap with potential immune-related adverse events (irAEs; eg, diarrhea and 
colitis/enteritis).  In these cases, both the AE and irAE guidance should be reviewed to determine 
the most appropriate management of dose interruptions and dose reductions of study 
medications. 


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Table C-4: 
Criteria for Dose Reductions for Nonhematologic Toxicities 
Criteria 
INCB001158 
Oxaliplatin 
5FU 
Bolus 
5FU 
Continuous 
Allergic reaction to oxaliplatin 
Discuss with medical monitor 
before restarting. 
Stop 
treatment 
No dose 
reduction 
No dose 
reduction 
AST/ALT 
Grade 1 
(< 3 × ULN) 
Continue and monitor LFTs twice 
weekly until resolves to ≤ Grade 1 
or baseline. 
No dose 
reduction 
No dose 
reduction 
No dose 
reduction 
Grade 2 
(3 × to 
< 5 × ULN)  
Hold LFTs twice weekly until 
resolves to ≤ Grade 1 or baseline.  
Resume at previous dose if 
recovers within 2 weeks.  If 
AST/ALT does not resolve within 
2 weeks, consider steroids.  When 
recovered, reduced 1 dose level.  If 
AST/ALT does not resolve within 
6 weeks, discontinue or discuss 
with medical monitor. 
No dose 
reduction 
No dose 
reduction 
No dose 
reduction 
Grade 3 or 4 
(> 5× ULN)  
Permanently discontinue. 
20% dose 
reduction 
Stop 
treatment 
No dose 
reduction 
Bilirubin 
Grade 2 
(> 1.5 × to 
3 × ULN)  
Hold and monitor LFTs twice 
weekly until resolves to ≤ Grade 1 
or baseline.  Resume at previous 
dose if recovers within 2 weeks.  If 
AST/ALT does not resolve within 
2 weeks, consider steroids.  When 
recovered, reduced 1 dose level.  If 
AST/ALT does not resolve within 
6 weeks, discontinue or discuss 
with medical monitor. 
No dose 
reduction 
No dose 
reduction 
No dose 
reduction 
Grade 3 
(> 3 × to 
10 × ULN)  
Permanently discontinue. 
20% dose 
reduction 
Stop 
treatment 
No dose 
reduction 
Grade 4 
(> 10 × ULN)  
Permanently discontinue. 
Stop 
treatment 
Stop 
treatment 
Stop 
treatment 
Hy's Lawa 
Permanently discontinue. 
Stop 
treatment 
Stop 
treatment 
Stop 
treatment 


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Table C-4: 
Criteria for Dose Reductions for Nonhematologic Toxicities (Continued) 
Criteria 
INCB001158 
Oxaliplatin 
5FU 
Bolus 
5FU 
Continuous 
Diarrhea 
Grade 1 
Continue, initiate supportive care. 
No dose 
reduction 
No dose 
reduction 
No dose 
reduction 
Grade 2 
Hold, initiate supportive care.  
Resume at previous dose if 
recovers to ≤ Grade 1 within 2 
weeks.  If diarrhea does not 
resolve within 2 weeks, consider 
steroids.  
When resolved to ≤ Grade 1 and 
steroids tapered, reduce 1 dose 
level.  If AE does not resolve 
within 6 weeks, discontinue or 
discuss with medical monitor. 
No dose 
reduction 
No dose 
reduction 
No dose 
reduction 
Grade 3 or 4 
Hold, initiate supportive care and 
steroids. 
When resolved to ≤ Grade 1 and 
steroids tapered, reduce 1 dose 
level.  If AE does not resolve 
within 6 weeks, discontinue or 
discuss with medical monitor. 
20% dose 
reduction 
Stop 
treatment 
No dose 
reduction 
Neurologic 
toxicities 
Grade 2 
Resume at same dose. 
20% dose 
reduction 
No dose reduction.  
Stop treatment for 
hyperammonemic 
encephalopathy, acute 
cerebellar syndrome, 
confusion, disorientation, 
ataxia or visual 
disturbances 
Grade 3 
Reduce 1 dose level. 
Stop 
treatment 
Respiratory symptoms 
indicative of pulmonary fibrosis 
due to oxaliplatin 
Discuss with medical monitor 
before restarting. 
Stop 
treatment 
No dose reduction 
Other 
nonhematologic 
toxicity 
Grade 3 
Reduce 1 dose level. 
20% dose 
reduction 
Stop 
treatment 
No dose 
reduction 
Grade 4 
Permanently discontinue unless 
discussed with medical monitor. 
Stop 
treatment 
Stop 
treatment 
Stop 
treatment 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; LFT = liver chemistry test; 
ULN = upper limit of normal. 
a Hy's law is defined as follows: 1) aminotransferase elevation (ALT or AST) > 3 × ULN; 2) total bilirubin > 2 × ULN, without 
initial findings of cholestasis (elevated serum ALP); 3) no other immediately apparent possible cause of aminotransferase 
elevation and hyperbilirubinemia, including, but not limited to, viral hepatitis, liver metastases, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic.  Permanently discontinue study therapy at the first 
occurrence of liver enzyme elevations meeting the criteria for Hy's law. 


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APPENDIX D. DOSE MODIFICATIONS FOR GEMCITABINE/CISPLATIN 
D.1. 
Criteria for Start of Cycle (Criteria for Administration on Day 1 of Each Cycle) 
A cycle of therapy may begin on a scheduled Day 1 if the following conditions are met:  
• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.  
• Platelet count is ≥ 100 × 109/L.  
• Sensory neuropathy has improved to ≤ Grade 2 or returned to baseline.  
• Any other AE that occurred has resolved to ≤ Grade 1 severity or returned to baseline.  
The guidelines shown in Table D-1 will determine the dose for use in the new cycle, and the 
investigator will take tolerability of the most recent dose into account.  
If new cycle starting requirements are not met, then regardless of dose modification, gemcitabine 
and/or cisplatin will be held, INCB001158 may be continued at the discretion of the investigator 
with the approval of the medical monitor, and the subject will be evaluated at least weekly until 
the toxicity has resolved. 
From the second cycle onwards, study treatment will be discontinued if therapy has not been 
initiated within the 14 days after the scheduled Day 1.  
D.2. 
Changes to Treatment Regimen During a Cycle for Hematologic Toxicities 
Recommended dose interruptions and modifications of INCB001158, gemcitabine, and cisplatin 
on Days 1 and 8 of a cycle for hematologic toxicity are shown in Table D-1. 
Table D-1: 
Modifications for Neutropenia and/or Thrombocytopenia at the Start of a 
Cycle or Within a Cycle 
Cycle Day 
ANC 
(× 109/L) 
 
Platelets 
(× 109/L) 
Gemcitabine and Cisplatin 
Day 1 
< 1.5 
OR 
< 100 
Delay dose until recovery 
Day 8 
0.5 to < 1.0 
OR 
50 to < 75 
Dose as scheduled 
< 0.5 
OR 
< 50 
Delay dose until recovery 
D.2.1. 
Gemcitabine and Cisplatin Dose Modifications 
Dose reductions or interruptions of gemcitabine and cisplatin on Days 1 and 8 are mandatory in 
the event of hematologic toxicities, as specified in Table D-1.  However, other interruptions or 
reductions may occur for safety reasons at the discretion of the investigator.  Gemcitabine and 
cisplatin treatment cycles may be delayed or the dose may be reduced for laboratory parameters 
or AEs that are judged to be related to gemcitabine or cisplatin.  A maximum of 1 dose reduction 
is allowed for gemcitabine (25% reduction) and for cisplatin (20%; Table D-2).  For dose 
reductions for safety, individual drug dose should follow prescribing information for dose 
modifications.  Day 1 of each study cycle will correspond with the first day of chemotherapy 
administration.  Thus, study cycles may become out-of-sync with the originally planned 
schedule.  All assessments will shift to coincide with the revised treatment (cycle) schedule. 


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Table D-2: 
Gemcitabine and Cisplatin Dose Level Reductions 
 
Gemcitabine 
Cisplatin 
Full dose  
100% 
100% 
First dose reduction  
25% reduction 
20% reduction 
If additional dose reduction required  
Discontinue 
Discontinue 
If neutropenia or thrombocytopenia reoccur (second occurrence) and are clearly associated with 
chemotherapy, then gemcitabine and cisplatin may be discontinued, and INCB001158 may be 
continued, at the discretion of the investigator and approval of the medical monitor. 
D.3. 
Other Adverse Drug Reactions in Subjects With Gemcitabine and Cisplatin 
Dose interruptions and modifications for gemcitabine and cisplatin for other adverse drug 
reactions are described in Table D-3. 
Table D-3: 
Dose Modifications for Gemcitabine and Cisplatin Adverse Drug Reaction 
 
Gemcitabine 
Cisplatin 
Febrile neutropenia:  Grade 3 or 4  
Withhold until fever resolved and ANC ≥ 1.5 × 109/L; resume at lower 
dose level. 
Peripheral neuropathy:  Grade 3 or 4 
No dose reduction. 
Withhold until improves to 
≤ Grade 1; resume at next lower dose 
level. 
Cutaneous toxicity:  Grade 2 or 3 
Reduce to lower dose level; 
discontinue treatment if toxicity 
persists. 
Reduce to lower dose level; 
discontinue treatment if toxicity 
persists. 
Gastrointestinal toxicity:  Grade 3 
mucositis or diarrhea  
Withhold until improves to 
≤ Grade 1; resume at lower dose 
level. 
Withhold until improves to ≤ Grade 
1; resume at lower dose level. 
Note:  If the subject meets more than 1 of the criteria listed, then dose modifications should always be based on the system 
showing the greatest degree of toxicity.  Dose interruptions and modifications will be made at the discretion of the investigator.  
If the toxicities listed in Table D-3 persist or reoccur despite 2 dose reductions and are clearly 
associated with chemotherapy, then gemcitabine cisplatin may be discontinued, and 
INCB001158 may be continued at the discretion of the investigator and approval of the medical 
monitor.  If cisplatin must be discontinued for peripheral neuropathy, then gemcitabine and 
INCB001158 may be continued at the discretion of the investigator and approval of the medical 
monitor. 
D.4. 
General Management Guidelines for Nonhematologic Toxicities 
Table D-4 provides guidance for dose reductions for the appearance of nonhematologic 
toxicities.  Toxicities must be resolved to Grade 0 or 1 before resuming study treatment.  Of note, 
some AEs will overlap with potential irAEs (eg, diarrhea and colitis/enteritis).  In these cases, 
both the AE and irAE guidance should be reviewed to determine the most appropriate 
management of dose interruptions and dose reductions of study medications. 


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Table D-4: 
Criteria for Dose Reductions for Nonhematologic Toxicities 
Criteria 
INCB001158 
Gemcitabine 
Cisplatin 
AST/ALT 
Grade 1  
(< 3 × ULN)  
Continue and monitor LFTs twice weekly 
until resolves to ≤ Grade 1 or baseline. 
No dose 
reduction  
No dose 
reduction  
Grade 2  
(3 × to 
< 5 × ULN)  
Hold and monitor LFTs twice weekly 
until resolves to ≤ Grade 1 or baseline. 
Resume at previous dose if recovers 
within 2 weeks. 
If AST/ALT does not resolve within 
2 weeks, consider steroids. 
When recovered, restart at the same dose 
level. 
If AST/ALT does not resolve within 
6 weeks, discontinue or discuss with 
medical monitor. 
No dose 
reduction  
Consider dose 
reduction  
Grade 3 or 4 
(> 5 × ULN)  
Permanently discontinue. 
No dose 
reduction  
Reduce at 
lower dose 
level 
Bilirubin 
Grade 2  
(> 1.5 × to 
3 × ULN) 
Hold and monitor LFTs twice weekly 
until resolves to ≤ Grade 1 or baseline. 
Resume at previous dose if recovers 
within 2 weeks. 
If AST/ALT does not resolve within 
2 weeks, consider steroids. 
When recovered, restart at the same dose 
level.  If AST/ALT does not resolve 
within 6 weeks, discontinue or discuss 
with medical monitor. 
No dose 
reduction  
No dose 
reduction  
Grade 3  
(> 3 × to 
10 × ULN)  
Permanently discontinue. 
No dose 
reduction  
Reduce at 
lower dose 
level 
Grade 4  
(> 10 × ULN) 
Permanently discontinue. 
Stop treatment  
Stop treatment  
Hy's Lawa 
Permanently discontinue. 
Stop treatment  
Stop treatment  


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Table D-4: 
Criteria for Dose Reductions for Nonhematologic Toxicities (Continued) 
Criteria 
INCB001158 
Gemcitabine 
Cisplatin 
Diarrhea 
Grade 1  
Continue, initiate supportive care. 
No dose 
reduction  
No dose 
reduction  
Grade 2  
Hold, and initiate supportive care. 
Resume at previous dose if recovers to 
≤ Grade 1 within 2 weeks. 
If diarrhea does not resolve within 
2 weeks, consider steroids. 
When resolved to ≤ Grade 1 and steroids 
tapered, reduced 1 dose level. 
If AE does not resolve within 6 weeks, 
discontinue or discuss with medical 
monitor. 
No dose 
reduction  
No dose 
reduction  
Grade 3 or 4  Hold, and initiate supportive care and 
steroids.  When resolved to ≤ Grade 1 and 
steroids tapered, reduce 1 dose level. 
If AE does not resolve within 6 weeks, 
discontinue or discuss with medical 
monitor. 
Reduce at 
lower dose 
level 
Reduce at 
lower dose 
level 
Neurologic 
toxicities  
Grade 2  
Resume at same dose. 
No dose 
reduction  
No dose 
reduction  
Grade 3  
Resume at same dose. 
No dose 
reduction  
Reduce at 
lower dose 
level 
Other 
nonhematologic 
toxicity 
Grade 3  
Withhold until Grade 0-1. 
Reduce 1 dose level. 
Reduce at 
lower dose 
level 
Reduce at 
lower dose 
level 
Grade 4  
Permanently discontinue unless discussed 
with medical monitor. 
Reduce at 
lower dose 
level 
Reduce at 
lower dose 
level 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; LFT = liver chemistry test; 
ULN = upper limit of normal.  
a Hy's law is defined as follows: 1) aminotransferase elevation (ALT or AST) > 3 × ULN; 2) total bilirubin > 2 × ULN, without 
initial findings of cholestasis (elevated serum ALP); 3) no other immediately apparent possible cause of aminotransferase 
elevation and hyperbilirubinemia, including, but not limited to, viral hepatitis, liver metastases, pre-existing chronic or acute 
liver disease, or the administration of other drug(s) known to be hepatotoxic.  Permanently discontinue study therapy at the first 
occurrence of liver enzyme elevations meeting the criteria for Hy's law. 


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APPENDIX E. DOSE MODIFICATIONS FOR PACLITAXEL 
E.1. 
Criteria for Start of Cycle (Criteria for Administration on Day 1 of Each Cycle) 
After confirmation that each subject satisfies criteria for the start of each cycle described in 
Table E-1, paclitaxel will be administered.  If any criteria are not met, then administration of 
therapy will be postponed.  From the second cycle onwards, study treatment will be discontinued 
if administration of therapy has not been initiated by 14 days after the estimated Day 1. 
Table E-1: 
Criteria for Administration of Paclitaxel on Day 1 of Each Cycle or Within a 
Cycle 
Parameter 
Criterion for Start 
White blood cell count 
≥ 2.5 × 109/L  
Neutrophil count  
≥ 1.0 × 109/L 
Platelet count  
≥ 100 × 109/L  
Renal function  
> 30 mL/min AND < 10% change in glomerular filtration rate 
from previous cycle  
Nonhematologic toxicities  
Bilirubin 
≤ 1.5 ULN 
ULN = upper limit of normal. 
If paclitaxel is held for any of the reasons noted in Table E-1, INCB001158 may be continued at 
the discretion of the investigator with the approval of the medical monitor, and the subject will 
be evaluated at least weekly until the toxicity has resolved.  The guidelines shown in Table E-2 
and Table E-3 will determine the dose selected for use in the new cycle, and the investigator will 
take tolerability of the most recent dose into account.  
E.2. 
Paclitaxel Dose Modifications 
Table E-2 provides guidance for dose reductions for the first appearance of the specified 
toxicities. 


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Table E-2: 
Criteria for Dose Reductions for Specified Toxicities 
Hematologic 
toxicity 
Dose modifications based on neutrophil and/or platelet count on day of treatment (Day 1) 
ANC 
 
Platelet 
Count 
Action 
Dose Modification 
Following Recovery 
≥ 1.0 × 109/L 
AND 
≥ 100 × 109/L 
Dose as scheduled 
Full dose 
< 1.0 × 109/L 
OR 
≤ 100 × 109/L 
Delay 1 week until recovery 
No dose reduction 
< 1.0 × 109/L 
AND 
≤ 100 × 109/L 
Delay 1 week until recovery 
No dose reduction 
NCI common 
toxicities 
Toxicity 
Definition 
Dose Modification 
Febrile 
neutropenia 
ANC < 0.5 × 109/L 
plus fever requiring 
IV antibiotics ± 
hospitalization 
Reduce at 60 mg/m2 for subsequent doses. 
Consider prophylactic ciprofloxacin. 
Peripheral 
Neuropathy 
Grade 2 
Reduce to 70 mg/m2. 
≥ Grade 3 
Discontinue if no recovery. 
Other 
toxicities 
Grade ≥ 2 toxicity 
(except alopecia) 
Defer therapy for 1 week until resolved to ≤ Grade 1 
and then resume at 70 mg/m2.  Discuss with medical 
monitor if > 1 week delay. 
ANC = absolute neutrophil count; IV = intravenous; NCI = National Cancer Institute. 
Table E-3 provides guidance for dose reductions for hepatic impairment.  
Table E-3: 
Management Guidelines for Hepatic Toxicity 
Hepatic 
impairment 
If hepatic function is impaired at baseline (bilirubin > 1.5 × ULN), then treatment should be 
started at reduced dose (70 mg/m2).  `For more severe impairment, treatment may proceed at 
reduced dose, at consultant's discretion, and with weekly monitoring of LFTs. 
LFT = liver chemistry test; ULN = upper limit of normal. 


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APPENDIX F. CYP2C8 AND CYP3A4 INHIBITORS AND INDUCERS 
Source:  University of Washington School of Pharmaceutics: Drug Interaction Database 
Program. 2002. http://www.druginteractioninfo.org.  Accessed October 2016.  Highlighted rows 
indicate recent additions to the lists at the time the database search was performed. 


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In Vivo CYP2C8 Inhibitors 
 


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In Vivo CYP2C8 Inducers 
 


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In Vivo CYP3A Inhibitors 
 


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I 
Weak CYP3A Inhibitors (AU Cr a 1.25 and < 2) 
I 
tabimorelin 
Hormone Replacement 
2.86-3.21 mg QD (7 d ays) 
midazolam 
1.93 
12610745 
2003 Feb 
ranolazine 
Cairdiovascular Drugs 
1000 mg BID (7 days) 
simvastatin 
1.89 
NDA#021526 
2006 
amlodipine 
Cailcium Channel Blockers 
10 mg QD (9 days) 
simvastatin 
ll.8 
23965645 
2014Apr 
lomitapide 
Ot her Antilipem ics 
60 mg QD (7 days) 
simvastatin 
1. 77 
24734312 
2014 Mar 
fosaprepitant (IV) 
Antiemetics 
150 mg single 30-min infusion 
midazolam 
1. 76 
21209230 
2011 Dec 
Seville orange juioe 
Food Products 
240 ml single dose 
felodipine 
1. 76 
11180034 
2001 Jan 
amiodarone 
Antiarrhythmics 
400 mg QD (4 days) 
simvastatin acid 
1. 76 
17301736 
2007 May 
chlorzoxazone 
Muscle Relaxants 
250 mg single d ose (part of a 6-drug cocktail) 
midazolam 
1. 68 
11736864 
2001 Nov 
M100240 
Antihypertensive Agents 
SO mg single dose 
midazolam 
1. 66 
15051745 
2004Apr 
fluvoxamine 
Antidepressants 
50-00 mg BID (12 days) 
midazolam 
1. 66 
14551182 
2003 Nov 
ranitidine 
H-:2 Receptor Antagonists 
150 mg BID (1.5 days) 
midazolam 
1. 66 
6135440 
1983 Jun 
fostamatinib5 
Anti-inflammatory Drugs 
100 mg BID (7 days) 
simvastatin 
1. 64 
26748647 
2016 Mar 
goldenseal 
Herbal Medications 
1,323 mg (= 24.1 mg isoquinolin e alkaloids) TID (14 days) 
midazolam 
1. 63 
17495878 
2008 Jan 
clotrimazole 
Antifungals 
10 mg TID (5 days) 
midazolam 
1. 61 
20233179 
2010 Feb 
tacrolimus 
lmmunosuppressants 
Not provided (1·5 years) 
midazolam 
1. 61 
21753749 
2011 Sep 
palbocklib 
Kinase Inhibitors 
125 mg QD (8 days) 
midazolam 
1. 58 
NDA#207103 
2015 
cilostazol 
Anti plat elets 
100 mg BID (7 days) 
lovastatin 
1. 56 
10702889 
1999 
ticagrelor 
Anti plat elets 
180 mg bid (7 days) 
simvastatin 
1. 56 
NDA#022433 
2011 
peppermint oil 
Food Products 
600 mg (= 300 ul peppermint oil) single dose 
felodipine 
1. 55 
12235445 
2002 Sep 
ivacaftor 
Cystic fibrosis treatments 
150 mg BID (6 days) 
midazolam 
1. 54 
25103957 
2015 Jan 
GSK2248761 
Transcriptase Inhibitors 
100 mg QD (12 days) 
midazolam 
1. 54 
22288567 
2012 Aug 
Guan Mai Ning 
Herbal Medications 
3 t ablets TID (7 days) 
simvastatin 
1. 51 
25801058 
2015 Sep 
A2D2327 
Depression Treatments 
15 mg QD (7 days) 
midazolam 
1.49 
26081137 
2015 Nov 
re.sveratrol 
Food Products 
500 mg QD (10 days) 
carbamazepine 
1.48 
25624269 
2015 May 
roxithromycin 
Antibiotics 
300 mg QD (6 days) 
midazolam 
1.47 
7995324 
1994 
suvorexant 
Hypnotics - Sedatives 
80 mg QD (14 days) 
midazolam 
1.47 
NDA#204569 
2014 
propiverine 
Anticholinergics 
15 mg BID (7 days) 
midazolam 
1.46 
16183781 
2005 Dec 
isoniazid 
Antibiotics 
90 mg BID (4 days) 
triazolam 
1.46 
6140941 
1983 Dec 
berberine 
Herbal Medications 
300 mg TID (14 days) 
midazolam 
1.45 
21870106 
2012 Feb 
oral contraceptives 
Oral contraceptives 
OC with low doses of estrogen (< 35 ug ethinylestradiol) (> 3 months) 
triazolam 
1.44 
6149030 
1984 Nov 
delavirdine 
NNRTls 
400 mg TID (9 days) 
indinavir 
1.44 
9665503 
1998 Jul 
dac:lata.svir 
Antivirals 
60 mg QD (7 days) 
simeprevir 
1.44 
NDA#205123 
2013 
simeprevir 
Protease Inhibitors 
150 mg QD (11 days) 
midazolam 
1.43 
NDA#205123 
2013 
atorvastatin 
HM G CoA Reductase Inhibitors (Stalins) 
10,40 mg/day (chronic treatment) 
midazolam IV 
1.41 
12911366 
2003 Sep 
tolvaptan 
Va sopressin Antagonists 
60 mg single dose 
lovastatin 
1.41 
NDA#022275 
2009 
almorexant 
Hypnotics - Sedatives 
200 mg QD (9 days) 
midazolam 
1.37 
22990330 
2013 Mar 
GSK1292263 
Ot her Antilipemics 
300 mg BID (9 days) 
simvastatin 
1.36 
23256625 
2013 Jun 
evacetrapid 
CETP inhibitors 
300 mg QD (15 days) 
midazolam 
1.35 
26264702 
2015 Dec 
linagliptin 
Dipeptidyl Peptidase 4 Inhibitors 
10 mg QD (6 days) 
simvastatin 
1.34 
20497745 
2010 Jun 
grazoprevir {ingredient of Zepotie r) Antivirals 
200 mg QD (7 days) 
midazolam 
1.34 
NDA # 208261 
2016 
lacidipine 
Cailcium Channel Blockers 
4 mg QD (8 days) 
simvastatin 
1.33 
11259986 
2001 Feb 
cranberry juioe 
Food Products 
240 ml double strength juice, 1 glass q 15 min x 3 
midazolam 
1.33 
19114462 
2009 Mar 
pazopanib 
Kinase Inhibitors 
800 mg QD (17 days) 
midazolam 
1.32 
20881954 
2010 Nov 
everolimu.s 
lmmunosuppressants 
10 mg QD (5 days) 
midazolam 
1.31 
23426978 
2013Apr 
blueberry juice 
Food Products 
two doses of 300 ml , separated by 16 hours 
buspirone 
1.31 
22943633 
2013Apr 
flibanserin 
Central Nervous System Agents 
50 mg BID (4 days) 
simvastatin 
1.31 
NDA#022526 
2015 
AMD070 
Fu,sion Inhibitors 
200 mg BID (8 days) 
midazolam 
1.29 
18362694 
2008Apr 


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In Vivo CYP3A Inducers 
 


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Weak Inducers {AUC de<reased by 20-50% or Cl increased by 20-100% {less than 2 fold)) 
eslicarbazepine 
Anticonvulsants 
simvastatin 
49.4 
98.4 
800 mg QD (14 days) 
23n5291 
2013Sep 
telaprevir 
Antivirals 
darunavir 
48.4 
Not Provided 
1125 mg BID (4 days) 
NDA#201917 
2011 
garlic 
Food Pro ducts 
saquinavir 
44.7 
Not Provided 
caplet of GarliPure BID (20 days) 
11740713 
2002 Jan 
bexarotene 
Other Antineoplastics 
atorvastatin 
45.3 
Not Provided 
400 mg/m2 QD (at least two 4-week cycles) 
22057855 
2012 Feb 
artesunate and mefloquine 
Antimalarials 
lopinavir 
43.1 
75.4 
4 mg/kg Q.D artesunate on Days 1·3 750 mg mefloquine on Day 1 and 500 IT 
26452725 
2015 
amprenavir {fosamprenavir) 
Protease Inhibitors 
lopinavir 
43.0 
Not Provided 
700 mg BID (2-4 weeks) 
15668539 
2005 Jan 
raltegravir 
HIV-lntegrase Strand Transfer Inhibitors 
darunavir 
42.0 
Not Provided 
400mg BID 
21958880 
2012 Feb 
lesinurad 
Antigout and Uricosuric Agents 
amlodipine 
41.9 
72.5 
400 mg QD (24 days) 
NDA#207988 
2015 
vemurafenib 
Kinase Inhibitors 
midazolam 
39.4 
Not Provided 
960 mg BID (15 days) 
NDA#202429 
2011 
troglitazone 
Thiazolidinediones 
simvastatin 
37.7 
Not Provided 
400 mg QD (24 days) 
11361054 
2001 M ay 
sorafenib 
Kinase Inhibitors 
sirolimus 
36.9 
Not Provided 
200 mg BID (11 days) 
21045832 
2010 Nov 
rufinamide 
Anticonvulsants 
triazolam 
36.7 
53.4 
400 mi: BID !11.5 da:1:sl 
NDA#021911 
2008 
sirukumab .. * 
lmmunomodulators Biolos;.ics 
midazolam 
35.7 
Not Provided 
300 ms; sins;le dose subcutaneous~ 
26054042 
2015 Dec 
pleconaril 
Antivirals 
midazolam 
34.6 
52.8 
400 mg TID (6 days) 
16467135 
2006 M ay 
s;insens 
Herbal Medications 
midazolam 
34.2 
50.7 
500 mi: BID !28 da:1:sl 
21646440 
2012 Jun 
boceprevir 
Antivirals 
darunavir 
34.2 
41.0 
800 mg every 8 hrs (6 days) 
23155151 
2013 Mar 
sulfinpyrazone 
Antigout and Uricosuric Agents 
cyd osporine 
33.9 (change in c,,1) 
200mg/day 
11124491 
2000 Dec 
ginkgo 
Herbal Medications 
midazolam 
33.7 
52.6 
120 mg BID (28 days) 
18205997 
2008 Feb 
vinblastine 
Vinca Alkaloids 
midazolam IV 
33.2 
48.8 
not provided (4 cycles) 
20959500 
2010 Nov 
nevirapine 
NNRTls 
indinavir 
32.5 
Not Provided 
200 mg QD (14 days). then BID (19 days) 
10191212 
1999 M ay 
armodafinil (R·modafinil) 
Psychostimulants 
midazolam 
32.2 
54.7 
100-250 mg/d ay (31 days) 
18076219 
2008 
ticagrelor 
Anticoagulants and Antiplatelets 
midazolam 
31.7 
46.5 
400 mg QD (6 days) 
23870610 
2013 Jul 
LCl161 
cancer Treatments 
midazolam 
29.8 
34.0 
600 mg single dose 
23585187 
2013 Jun 


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APPENDIX G. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
31 OCT 2017 
Amendment (Version) 2: 
27 SEP 2018 
Amendment (Version) 3: 
17 MAY 2019 
Amendment (Version) 4: 
09 DEC 2020 
Amendment 4 (09 DEC 2020) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to provide 
guidance for the management of ongoing subjects, as enrollment is complete and sufficient data 
have been collected for primary and secondary endpoint analysis. 
1. Synopsis; Section 4.5, Overall Study Duration; Section 5.2.1.4, Instructions to 
Subjects for Handling Study Drug (INCB001158); Section 5.5.1, Withdrawal 
Criteria; Section 5.6, Concomitant Medications; Section 5.6.3, Prohibited 
Medications; Section 6, Study Assessments (Table 15:  Schedule of Assessments for 
All Subjects [as of Protocol Amendment 4]); Section 6.2, Treatment, Section 6.4.1, 
Safety Follow-Up; Section 6.4.2, Disease Status Follow-Up; 
 
 Section 7.6, Safety Assessments; Section 7.6.5, Laboratory Assessments; 
Section 7.6.5.4, Pregnancy Testing; Section 7.7, Efficacy Assessments; 
Section 7.7.1.3, End-of-Treatment and Follow-Up Imaging; 
 
; Section 8, Safety Monitoring and Reporting; 
Section 8.1.2, Reporting; Section 8.2, Laboratory Test Abnormalities; Section 8.3.2, 
Reporting; Section 8.5, Pregnancy 
Description of change:  Study assessments for all subjects remaining on study treatment 
have been limited to standard of care for the subject's condition.  Safety and efficacy data 
will only be collected for SAEs, AESIs, and disease assessment before Week 96.  
 
 
 
Rationale for change:  To update the study assessments as enrollment is complete and 
all ongoing subjects have been on study for more than 6 months or have met the 
definition of EOS as defined in Section 4.5.  
2. Section 4.6, Study Termination; Section 10.1.1, Identification of the Coordinating 
Principal Investigator; Section 10.6, Publication Policy; Section 10.7, Study and Site 
Closure 
Description of change:  Included the process for identification of the coordinating 
principal investigator and for study and site closure.  Clarified the policy for study 
publications. 
Rationale for change:  To update applicable sections as per current protocol template. 
3. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment 


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Amendment 3 (17 MAY 2019) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to change 
the study drug formulation. 
1. Sections 5.2.1,  INCB001158; 5.3, Treatment Compliance 
Description of change:  Replaced INCB001158 capsule formulation and blister card 
packaging with INCB001158 tablet formulation and bottle packaging. 
Rationale for change:  Introduction of the study drug formulation and associated 
packaging. 
2. Section 6,  Study Assessments (Table 11: Schedule of Assessments for Subjects 
Treated With INCB001158 + mFOLFOX6 or INCB001158 + Paclitaxel) 
Description of change:  Clarified that some clinical assessments planned on Day 8 of the 
treatment cycle are only for subjects receiving paclitaxel. 
Rationale for change:  Clarification. 
3. Section 7.7.1,  Tumor Imaging and Assessment of Disease 
Description of change:  Clarified that the images from scans may be sent to a central 
reader for independent image analysis. 
Rationale for change:  Clarification. 
4. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


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Amendment 2 (27 SEP 2018) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to update 
the inclusion criteria for the microsatellite stable colorectal cancer (MSS-CRC) expansion 
cohort. 
1. Synopsis; Section 1.1.4, Overview of FOLFOX in Colorectal Cancer; Section 3.1, 
Subject Inclusion Criteria (Inclusion Criterion #12)  
Description of change:  Inclusion Criterion #12 was revised to indicate that subjects 
must have received 1 or 2 prior chemotherapy regimens for locally advanced/metastatic 
CRC. 
Rationale for change:  To include subjects with 2 prior chemotherapy treatment lines. 
2. Synopsis; Section 3.1, Inclusion Criteria (Inclusion Criterion #16) 
Description of change:  Inclusion Criterion #16 was revised to indicate that subjects 
must have received 1 or 2 prior chemotherapy regimens for locally advanced/metastatic 
endometrial cancer. 
Rationale for change:  To include subjects with 2 prior chemotherapy treatment lines. 
3. Section 6,  Study Assessments (Table 11, Schedule of Assessments for Subjects 
Treated With INCB001158 + mFOLFOX6 or INCB001158 + Paclitaxel; Table 12, 
Schedule of Laboratory Assessments for Subjects Treated With INCB001158 + 
mFOLFOX6 or INCB001158 + Paclitaxel) 
Description of change:  Clarified that clinical and laboratory assessments planned on 
Day 8 of Cycle 2 and beyond are only for subjects who receive paclitaxel. 
Rationale for change:  Clarification. 
4. Section 6, Study Assessments (Table 13, Schedule of Assessments for Subjects 
Treated With INCB001158 + Gemcitabine/Cisplatin; Table 14, Schedule of 
Laboratory Assessments for Subjects Treated With INCB001158 + 
Gemcitabine/Cisplatin) 
Description of change:  Clarified that administrative, clinical, and laboratory 
assessments planned on Day 15 of Cycle 2 and beyond are not performed. 
Rationale for change:  Clarification. 
5. Section 6,  Study Assessments (Tables 15, Laboratory Tests:  Required Analytes) 
Description of change:  Clarified that amylase, lipase, urea, and CO2 are included in the 
chemistries. 
Rationale for change:  Clarification. 
6. Appendix A,  Information Regarding Effectiveness of Contraceptive Methods 
Description of change:  Provided the contraception method required for male subjects. 
Rationale for change:  Informational. 


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7. Appendix C, Dose Modifications for mFOLFOX6; Appendix D, Dose Modifications 
for Gemcitabine/Cisplatin; Appendix E, Dose Modifications for Paclitaxel 
Description of change:  Clarified that when the chemotherapy agents are held, 
INCB001158 may be continued at the discretion of the investigator with the approval of 
the medical monitor. 
Rationale for change:  Clarification. 
8. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


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Amendment 1 (31 OCT 2017) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to address 
changes requested by the Medicines & Healthcare products Regulatory Agency (MHRA) in the 
United Kingdom. 
1. Section 1.3.1, Risk from INCB001158 
Description of change:  A statement was added noting that investigators advise patients 
take measures to minimize exposure to sun/ultraviolet light for the duration of the study 
and for 2 weeks after the last dose of study drug. 
Rationale for change:  Requested by MHRA. 
2. Section 1.3.2, Risks From mFOLFOX6; Section 1.3.3. Risks From 
Gemcitabine/Cisplatin; Section 1.3.4, Risks From Paclitaxel 
Description of change:  A statement was added noting that investigators should advise 
male patients to consider conservation of sperm before enrollment in the study. 
Rationale for change:  Requested by MHRA in line with the SmPCs of the 
chemotherapy agents. 
3. Section 3.1, Subject Inclusion Criteria 
Description of change:  Inclusion criterion 5 was revised to indicate that contraception 
must continue until 6 months after the last dose of the last component of study treatment. 
Rationale for change:  Requested by MHRA in line with the SmPCs of the 
chemotherapy agents. 
4. Section 6, Study Assessments (Tables 12 and 14, Schedule of Laboratory 
Assessments; Table 15, Local Laboratory Tests: Required Analytes); Section 7.6.5.4, 
Pregnancy Testing  
Description of change:  Revised to indicate that urine pregnancy testing occurs on 
Cycle 1 Day 1 and Day 1 of each subsequent cycle. 
Rationale for change:  Requested by MHRA. 
5. Sections 5.6.2, Restricted Medications; 5.6.3. Prohibited Medications; Appendix F, 
CYP2C8 and CYP3A4 Inhibitors and Inducers 
Description of change:  A statement was added noting that drugs that inhibit CYP2C8 or 
CYP3A4 must be used with caution, and drugs that induce CYP2C8 or CYP3A4 are not 
recommended with paclitaxel. 
Rationale for change:  Requested by MHRA in line with the paclitaxel SmPC. 
6. Sections 5.6.2, Restricted Medications 
Description of change:  A statement was added noting that caution be used with 
concomitant therapies that are nephrotoxic or ototoxic to avoid additive toxicity with 
cisplatin. 
Rationale for change:  Requested by MHRA in line with the cisplatin SmPC. 


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7. Section 5.6.3, Prohibited Medications 
Description of change:  A statement was added noting that live vaccines must also be 
avoided for 3 months after the last dose of any component of study therapy. 
Rationale for change:  Requested by MHRA. 
8. Section 1.3.1.3, Alterations in Hemodynamic Status; Section 6, Study Assessments 
(Tables 11 and 13, Schedule of Assessments); Section 7.6.3, Vital Signs 
Description of change:  A statement was added noting that orthostatic blood pressure 
will be monitored. 
Rationale for change:  Requested by MHRA. 
9. Section 7.6, Safety Assessments 
Description of change:  A statement was added to clarify that subject safety 
management guidelines within the prescribing information for the chemotherapy agents 
should be followed as appropriate. 
Rationale for change:  To ensure that the recommended safety management guidelines 
for the chemotherapy SmPCs are being followed. 
10. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


Signature Page for VV-CLIN-000593 v6.0
Signature Page for VV-CLIN-000593 v6.0
Approval
Approver
09-Dec-2020 17:38:22 GMT+0000
Approval
Approver
09-Dec-2020 17:41:40 GMT+0000
Approval
Approver
09-Dec-2020 19:43:16 GMT+0000
Approval
Approver
10-Dec-2020 08:40:24 GMT+0000
Approval
Approver
10-Dec-2020 11:23:06 GMT+0000

SAP_001.pdf: 
Official Title:         A Phase 1/2 Study to Evaluate the Safety, Tolerability, and 
 Efficacy of INCB001158 in Combination With Chemotherapy, in               
Subjects With Advanced or Metastatic Solid Tumors
NCT Number:      NCT03314935 
Document Date: Statistical Analysis Plan Amendment (Version) 1: 08-March-2021


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Incyte Corporation 
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INCB 01158-203 Statistical Analysis Plan Am 1 
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VV-CLIN-000131 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................8 
2.1. 
Protocol and Case Report Form Version ......................................................................8 
2.2. 
Study Objectives and Endpoints ...................................................................................8 
3. 
STUDY DESIGN .......................................................................................................11 
3.1. 
Phase 1 – Dose Escalation ..........................................................................................11 
3.2. 
Phase 2 – Tumor Expansion Cohorts..........................................................................14 
3.3. 
Control of Type I Error ...............................................................................................15 
3.4. 
Sample Size Considerations .......................................................................................15 
3.4.1. 
Sample Size for Phase 1 .............................................................................................15 
3.4.2. 
Sample Size for Phase 2 .............................................................................................15 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................16 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................16 
4.1.1. 
Day 1 ...........................................................................................................................16 
4.1.2. 
Study Day ...................................................................................................................16 
4.1.3. 
Baseline Value ............................................................................................................16 
4.1.4. 
Handling of Missing and Incomplete Data .................................................................17 
4.1.5. 
Cycle Length and Duration .........................................................................................17 
4.2. 
Variable Definitions ....................................................................................................18 
4.2.1. 
Age ..............................................................................................................................18 
4.2.2. 
Prior and Concomitant Medication .............................................................................18 
5. 
STATISTICAL METHODOLOGY ...........................................................................19 
5.1. 
General Methodology .................................................................................................19 
5.2. 
Treatment Groups .......................................................................................................19 
5.3. 
Analysis Populations ..................................................................................................20 
5.3.1. 
Full Analysis Set .........................................................................................................20 
5.3.1.1. 
mFOLFOX6 FAS Population .....................................................................................20 
5.3.1.2. 
Gemcitabine/Cisplatin FAS Population ......................................................................20 
5.3.1.3. 
Paclitaxel FAS Population ..........................................................................................21 
5.3.2. 
Response Evaluable Population ..................................................................................21 


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5.3.3. 
DLT Evaluable Population in Phase 1 ........................................................................21 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES ...............................................................................................................21 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............21 
6.1.1. 
Demographic Characteristics ......................................................................................21 
6.1.2. 
Baseline Disease Characteristics and Disease History ...............................................21 
6.1.3. 
Prior Therapy ..............................................................................................................22 
6.1.4. 
Medical History ..........................................................................................................22 
6.2. 
Disposition of Participants ..........................................................................................22 
6.3. 
Protocol Deviations ....................................................................................................22 
6.4. 
Exposure .....................................................................................................................22 
6.4.1. 
Exposure for INCB001158 .........................................................................................22 
6.4.2. 
Exposure for mFOLFOX6 ..........................................................................................23 
6.4.2.1. 
Exposure for Oxaliplatin .............................................................................................23 
6.4.2.2. 
Exposure for Leucovorin ............................................................................................23 
6.4.2.3. 
Exposure for 5-Fluorouracil .......................................................................................23 
6.4.3. 
Exposure for Gemcitabine/Cisplatin ...........................................................................23 
6.4.3.1. 
Exposure for Gemcitabine ..........................................................................................24 
6.4.3.2. 
Exposure for Cisplatin ................................................................................................24 
6.4.4. 
Exposure for Paclitaxel ...............................................................................................24 
6.5. 
Study Drug Compliance .............................................................................................24 
6.6. 
Prior and Concomitant Medication .............................................................................25 
7. 
EFFICACY .................................................................................................................25 
7.1. 
General Considerations ...............................................................................................25 
7.2. 
Efficacy Hypotheses ...................................................................................................25 
7.3. 
Analysis of the Efficacy Parameters ...........................................................................25 
7.3.1. 
Response Criteria ........................................................................................................25 
7.3.2. 
Objective Response Rate and Best Overall Response ................................................25 
7.3.2.1. 
Confirmed ORR and Confirmed BOR by RECIST v1.1 ............................................25 
7.3.3. 
Duration of Response .................................................................................................28 
7.3.4. 
Disease Control Rate ..................................................................................................28 
7.3.5. 
Largest Percent Reduction in Sum of Diameters of Target Lesions ..........................28 
7.3.6. 
Percentage Change in Sum of Diameters of Target Lesions Over Time ....................28 


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7.3.7. 
Progression-Free Survival ..........................................................................................28 
 
29 
8. 
SAFETY AND TOLERABILITY ..............................................................................30 
8.1. 
General Considerations ...............................................................................................30 
8.2. 
Adverse Events ...........................................................................................................30 
8.2.1. 
Adverse Event Definitions ..........................................................................................30 
8.2.2. 
Dose-Limiting Toxicities ............................................................................................31 
8.2.3. 
Adverse Events of Special Interest .............................................................................31 
8.2.4. 
Adverse Event Summaries ..........................................................................................31 
8.3. 
Clinical Laboratory Tests ...........................................................................................33 
8.3.1. 
Laboratory Value Definitions .....................................................................................33 
8.3.2. 
Laboratory Value Summaries .....................................................................................33 
8.4. 
Vital Signs ..................................................................................................................34 
8.5. 
Electrocardiograms .....................................................................................................34 
9. 
INTERIM ANALYSES ..............................................................................................35 
9.1. 
Overview of Interim Analyses ....................................................................................35 
9.1.1. 
Interim Analyses for the BOIN Design ......................................................................35 
9.1.2. 
Interim Analyses for the Simon 2-Stage Design ........................................................35 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................36 
10.1. 
Changes to Protocol-Defined Analyses ......................................................................36 
10.2. 
Changes to the Statistical Analysis Plan .....................................................................36 
10.2.1. 
Original to Amendment 1 ...........................................................................................36 
11. 
REFERENCES ...........................................................................................................38 
APPENDIX A. PLANNED TABLES AND FIGURES .............................................................39 
 
LIST OF TABLES 
Table 1: 
Objectives and Endpoints .............................................................................................9 
Table 2: 
INCB001158 Dose Levels and Cohorts .....................................................................12 
Table 3: 
Dose Escalation, De-Escalation, and Elimination Boundaries for Target DLT 
Rate of 33% in Phase 1 ...............................................................................................13 
Table 4: 
Dose Escalation, De-Escalation, and Elimination Boundaries for Target DLT 
Rate of 33% for Cohort Expansion in Phase 1 ...........................................................13 
Table 5: 
Phase 2:  Simon 2-Stage Design .................................................................................14 


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Table 6: 
Treatment Groups for Participants Enrolled in Phase 1 Dose Escalation ..................19 
Table 7: 
Expansion Cohorts for Participants Enrolled in Phase 2 Tumor Expansion ..............20 
Table 8: 
Derivation of Confirmed Best Overall Response .......................................................27 
Table 9: 
RECIST v1.1 Evaluation Criteria for Overall Response:  Measurable Disease 
at Baseline ...................................................................................................................27 
Table 10: Evaluation and Censoring of Progression-Free Survival ............................................29 
Table 11: Identification of Baseline Record ...............................................................................33 
Table 12: Identification of Records for Postbaseline By-Visit Summaries ................................33 
Table 13: Criteria for Clinically Notable Vital Sign Abnormalities ...........................................34 
Table 14: Criteria for Clinically Notable Electrocardiogram Abnormalities .............................35 
Table 15: Probability of Early Termination for Simon 2-Stage Design .....................................36 
Table 16: Statistical Analysis Plan Versions ..............................................................................36 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Design ..................................................................................................11 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
AUC0-t 
area under the plasma or serum concentration-time curve from time = 0 to the last 
measurable concentration at time = t 
AUC0- 
area under the steady-state plasma or serum concentration-time curve over 1 dose 
interval 
BID 
twice daily dosing  
BOIN 
Bayesian Optimal Interval 
BOR 
best overall response 
BTC 
biliary tract cancer  
BUN 
blood urea nitrogen 
CI 
confidence interval 
Cmin 
minimum observed concentration 
Cmax 
maximum observed concentration 
CR 
complete response 
CRC 
colorectal cancer  
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
disease control rate  
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EC 
endometrial cancer  
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ECOG 
Eastern Cooperative Oncology Group 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GC 
gastroesophageal cancer  
IC90 
concentration that results in 90% inhibition 
irAE 
immune-related adverse event 
 
IV 
intravenously 


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Abbreviation 
Term 
MedDRA 
Medical Dictionary for Regulatory Activities  
MSS 
microsatellite stable 
MTD 
maximum tolerated dose 
NE 
not evaluable 
OC 
ovarian cancer 
ORR 
objective response rate 
 
 
PAD 
pharmacologically active dose 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PO 
orally 
PR 
partial response 
PT 
preferred term 
QTc 
corrected QT interval 
QTcB 
QT interval corrected using the Bazett method 
QTcF 
QT interval corrected using the Fridericia formula 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RP2D 
recommended Phase 2 dose 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
tmax 
time of occurrence of Cmax 
WHO 
World Health Organization  


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1. 
INTRODUCTION 
This is an open-label, nonrandomized, Phase 1/2 study to evaluate the safety, tolerability, and 
antitumor activity of INCB001158 in combination with 3 different chemotherapy regimens.  
Phase 1 consists of dose escalation using a BOIN design and will determine the RP2D of 
INCB001158 when given in combination with each chemotherapy regimen; efficacy will also be 
explored.  Participants with advanced or metastatic solid tumors for whom treatment with one of 
the chemotherapy regimens is appropriate are enrolled in Phase 1. 
Phase 2 evaluates ORRs using a Simon 2-stage design to determine whether the combinations 
have sufficient antitumor activity to warrant further testing in subsequent clinical studies and will 
further evaluate the safety and tolerability of the RP2D of INCB001158 when given in 
combination with chemotherapy.  Participants with advanced or metastatic CRC, BTC, OC, GC, 
and EC are enrolled in the Phase 2 expansion cohorts. 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the Study INCB 01158-203 Protocol.  The scope of this plan includes the interim and final 
analyses that are planned and will be executed by the Department of Biostatistics or 
designee.  The analyses of 
 PK  
 not described in this 
SAP. 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 01158-203 Protocol Amendment 4 dated 09 DEC 2020 and CRFs 
approved 10 DEC 2020.  Unless superseded by an amendment, this SAP will be effective for all 
subsequent Protocol amendments and eCRF versions. 
2.2. 
Study Objectives and Endpoints 
Table 1 presents the objectives and endpoints. 


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Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Phase 1:  To assess the safety and tolerability, and 
determine the RP2D of INCB001158 in combination 
with chemotherapy. 
Safety, tolerability, DLTs, and RP2D of INCB001158 
in combination with chemotherapy, as assessed by 
AEs, clinical laboratory tests, physical examination 
results, and 12-lead ECG results. 
Phase 2:  To evaluate the efficacy of INCB001158 
when given in combination with chemotherapy by 
assessing ORR per RECIST v1.1. 
ORR, defined as the percentage of participants having 
a CR or PR, as determined by investigator assessment 
of radiographic disease assessments per RECIST v1.1. 
Secondary 
Phase 2:  To assess the safety, tolerability, and RP2D 
of INCB001158 in combination with chemotherapy 
Safety and tolerability at RP2D of INCB001158 in 
combination with chemotherapy, as assessed by AEs, 
clinical laboratory tests, physical examination results, 
and 12-lead ECG results. 
To evaluate the antitumor effect of INCB001158 in 
combination with chemotherapy 
• ORR, defined as the percentage of participants
having a CR or PR, as determined by investigator
assessment of radiographic disease assessments per
RECIST v1.1 (Phase 1 only).
• DOR, defined as the time from the earliest date of
CR or PR until earliest date of disease progression or
death due to any cause, if occurring sooner than
progression, as determined by investigator
assessment of radiographic disease assessments per
RECIST v1.1.
• DCR, defined as the percentage of participants
having a CR, PR, or SD for at least 8 weeks, as
determined by investigator assessment of
radiographic disease assessments per RECIST v 1.1.
• PFS, defined as the time from the date of first dose
of study drug until the earliest date of disease
progression or death due to any cause, if occurring
sooner than progression, as determined by
investigator assessment of radiographic disease
assessments per RECIST v1.1.
To determine the PK of INCB001158 in participants 
treated with INCB001158 in combination with 
chemotherapy. 
PK of INCB001158 will be assessed by summarizing 
Cmax, tmax, Cmin, AUC0-t and AUC0-. 


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Table 1: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 


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3. 
STUDY DESIGN 
This is an open-label, nonrandomized, Phase 1/2 study to evaluate the safety, tolerability, and 
antitumor activity of INCB001158 in combination with 3 different chemotherapy regimens.   
 
3.1. 
Phase 1 – Dose Escalation 
In Phase 1, a BOIN design will be used to determine the RP2D of the combination of 
INCB001158 and chemotherapy in 21-day (for gemcitabine/cisplatin) or 28-day (for 
mFOLFOX6 or paclitaxel) treatment cycles in participants with advanced or metastatic solid 
tumors.  The RP2D will then be further assessed in tumor expansion cohorts in Phase 2. 
Dose escalation will begin with a starting dose (50 mg BID) of INCB001158 at least 2 dose 
levels below the maximum tolerated and tested dose from Study INCB 01158-101.  The doses of 
INCB001158 to be evaluated and the scenarios for dose escalation and de-escalation are 
summarized in Table 2. 


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Table 2: 
INCB001158 Dose Levels and Cohorts 
INCB001158 Dose Cohort 
INCB001158 Dose Levels for Phase 1 
-1 
25 mg BID 
1 (starting dose) 
50 mg BIDa 
2 
75 mg BID 
3 
100 mg BID 
4 
150 mg BID 
a If INCB001158 50 mg BID is not tolerated within a treatment group, INCB001158 25 mg BID may be evaluated. 
The INCB001158 dose will be escalated using an open-label BOIN design in each chemotherapy 
regimen, and a PAD or the MTD will be determined, or the maximum dose of INCB001158 
(150 mg BID) will be reached.  A PAD of INCB001158 is defined as a dose that achieves a 
trough (Cmin) plasma concentration of INCB001158 at steady state of ≥ 1 μM that is equivalent 
to the IC90 for arginase 1.  This definition may be modified based on emerging data from Study 
INCB 01158-101, the first-in-human study, upon agreement between the medical monitor and 
the study investigators.  The MTD is the maximum tolerated or tested dose of INCB001158, 
such that fewer than 33% of the participants receiving the combination experience a DLT during 
the first 28 days on study drug.  After the dose escalation is completed, one of the INCB001158 
dose levels that is pharmacologically active and tolerable in combination with each 
chemotherapy regimen (ie, MTD or lower) will be the RP2D. 
Dose interruptions and/or modifications may be implemented based on toxicity.  Dose 
modifications should not be made during the DLT observation period without discussion with 
the medical monitor.  Intraparticipant dose escalation is not permitted. 
Dose escalation and de-escalation in Phase 1 will follow the BOIN design algorithm.  Given the 
target DLT rate of 33% for the INCB001158 in combination with chemotherapy, the dose 
escalation and de-escalation rules are shown in Table 3.  The BOIN design also includes an 
elimination rule.  When ≥ 3 participants have been treated, if the probability that the estimated 
toxicity rate that is above the target DLT rate is > 95% at a certain dose level, then this dose level 
and higher dose levels are assumed to be too toxic and will be eliminated.  If the lowest dose 
level is eliminated, then the whole dose escalation will be terminated.  Table 3 (in the bottom 
row) provides the elimination rules.  Based on this algorithm, a minimum of 3 evaluable 
participants and a maximum of 9 evaluable participants will be enrolled at each tested dose level.  
The dose escalation will continue, based on the rules in Table 3, until at least 1 of the following 
occurs: 
• Enrollment of additional participants in a dose cohort that already has 9 evaluable 
participants, or 
• Dose escalation to a dose level that has already been eliminated, or 
• Dose escalation above the maximum allowable dose level identified in 
Study INCB 01158-101. 
At that point, the dose escalation will be stopped. 


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Table 3: 
Dose Escalation, De-Escalation, and Elimination Boundaries for Target DLT 
Rate of 33% in Phase 1 
Action 
Number of Participants Treated at the Current Dose 
1 
2 
3 
4 
5 
6 
7 
8 
9a 
Escalate if # of 
DLTs ≤ 
0  
0  
0  
1  
1  
1  
1  
2  
2  
De-escalate if 
# of DLTs ≥ 
1  
1  
2  
2  
2  
3  
3  
4  
4  
Elimination if 
# of DLTs ≥  
N/A  
N/A  
3  
3  
4  
4  
5  
5  
6  
a If 9 evaluable participants are enrolled in a dose cohort, and 3 of those participants experience a DLT, the medical monitor and 
the investigators will review the entirety of the data and decide whether to escalate the dose level, de-escalate the dose level, or 
stop at that dose level. 
When applying the BOIN design, a maximum of 9 evaluable participants will be used at each 
dose level for initially identifying the MTD; however, the MTD of INCB001158 for one of the 
chemotherapy combinations may be a dose level below the other MTDs.  After the PADs or 
MTDs are selected for each of the 3 combinations, the cohort may be expanded to 12 (and then 
to 15) in one of the chemotherapy combinations, and an MTD will be redetermined if all the 
following conditions are satisfied: 
• If, and only if, a single one of the chemotherapy combinations has a lower MTD than 
the others. 
• The Incyte medical monitor and the investigators review the entirety of the safety 
data and agree that the dose with the lower MTD needs to be re-challenged. 
• The de-escalation and elimination boundaries are not crossed during the dose 
rechallenge and dose levels are retested.  (Neither the de-escalation nor the 
elimination boundaries are touched.) 
For expanding the cohorts, the decisions rules are presented in Table 4. 
Table 4: 
Dose Escalation, De-Escalation, and Elimination Boundaries for Target DLT 
Rate of 33% for Cohort Expansion in Phase 1 
Action 
Number of Participants Treated at the Current Dose 
10 
11 
12 
13 
14 
15 
Escalate if # of 
DLTs ≤  
2 
2 
3 
3 
3 
3 
De-escalate if # 
of DLTs ≥  
4 
5 
5 
6 
6 
6 
Elimination if # 
of DLTs ≥  
6 
7 
7 
8 
8 
8 
 
 
 


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3.2. 
Phase 2 – Tumor Expansion Cohorts 
To determine whether the combinations result in adequate ORRs to warrant further testing in 
subsequent clinical studies, a Simon 2-stage design will be used for each tumor expansion cohort 
to evaluate the ORR of the RP2D of INCB001158 determined in Phase 1 in combination with 
chemotherapy and to further evaluate the safety and tolerability of the combination.  If, at the 
time of completion of enrollment in Stage 1, it is not known whether the target ORR to proceed 
to Stage 2 will be met, then enrollment will be paused until and unless the ORR to proceed has 
been met. 
Enrollment in a specific expansion cohort will begin when the RP2D of INCB001158 for the 
corresponding treatment group in Phase 1 has been determined. 
The expansion cohorts will be limited to the following advanced/metastatic or recurrent tumor 
types: 
• Cohort A1:  MSS-CRC (INCB001158 + mFOLFOX6) 
• Cohort B1:  BTC (INCB001158 + gemcitabine/cisplatin) 
• Cohort B2:  OC (INCB001158 + gemcitabine/cisplatin) 
• Cohort C1:  GC (INCB001158 + paclitaxel) 
• Cohort C2:  EC (INCB001158 + paclitaxel) 
• Cohort C3:  OC (INCB001158 + paclitaxel) 
Continuous evaluation of toxicity events will be performed in the expansion cohorts.  If the 
cumulative incidence of ≥ Grade 3 INCB001158-related AEs or ≥ Grade 3 chemotherapy-related 
AEs is > 40% after 10 participants are enrolled in a specific expansion cohort within Phase 2, 
then further enrollment in that cohort will be interrupted until the sponsor and investigators 
determine the appropriate course of action.  If an expansion cohort is discontinued due to 
toxicity, a new cohort may be initiated at a previously tested lower dose level. 
In each cohort, a Simon 2-stage design (see Table 5) will be used to assess the antitumor activity 
of the INCB001158 + chemotherapy combination to determine whether the combination results 
in sufficient antitumor activity to warrant further testing in subsequent clinical studies.  See 
Sections 1.1 and 1.2 of the Protocol for background and target ORRs rational for each cohort. 
Table 5: 
Phase 2:  Simon 2-Stage Design 
Cohort 
(Tumor Type) 
Backgroun
d ORR 
Target 
ORR 
Alpha 
Power 
(%) 
N for 
Stage 1 
ORR to 
Proceed 
N for 
Stage 2 
ORR for 
Positive 
Cohort 
A1 (MSS-
CRC) 
10% 
30% 
0.1 
80 
7 
≥ 1/7 
11 
≥ 4/18 
B1 (BTC) 
20% 
40% 
0.1 
80 
12 
≥ 3/12 
13 
≥ 8/25 
B2 (OC) 
15% 
35% 
0.1 
80 
9 
≥ 2/9 
14 
≥ 6/23 
C1 (GC) 
15% 
35% 
0.1 
80 
9 
≥ 2/9 
14 
≥ 6/23 
C2 (EC) 
15% 
35% 
0.1 
80 
9 
≥ 2/9 
14 
≥ 6/23 
C3 (OC) 
15% 
35% 
0.1 
80 
9 
≥ 2/9 
14 
≥ 6/23 


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3.3. 
Control of Type I Error 
For the primary efficacy endpoints, the 1-sided Type I error will be controlled at 0.1 for each 
individual cohort expansion.  Note that this level of significance does not account for the 
multiple expansion cohorts.  For other endpoints, CIs will be reported at a 95% confidence level.  
3.4. 
Sample Size Considerations 
3.4.1. 
Sample Size for Phase 1 
In Phase 1, the BOIN design will be used to determine the RP2D of INCB001158 when given in 
combination with chemotherapy in participants with advanced or metastatic solid tumors.  The 
details of the dose escalation, de-escalation, and elimination rules according to the BOIN design 
are provided in Section 3.1. 
3.4.2. 
Sample Size for Phase 2 
Phase 2 will further evaluate the safety, tolerability, preliminary efficacy, PK, and pharmacologic 
activity of the recommended dose of INCB001158 in combination with chemotherapy.  A Simon 
2-stage design will be run for each tumor type within a given expansion cohort. 
The sample size for each tumor type within a given expansion cohort will be guided by the 
Simon 2-stage design.  The planned Simon 2-stage designs are summarized in Table 5.  Each 
Simon 2-stage design will have a stopping rule to allow early termination of a particular tumor 
type within the given cohort at the end of Stage 1 if there is insufficient response observed, while 
enrolling enough participants to predict possible target responses worthy of cohort expansion and 
potentially further evaluation in future studies.  The individual Simon 2-stage designs run for 
each tumor type within each cohort will have design parameters that are determined by historical 
response rates. 
In order to determine whether the target response rate (p1%) is likely, an initial number of 
evaluable participants (n1 participants) will be treated at the RP2D of INCB001158 in 
combination with each chemotherapy (Stage 1).  If there are r1 or fewer responses in the 
expansion cohort, then it will be concluded that the true response rate is unlikely to be ≥ the 


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target rate, and no more participants will be enrolled in that tumor type for that cohort in Stage 2.  
In the cohorts in which > r1 responses are observed among the Stage 1 participants, n2 additional 
evaluable participants will be treated in Stage 2 to estimate the response rate.  At the end of 
Stage 2, if ≤ r participants have responded among the n evaluable participants, then the drug will 
be declared nonpromising for that cohort.  The detailed calculations for each tumor type–specific 
cohort are based on a 1-sided Type I error of 0.1 and power of 80%. 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Day 1 
Day 1 is the date that the first dose of study treatment (INCB001158, mFOLFOX6, 
gemcitabine/cisplatin, or paclitaxel) is administered to the participants. 
4.1.2. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (Visit/Reporting Date – Day 1 date + 1). 
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (Visit/Reporting Date – Day 1 date). 
A study day of −1 indicates 1 day before Day 1. 
4.1.3. 
Baseline Value 
Baseline is the last nonmissing measurement obtained before the first administration of 
INCB001158, mFOLFOX6, gemcitabine/cisplatin, or paclitaxel, unless otherwise defined. 
When scheduled assessments and unscheduled assessments occur on the same day and time of 
the assessment or time of first dose is not available, use the following convention to determine 
baseline: 
• If both a scheduled and an unscheduled visit are available on the day of the first dose, 
and the time is missing, use the scheduled assessment as baseline. 
• If all scheduled assessments are missing on the day of the first dose, and an 
unscheduled assessment is available, use the unscheduled assessment as baseline. 


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4.1.4. 
Handling of Missing and Incomplete Data 
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified in this section or relevant sections. 
Partial disease diagnosis date will be handled as follows: 
• If only the day is missing, then the imputed day will be the first of the month. 
• If both the month and day are missing, then the imputed day and month will be 
01 JAN. 
• No imputation will be done if the date is completely missing. 
Missing or partial date of last dose will be handled as follows: 
• If only the day is missing, then the imputed date of the last dose will be the earlier 
date of the first day of the month or the date that the participant discontinued 
treatment. 
• Otherwise, the date that the participant discontinued treatment will be used as the date 
of the last dose. 
For relevant efficacy endpoints, partial death date will be imputed as follows: 
• If mmyyyy for the last contact date = mmyyyy for the death date, then the death date 
will be set to the day after the last contact date. 
• If mmyyyy for the last contact date < mmyyyy for the death date, then the death date 
will be set to the first day of the death month. 
• Otherwise, the partial death date will not be imputed. 
4.1.5. 
Cycle Length and Duration 
Cycle 1 Day 1 is the day that the first dose of INCB001158, mFOLFOX6, gemcitabine/cisplatin, 
or paclitaxel is administered.  If mFOLFOX6, gemcitabine/cisplatin, or paclitaxel is 
discontinued, the cycle definition of INCB001158 can be maintained depending on the treatment 
group assigned (28 days for mFOLFOX6 and paclitaxel and 21 days for gemcitabine/cisplatin). 
• INCB001158:  In Phase 1 dose escalation, INCB001158 will be administrated PO 
BID with the dose corresponding to cohort assignment.  In Phase 2 expansion 
cohorts, INCB001158 will be administrated PO BID at the RP2D determined in the 
dose escalation as long as the participant is deriving benefit and has not met any of 
the Protocol-defined conditions for treatment withdrawal. 
• mFOLFOX6 
− Oxaliplatin 85 mg/m2 IV on Days 1 and 15 of a 28-day cycle. 
− Leucovorin 400 mg/m2 IV on Days 1 and 15 of a 28-day cycle. 
− 5-Fluorouracil 400 mg/m2 IV bolus on Day 1, then 1200 mg/m2 per day IV 
infusion over 46 hours for a total dose of 2400 mg/m2 on Days 1 and 15 of a 
28-day cycle. 


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• Gemcitabine and Cisplatin:  Will be administered on Days 1 and 8 of a 21-day 
cycle.  For Phase 1 dose escalation, participants with advanced or metastatic disease 
will receive gemcitabine 1000 mg/m2 IV over 30 minutes (± 5 min) and cisplatin 
30 mg/m2 IV over 30 minutes (± 5 min) on Days 1 and 8 of each 21-day cycle.  For 
Phase 2 tumor expansion cohorts, participants will receive the gemcitabine/cisplatin 
regimen that is the standard dose and schedule used for the corresponding tumor type: 
− Cohort B1 (BTC):  Gemcitabine 1000 mg/m2 IV infusion on Days 1 and 8 of a 
21-day cycle and cisplatin 25 mg/m2 IV infusion on Days 1 and 8 of each 21-day 
cycle. 
− Cohort B2 (OC):  Gemcitabine 750 mg/m2 IV infusion and cisplatin 30 mg/m2 IV 
infusion on Days 1 and 8 of a 21-day cycle. 
• Paclitaxel:  Will be administrated weekly at 80 mg/m2 IV infusion on Days 1, 8, and 
15 of a 28-day cycle. 
4.2. 
Variable Definitions 
The following variables will only be calculated if not reported on the eCRF. 
4.2.1. 
Age 
Participant age will be calculated as the integer part of the number of years from date of birth to 
the date of signing the ICF, using the following formula: 
Age = integer part of (date of informed consent – date of birth + 1) / 365.25. 
4.2.2. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first dose of 
INCB001158, mFOLFOX6, gemcitabine/cisplatin, or paclitaxel. 
Concomitant medication is defined as any nonstudy medication that is started accordingly:  
• Before the date of first administration of INCB001158, mFOLFOX6, 
gemcitabine/cisplatin, or paclitaxel and is ongoing throughout the study or ends 
on/after the date of first study drug administration. 
• On/after the date of first administration of INCB001158, mFOLFOX6, 
gemcitabine/cisplatin, or paclitaxel and is ongoing or ends during the course of study 
drug. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first dose of INCB001158, mFOLFOX6, gemcitabine/cisplatin, or paclitaxel.  
In the listing, it will be indicated whether a medication is prior-only, concomitant-only, or both 
prior and concomitant medication. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 


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5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS® software (SAS Institute Inc, Cary, NC; v9 or later) will be used 
for the generation of all tables, graphs, and statistical analyses.  Descriptive summaries for 
continuous variables will include, but not be limited to, the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Descriptive summaries for categorical 
variables will include the number and percentage of participants in each category. 
Interim analyses are planned for this study as defined in Section 9. 
5.2. 
Treatment Groups 
In Phase 1, a BOIN design will be used to determine the RP2D of the combination of 
INCB001158 and chemotherapy in 21-day (for gemcitabine/cisplatin) or 28-day (for 
mFOLFOX6 or paclitaxel) treatment cycles in participants with advanced or metastatic solid 
tumors.  The RP2D will then be further assessed in tumor expansion cohorts in Phase 2. 
Participants with advanced or metastatic solid tumors will be assigned to 1 of the treatment 
groups summarized in Table 6 based on the chemotherapy regimen most appropriate for the 
participant's tumor type. 
Table 6: 
Treatment Groups for Participants Enrolled in Phase 1 Dose Escalation 
Treatment Group A 
INCB001158 
mFOLFOX6 
25-150 mg PO BID continuous daily 
dosing  
• Oxaliplatin 85 mg/m2 IV on Days 1 and 
15 of a 28-day cycle  
• Leucovorin 400 mg/m2 IV on Days 1 
and 15 of a 28-day cycle  
• 5-Fluorouracil 400 mg/m2 IV bolus on 
Day 1, then 1200 mg/m2 per day IV 
infusion over 46 hours for a total dose 
of 2400 mg/m2 on Days 1 and 15 of a 
28-day cycle  
Treatment Group B 
INCB001158 
Gemcitabine and Cisplatin 
25-150 mg PO BID continuous daily 
dosing  
• Gemcitabine 1000 mg/m2 IV infusion 
on Days 1 and 8 of a 21-day cycle  
• Cisplatin 30 mg/m2 IV infusion on 
Days 1 and 8 of a 21-day cycle  
Treatment Group C 
INCB001158 
Paclitaxel 
25-150 mg PO BID continuous daily 
dosing  
Paclitaxel 80 mg/m2 IV infusion on 
Days 1, 8, and 15 of a 28-day cycle  
In Phase 2, the expansion cohorts will be limited to the advanced/metastatic or recurrent tumor 
types summarized in Section 3.2.  Participants will be assigned to the expansion cohorts 
summarized in Table 7. 


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Table 7: 
Expansion Cohorts for Participants Enrolled in Phase 2 Tumor Expansion 
Expansion Cohort A1 
INCB001158 
mFOLFOX6 
PO BID continuous daily dosing  
• Oxaliplatin 85 mg/m2 IV on Days 1 
and 15 of a 28-day cycle  
• Leucovorin 400 mg/m2 IV on Days 1 
and 15 of a 28-day cycle  
• 5-Fluorouracil 400 mg/m2 IV bolus on 
Day 1, then 1200 mg/m2 per day IV 
infusion over 46 hours for a total dose 
of 2400 mg/m2 on Days 1 and 15 of a 
28-day cycle  
Expansion Cohort B1 
INCB001158 
Gemcitabine and Cisplatin 
PO BID continuous daily dosing 
• Gemcitabine 1000 mg/m2 IV infusion 
on Days 1 and 8 of a 21-day cycle  
• Cisplatin 25 mg/m2 IV infusion on 
Days 1 and 8 of a 21-day cycle  
Expansion Cohort B2 
INCB001158 
Gemcitabine and Cisplatin 
PO BID continuous daily dosing 
• Gemcitabine 750 mg/m2 IV infusion 
on Days 1 and 8 of a 21-day cycle  
• Cisplatin 30 mg/m2 IV infusion on 
Days 1 and 8 of a 21-day cycle  
Expansion Cohorts C1, 
C2, and C3 
INCB001158 
Paclitaxel 
PO BID continuous daily dosing 
Paclitaxel 80 mg/m2 IV infusion on 
Days 1, 8, and 15 of a 28-day cycle  
5.3. 
Analysis Populations 
For all populations, for safety (exposure, AE, laboratory, ECG, and vital sign) analysis, Phase 1 
and Phase 2 FAS populations will be combined, and table summaries will be provided by 
treatment group and dose level; for disposition, baseline and demographic characteristics, prior 
and concomitant medication, medical history, and efficacy analysis, table summaries will be 
provided by treatment group and dose level for Phase 1 and by treatment group and expansion 
cohort (tumor type) for Phase 2. 
5.3.1. 
Full Analysis Set 
The FAS population includes all participants enrolled in the study who received at least 1 dose of 
INCB001158, mFOLFOX6, gemcitabine/cisplatin, or paclitaxel.  This population will be used in 
the analyses of demographic, baseline, safety, study treatment administration, PFS, 
 data.  
5.3.1.1. 
mFOLFOX6 FAS Population 
The mFOLFOX6 FAS population includes all participants in the FAS population who received 
at least 1 dose of any component of mFOLFOX6 (oxaliplatin, leucovorin, or 5-fluorouracil). 
5.3.1.2. 
Gemcitabine/Cisplatin FAS Population 
The gemcitabine/cisplatin FAS population includes all participants in the FAS population who 
received at least 1 dose of gemcitabine or cisplatin. 


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5.3.1.3. 
Paclitaxel FAS Population 
The paclitaxel FAS population includes all participants in the FAS population who received at 
least 1 dose of paclitaxel. 
5.3.2. 
Response Evaluable Population 
The response evaluable population includes all participants who received at least 1 dose of study 
treatment (INCB001158, mFOLFOX6, gemcitabine/cisplatin, or paclitaxel), completed a 
baseline scan, and met at least 1 of the following criteria: 
• The participant had ≥ 1 postbaseline scan. 
• The participant was on the study for a minimum of 63 days (8 weeks + 1 week 
window) days of follow-up. 
• The participant discontinued from study treatment. 
5.3.3. 
DLT Evaluable Population in Phase 1 
The DLT evaluable population includes participants enrolled in Phase 1 treated with the assigned 
dose level of INCB001158 and who have received at least 32 of the 42 doses to be given in a 21-
day cycle regimen, or at least 42 of the 56 doses prescribed for a 28-day cycle regimens (both 
representing ≥ 75% of the dose planned), or participants who have had a DLT.  This population 
will be considered evaluable for determining the tolerability of the given dose. 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES 
A list of data displays will be provided in Appendix A, and the sample data displays will be 
provided in a separate document. 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease 
History 
6.1.1. 
Demographic Characteristics 
The following demographic characteristics will be summarized for all participants in the Phase 1 
FAS population by treatment group and dose level and the Phase 2 FAS population by treatment 
group and tumor type:  age, sex, race, ethnicity, weight, height, and ECOG performance status. 
6.1.2. 
Baseline Disease Characteristics and Disease History 
Primary tumor histology, time from initial diagnosis in months, stage at initial diagnosis, current 
stage of disease, current site of disease, tumor markers, and ECOG performance status will be 
summarized for all participants in the Phase 1 FAS population by treatment group and dose level, 
and Phase 2 FAS population by treatment group and tumor type.  Tumor type–specific baseline 
characteristics and disease history will be summarized for the Phase 2 FAS population by 
treatment group and tumor type and will be provided in the listing for the Phase 1 FAS 
population by treatment group and dose level. 


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6.1.3. 
Prior Therapy 
Prior systemic cancer therapy regimens will be summarized by total number and by number of 
prior systemic cancer therapies taken for both advanced and metastatic disease for all 
participants in the Phase 1 FAS population by treatment group and dose level and the Phase 2 
FAS population by treatment group and tumor type.  Regimen name, component drugs, start and 
stop date, purpose of the regimen, best response, reason for discontinuation, and date of 
relapse/progression will be listed. 
The number (%) of participants who received prior radiation will be summarized in the Phase 1 
FAS population by treatment group and dose level and the Phase 2 FAS population by treatment 
group and tumor type.  Radiotherapy type, body site, start and stop date, total dose, and best 
response will be listed. 
The number (%) of participants who had prior surgery or surgical procedure for the malignancies 
under study will be summarized in the Phase 1 FAS population by treatment group and dose 
level and the Phase 2 FAS population by treatment group and tumor type.  Date and description 
of the surgery/procedure will be listed. 
6.1.4. 
Medical History 
Medical history will be summarized in the Phase 1 FAS population by treatment group and dose 
level and the Phase 2 FAS population by treatment group and tumor type.  This summation will 
include the number and percentage of participants with significant medical history for each body 
system/organ class as documented on the eCRF. 
6.2. 
Disposition of Participants 
The number and percentage of participants who were enrolled, screened, screen failed, treated, 
completed the study, discontinued study treatment with a primary reason for discontinuation, and 
withdrew from the study with a primary reason for withdrawal will be summarized in the Phase 1 
FAS population by treatment group and dose level and the Phase 2 FAS population by treatment 
group and tumor type.  The number of participants enrolled by country and site will also be 
provided by treatment group. 
6.3. 
Protocol Deviations  
Protocol deviations recorded on the eCRF will be presented in a table and in the participant data 
listings. 
6.4. 
Exposure 
6.4.1. 
Exposure for INCB001158 
For participants in the Phase 1 and Phase 2 combined FAS population, exposure to INCB001158 
will be summarized descriptively as the following: 
• Total actual dose (mg):  Total actual dose taken of INCB001158. 
• Duration of treatment (day):  Date of last dose of INCB001158 – date of first dose 
of INCB001158+1. 


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• Average daily dose (mg):  Total actual dose taken on INCB001158 (mg) divided by 
the duration of INCB001158 with non-zero dosing (days). 
6.4.2. 
Exposure for mFOLFOX6 
For participants in the Phase 1 and Phase 2 mFOLFOX6 FAS populations, exposure to 
mFOLFOX6 will be summarized descriptively by dose level and treatment group as follows. 
6.4.2.1. 
Exposure for Oxaliplatin 
• Number of Infusions:  Number of administered, non-zero infusions of oxaliplatin 
recorded on the Oxaliplatin Dosing eCRF. 
• Average Dose (mg/m2):  Sum of the doses of oxaliplatin recorded (mg/m2) on the 
Oxaliplatin Dosing eCRF divided by the number of infusions of oxaliplatin. 
• Dose Administered per Cycle (mg/m2):  The actual dose of oxaliplatin administered 
(mg/m2) per cycle. 
6.4.2.2. 
Exposure for Leucovorin 
• Number of Infusions:  Number of administered, non-zero infusions of leucovorin 
recorded on the Leucovorin Dosing eCRF. 
• Average Dose (mg/m2):  Sum of the doses of leucovorin recorded (mg/m2) on the 
Leucovorin Dosing eCRF divided by the number of infusions of leucovorin. 
• Dose Administered per Cycle (mg/m2):  The actual dose of leucovorin administered 
(mg2) per cycle. 
6.4.2.3. 
Exposure for 5-Fluorouracil 
• Number of Infusions:  Number of administered, non-zero infusions of 5-fluorouracil 
recorded on the 5-fluorouracil Dosing eCRF. 
• Average Dose (mg/m2):  Sum of the doses of 5-fluorouracil recorded (mg/m2) on the 
5-Fluorouracil Dosing eCRF divided by the number of infusions of 5-fluorouracil. 
• Dose Administered per Cycle (mg/m2):  The actual dose of 5-fluorouracil 
administered (mg/m2) per cycle. 
6.4.3. 
Exposure for Gemcitabine/Cisplatin 
For participants in the Phase 1 and Phase 2 gemcitabine/cisplatin FAS populations, exposure to 
gemcitabine/cisplatin will be summarized descriptively by dose level and treatment group as 
follows. 


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6.4.3.1. 
Exposure for Gemcitabine 
• Number of Infusions:  Number of administered, non-zero infusions of gemcitabine 
recorded on the Gemcitabine Dosing eCRF. 
• Average Dose (mg/m2):  Sum of the doses of gemcitabine recorded on the 
Gemcitabine Dosing eCRF divided by the number of infusions of gemcitabine. 
• Dose Administered per Cycle (mg/m2):  The actual dose of gemcitabine 
administered (mg/m2) per cycle. 
6.4.3.2. 
Exposure for Cisplatin 
• Number of Infusions:  Number of administered, non-zero infusions of cisplatin 
recorded on the Gemcitabine/Cisplatin Dosing eCRF. 
• Average Dose (mg/m2):  Sum of the doses of cisplatin recorded on the Cisplatin 
Dosing eCRF divided by the number of infusions of cisplatin. 
• Dose Administered per Cycle (mg/m2):  The actual dose of cisplatin administered 
(mg/m2) per cycle. 
6.4.4. 
Exposure for Paclitaxel 
For participants in the Phase 1 and Phase 2 paclitaxel FAS populations, exposure to paclitaxel 
will be summarized descriptively by dose level and treatment group as the following: 
• Number of Infusions:  Number of administered, non-zero infusions of paclitaxel 
recorded on the Paclitaxel Dosing eCRF. 
• Average Dose (mg/m2):  Sum of the doses of paclitaxel recorded (mg/m2) on the 
Paclitaxel Dosing eCRF divided by the number of infusions of paclitaxel. 
• Dose Administered per Cycle (mg/m2):  The actual dose of paclitaxel administered 
(mg/m2) per cycle. 
6.5. 
Study Drug Compliance 
For participants in the FAS, overall compliance (%) for INCB001158 will be calculated for all 
participants as 
Overall compliance (%) = 100  [total dose actually taken] / [total prescribed dose]. 
The total prescribed dose is defined as the sum of the doses prescribed by the investigator, 
accounting for dose modifications.   
The total actual dose taken will be calculated based on information entered on the drug 
accountability CRF.  If there is dispensed drug that has not been returned yet, the actual dose 
taken starting from the dispense date of the unreturned drug will be imputed by the dose taken as 
reported on the dosing CRF.  


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6.6. 
Prior and Concomitant Medication 
Prior medications and concomitant medications will be coded using the WHO Drug Dictionary 
and summarized by WHO drug class and WHO drug term in the Phase 1 FAS population by 
treatment group and dose level and the Phase 2 FAS population by treatment group and tumor 
type.  Results will be summarized as number and percentage of participants with prior and 
concomitant medications by PT and WHO drug class. 
7. 
EFFICACY 
Appendix A provides a list of data displays. 
7.1. 
General Considerations 
The primary efficacy endpoint for this study is ORR by investigator assessment based on 
RECIST v1.1 assessed in the Phase 2 response evaluable population.  Secondary efficacy 
endpoints of this study include ORR (Phase 1), DOR, DCR, and PFS by investigator assessment 
based on RECIST v1.1.  
7.2. 
Efficacy Hypotheses 
Each Simon 2-stage design will test the null hypothesis that the true ORR is less than or equal to 
the clinically insignificant response rate p0% against the alternative hypothesis that the true ORR 
is equal to the target rate of p1%.  For each Simon 2-stage design, the value for p0 is determined 
by a historical response rate.  The same values for p0 and p1 will be used for alternative dosing 
sequences in the same tumor type and treatment combination. 
7.3. 
Analysis of the Efficacy Parameters 
7.3.1. 
Response Criteria 
Overall disease status will be categorized using RECIST v1.1.  Participants will have their 
overall response evaluated as CR, PR, SD, PD, or NE at each postbaseline radiological 
assessment based on changes in target lesions, nontarget lesions, and appearance of new lesions. 
7.3.2. 
Objective Response Rate and Best Overall Response 
7.3.2.1. 
Confirmed ORR and Confirmed BOR by RECIST v1.1 
Per RECIST v1.1, in nonrandomized trials where response is the primary endpoint, confirmation 
of PR and CR is required to ensure responses are not the result of measurement error.  Therefore, 
a participant is defined as a confirmed objective responder if the participant has an overall 
response of CR or PR at any postbaseline visit that is confirmed at a subsequent timepoint at 
least 4 weeks later, or at the next scheduled scan (ie, 8 weeks later), whichever is clinically 
indicated, before the first occurrence of PD.  Confirmed objective responders will be assessed 
based on RECIST v1.1. 


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Confirmed ORR is defined as the proportion of participants with confirmed objective responses 
of CR or PR.  Confirmed ORR will be estimated with 95% CIs.  Confidence intervals will be 
based on the method for Simon 2-stage CIs of response rates outlined in Koyama and Chen 
(2008). 
Confirmed ORR will be summarized by treatment group and tumor type as primary endpoint for 
the Phase 2 response evaluable population. 
In general, confirmed BOR is the best response recorded postbaseline prior to and including the 
first PD, before any new anticancer therapies, in the order of CR, PR, SD, PD and NE, in which 
CR and PR must be confirmed at a subsequent timepoint at least 4 weeks after the CR or PR is 
observed.  Responses of CR, PR, or SD after the first assessment of PD will not be considered.  
In the case of SD, measurements must meet the SD criteria at least once after the date of first 
dose at a minimum interval of 49 (= 56-7) days.  Participants that fail to meet this criterion will 
have confirmed best overall response of PD, if the next available assessment indicates PD, or 
NE, if there is no additional assessment available. 
Under RECIST v1.1, if radiologic imaging shows CR or PR, a tumor assessment should be 
repeated at a minimum of 4 weeks to confirm the response in order to claim the CR or PR as the 
confirmed BOR.  If there is no second CR or PR tumor assessment, the CR or PR will be 
unconfirmed.  Table 8 lists the scenarios of responses that can occur after an unconfirmed CR or 
PR and provides a rule for determining the confirmed BOR in each scenario.   
For determination of confirmed BOR, confirmatory scans with a response of NE will be 
subsequently followed by another scan at a minimum of 4 weeks.  For example, in the case of PR 
at the first timepoint followed by NE at a subsequent timepoint, if a third scan shows a PR then 
the confirmed BOR will be PR.  There will be no third confirmatory scans performed for a loss 
of response.  For example, if a response of PR at the first timepoint is followed by a response of 
SD or PD at a subsequent timepoint, the confirmed BOR will be determined using the rules in 
Table 8. 


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Table 8: 
Derivation of Confirmed Best Overall Response 
Overall Response at First 
Timepoint 
Overall Response at 
Subsequent Timepoint 
Confirmed Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SDa,provided minimum criteria for SD 
duration are met; otherwise, PD 
CR 
PD 
SDa, provided minimum criteria for SD 
duration are met; otherwise, PD 
CR 
NE 
SDa, provided minimum criteria for SD 
duration are met; otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration are met; otherwise, PD 
PR 
NE 
SDa, provided minimum criteria for SD 
duration are met; otherwise NE 
NE 
NE 
NE 
a If a CR is truly met at the first timepoint, then any disease seen at a subsequent timepoint, even disease meeting PR criteria 
relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  Confirmed BOR would 
depend on whether the 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 participant had a PR, not a CR, at the first timepoint.  Under these 
circumstances, the original CR should be changed to a PR, and the confirmed BOR is PR. 
For participants with measurable disease at baseline, the RECIST v1.1 assessment criteria 
presented in Table 9 can be used to determine the overall disease status at a given timepoint 
based on the target lesion, nontarget lesion, and new lesion assessment. 
Table 9: 
RECIST v1.1 Evaluation Criteria for Overall Response:  Measurable Disease 
at Baseline 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
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 


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7.3.3. 
Duration of Response 
For objective responders, the DOR is the time from the first overall response contributing to an 
objective response to the earlier of the participant's death or first overall response of PD as 
assessed by RECIST v1.1 occurring after the first overall response contributing to the objective 
response.  Partial death dates will be handled using the rules described in Section 4.1.4.  
Censoring of DOR will follow the same algorithm as the censoring of PFS. 
Kaplan-Meier curves for DOR will be presented by treatment group and dose level for the 
Phase 1 response evaluable population and by treatment group and tumor type for the Phase 2 
response evaluable population.  The Kaplan-Meier estimate of median DOR will be presented 
with its 95% CI.  The 95% CI will be calculated using Brookmeyer and Crowley's method 
(Brookmeyer and Crowley 1982).   
7.3.4. 
Disease Control Rate 
Disease control rate, defined as the proportion of participants who have disease control (CR + PR 
+ SD for at least 8 weeks), as per RECIST v1.1 will be summarized.  For the determination of 
DCR, responses of CR and PR do not need to be confirmed at a subsequent timepoint.  In the 
case of SD, measurements must meet the SD criteria at least after the date of first dose at a 
minimum of 49 (= 56-7) days.  Participants who fail to meet this criterion will have confirmed 
BOR of PD if the next available assessment indicated PD or NE if there is no additional 
assessment available.  Disease control rate will be estimated with 95% CIs.  Confidence intervals 
will be calculated based on the exact method for binomial distributions. 
7.3.5. 
Largest Percent Reduction in Sum of Diameters of Target Lesions 
For each participant in the response evaluable population with target lesions at baseline, target 
lesion sizes will be measured by sum of diameters.  The best percentage change from baseline, 
defined as the largest decrease (or the smallest increase if there is no decrease) in target lesion 
size for each participant, will be summarized descriptively, and a waterfall plot of the best 
percentage change will be generated. 
Per RECIST v1.1, target lesions considered "too small to measure" will be assigned a default 
value of 5 mm for purposes of this analysis.  Likewise, target lesions identified as "not present" 
at postbaseline assessments will be assigned 0 mm for this analysis.  In the event a target lesion 
is unaccounted for in a particular postbaseline timepoint (ie, assessment missing or NE), then the 
overall sum of diameters for target lesions will not be evaluable for that postbaseline timepoint. 
7.3.6. 
Percentage Change in Sum of Diameters of Target Lesions Over Time 
For each participant in the response evaluable population with target lesions at baseline, target 
lesion sizes will be measured by sum of diameters.  The percentage change in sum of diameter of 
target lesions over time will be listed, and a spider plot will be generated. 
7.3.7. 
Progression-Free Survival 
Progression-free survival is defined as the length of time between the date of first dose of study 
drug and the earlier of death or PD as assessed by RECIST v1.1.  Date of death will be 


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determined using the Death Report, the Survival Follow-Up, and the Subject Status eCRFs, and 
analyses will be summarized for the FAS population. 
Censoring for PFS will follow the algorithm outlined in Table 10, which is based on the FDA 
Guidance for Industry:  Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 
(FDA 2015, FDA 2018).  
Kaplan-Meier curves for PFS will be presented by cohort-specific tumor type.  The 
Kaplan-Meier estimate of median PFS will be presented with its 95% CI.  The 95% CI will be 
calculated using Brookmeyer and Crowley's method (Brookmeyer and Crowley 1982). 
Table 10: 
Evaluation and Censoring of Progression-Free Survival 
Situation 
Outcome 
Date of Progression or Censoring 
No baseline tumor assessments 
Censored 
Date of Day 1 
No valid postbaseline response assessments 
Censored 
Date of Day 1 
Progression documented between scheduled 
response assessments 
Progressed 
Date of first overall response of PD 
No progression 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing) 
Study discontinuation for undocumented 
progression 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing) 
Study discontinuation for toxicity or other reason 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing) 
New anticancer treatment started 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing). 
Death before first progressive response 
assessment 
Progressed 
Date of death 
Death between adequate response assessments 
Progressed 
Date of death 
Death or progression after more than 1 missed 
assessment 
Censored 
Date of last valid radiologic assessment 
(not NE and not missing) before death 


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8. 
SAFETY AND TOLERABILITY 
Appendix A provides a list of data displays. 
8.1. 
General Considerations 
Phase 1 and Phase 2 FAS populations will be combined for safety analysis, and table summaries 
will be provided by treatment group and dose level.  Summary tables may be replaced with 
listings when appropriate.  For instance, an AE frequency table may be replaced with a listing if 
it only contains a few unique PTs reported on relatively few participants. 
Unless otherwise stated, table summaries will be limited to TEAEs. 
8.2. 
Adverse Events 
8.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first dose of study drug.  For the participants in the FAS population, analysis of AEs (as 
discussed below) will be limited to TEAEs, but data listings will include all AEs regardless of 
their timing in relation to study drug administration. 
Adverse events will be tabulated by MedDRA v20.1 PT and SOC.  Severity of AEs will be 
graded using the National Cancer Institute CTCAE.  The CTCAE v4.03 is used for this study.  
The CTCAE reporting guidelines and grading details are available on the Cancer Therapy 
Evaluation Program website. 
The subset of AEs considered by the investigator to be related to INCB001158, mFOLFOX6, 
gemcitabine/cisplatin, or paclitaxel will be considered to be treatment-related AEs and will be 
summarized.  If the investigator does not specify the relationship of the AE to study drug, the AE 
will be considered to be treatment-related.  The incidence of AEs and treatment-related AEs will 
be tabulated.  In addition, SAEs will also be tabulated. 
A grading (severity) scale is provided for each AE term.  If the toxicity is not included in the 
CTCAE v4.03 criteria, it will be rated on a scale of 1 to 5 as follows: 1 = mild, 2 = moderate, 
3 = severe, 4 = life threatening, and 5 = death related to AE.  All toxicities will be graded based 
on the worst level reached, not the level they may have reached if they had not been treated.  
When the intensity of an AE changes over time for a reporting period (eg, between visits), each 
change in intensity will be collected as an AE until the event resolves.  Only the worst grade will 
be reported in AE summaries.  Also, the Grade 3 or higher AEs will be summarized. 
Any missing onset date, causality, or severity must be queried for resolution.  Unresolved 
missing causality and severity will be handled according to the following rules: 
• An unresolved missing causality will be considered treatment-related. 
• An unresolved missing severity will be identified as an unknown severity.  
For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment emergent. 


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8.2.2. 
Dose-Limiting Toxicities 
The number of participants in the DLT evaluable population with DLTs and the type of DLT will 
be listed by dose level and treatment group.  An AE for a participant will be identified as a DLT 
if the event is recorded as a Protocol-defined DLT on the Adverse Event eCRF. 
8.2.3. 
Adverse Events of Special Interest 
Adverse events of special interest include irAEs that are seen with immunotherapy and any other 
observed autoimmune phenomenon. 
An overall summary of irAEs by treatment group and dose level for the Phase 1 and Phase 2 
combined FAS population as applicable will include the following: 
• Number (%) of participants reporting any irAEs 
• Number (%) of participants reporting any Grade 3 or higher irAEs 
• Number (%) of participants reporting any irAEs related to INCB001158 
• Number (%) of participants who had fatal irAEs 
• Number (%) of participants who had irAEs leading to temporary interruption of 
INCB001158  
• Number (%) of participants who had irAEs leading to permanent discontinuation of 
INCB001158 
• Number (%) of participants who had irAEs leading to INCB001158 dose reductions 
8.2.4. 
Adverse Event Summaries 
An overall summary of AEs by treatment group and dose level for the Phase 1 and Phase 2 
combined FAS population as applicable will include the following: 
• Number (%) of participants reporting any TEAEs 
• Number (%) of participants reporting any SAEs 
• Number (%) of participants reporting any Grade 3 or higher TEAEs 
• Number (%) of participants reporting any TEAEs related to INCB001158 
• Number (%) of participants reporting any TEAEs related to chemotherapy 
• Number (%) of participants reporting any TEAEs related to INCB001158 and/or 
chemotherapy 
• Number (%) of participants reporting any Grade 3 or higher TEAEs related to 
INCB001158 
• Number (%) of participants reporting any SAEs related to INCB001158 and/or 
chemotherapy 
• Number (%) of participants reporting any Grade 3 or higher TEAEs related to 
INCB001158 and/or chemotherapy 


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• Number (%) of participants who had TEAEs leading to temporary interruption of 
INCB001158  
• Number (%) of participants who had TEAEs leading to permanent discontinuation of 
INCB001158 
• Number (%) of participants who had TEAEs leading to INCB001158 dose reductions  
• Number (%) of participants who had fatal TEAEs 
• Number (%) of participants who had TEAEs leading to study withdrawal 
• Number (%) of participants who had irAEs 
The following summaries will be produced by MedDRA term for the Phase 1 and Phase 2 
combined FAS population: 
• Summary of TEAEs by SOC and PT 
• Summary of TEAEs by PT in decreasing order of frequency 
• Summary of Grade 3 or higher TEAEs by PT in decreasing order of frequency 
• Summary of treatment-emergent SAEs by PT in descending order of frequency 
• Summary of INCB001158 treatment-related TEAEs by PT in decreasing order of 
frequency 
• Summary of mFOLFOX6 treatment-related TEAEs by PT in decreasing order of 
frequency 
• Summary of gemcitabine/cisplatin treatment-related TEAEs by PT in decreasing 
order of frequency 
• Summary of paclitaxel treatment-related TEAEs by PT in decreasing order of 
frequency 
• Summary of Grade 3 or higher INCB001158 treatment-related TEAEs by PT in 
decreasing order of frequency 
• Summary of TEAEs with a fatal outcome by SOC and PT 
• Summary of TEAEs leading to INCB001158 dose reduction by PT in decreasing 
order of frequency 
• Summary of TEAEs leading to INCB001158 dose interruption by PT in decreasing 
order of frequency 
• Summary of TEAEs leading to discontinuation of INCB001158 by PT in decreasing 
order of frequency 
• Summary of immune-related TEAEs by PT in decreasing order of frequency 


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8.3. 
Clinical Laboratory Tests 
8.3.1. 
Laboratory Value Definitions 
Laboratory values and change from baseline values will be summarized descriptively by visit.  
The baseline value will be determined using the nonmissing values collected before the first dose 
using the priority defined in Table 11.  The last record before administration in the highest 
priority will be considered the baseline record.  For baseline laboratory candidates with the same 
date and time in the same priority category, additional rules may be provided after consultation 
with the medical monitor to delineate which value will be defined as baseline. 
Table 11: 
Identification of Baseline Record 
Priority 
Laboratory Visit 
Central or Local Laboratory 
1 
Scheduled 
Central 
2 
Scheduled 
Local 
3 
Unscheduled 
Central 
4 
Unscheduled 
Local 
Laboratory test values will be assessed for severity based on the numerical component of 
CTCAE v4.03. 
8.3.2. 
Laboratory Value Summaries 
All test results and associated normal ranges from central laboratories will be reported in SI 
units.  Any laboratory test results and associated normal ranges from local laboratories will be 
converted to SI units. 
When there are multiple nonmissing laboratory values for a participant's particular test within a 
visit window, the convention described in Table 12 will be used to determine the record used for 
by-visit tabulations and summaries.  If a tie still exists, the laboratory value with the smallest 
laboratory sequence number will be used. 
Table 12: 
Identification of Records for Postbaseline By-Visit Summaries 
Priority 
Laboratory Visit 
Central or Local 
Laboratory 
Proximity to Visit 
Window 
Tiebreaker 
1 
Scheduled 
Central 
In-window 
Use smallest 
laboratory sequence 
number 
2 
Scheduled 
Local 
In-window 
3 
Unscheduled 
Central 
In-window 
4 
Unscheduled 
Local 
In-window 
5 
Scheduled 
Central 
Out-of-window 
6 
Scheduled 
Local 
Out-of-window 
For coagulation and urinalysis laboratory values, listings will be provided. 


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Numeric chemistry and hematology laboratory values will be summarized descriptively in SI 
units, and non-numeric test values will be tabulated when necessary.  
Severity grades will be assigned to laboratory test values based on the numerical component of 
CTCAE v4.03.  The number of participants who experienced worsening of laboratory 
abnormalities will be summarized by maximum severity. 
In cases where differentials of hematology parameters are obtained without corresponding 
absolute count data, efforts will be made to investigate if the conversion to an absolute value will 
lead to additional abnormalities.  This will be discussed with the clinical team regarding 
appropriate documentation and action. 
8.4. 
Vital Signs 
Values at each scheduled visit, change, and percent change from baseline for vital signs, 
including systolic blood pressure and diastolic blood pressure, will be summarized descriptively.  
Listings will be provided for all vital sign parameters. 
Normal ranges for vital sign values are defined in Table 13.  For participants exhibiting vital sign 
abnormalities, the abnormal values will be listed along with their assigned treatment group.   
Table 13: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24 breaths/min 
< 8 breaths/min 
8.5. 
Electrocardiograms 
Twelve-lead ECGs including heart rate, PR, QRS, QT, and QTc (or QTcF, QTcB) intervals will 
be obtained for each participant at the screening, end of treatment, and safety follow-up visits 
during the study.  Baseline will be determined as the average of all nonmissing values before the 
first administration of INCB001158, mFOLFOX6, gemcitabine/cisplatin, or paclitaxel. 
Normal ranges for ECG values are defined in Table 14.  Electrocardiogram values will also be 
considered abnormal if the absolute percentage change from baseline is more than 25% (30% for 
QRS interval).  Participants exhibiting ECG abnormalities will be listed with study visit and 
assigned treatment group.  Outliers of QT and QTcF values, defined as absolute values 
> 450 milliseconds, > 500 milliseconds, or change from baseline > 30 milliseconds, will be 
summarized. 


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Table 14: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
PR  
> 220 ms 
< 75 ms 
QRS  
> 120 ms 
< 50 ms 
QT  
> 500 ms 
< 300 ms 
QTc, QTcF, QTcB  
> 480 ms 
< 295 ms 
RR 
> 1330 ms 
< 600 ms 
RR = 60,000 ms/heart rate. 
9. 
INTERIM ANALYSES 
9.1. 
Overview of Interim Analyses 
9.1.1. 
Interim Analyses for the BOIN Design 
In Phase 1, the BOIN design will be used to determine the RP2D of INCB001158 in combination 
with each chemotherapy regimen.  For the design parameters, let 𝜙 denote the target DLT rate, 
𝜙1denote the highest toxicity probability below the MTD so that dose escalation is required, and 
𝜙2 denote the lowest toxicity probability deemed overly toxic so that dose de-escalation is 
required.  We assume that 𝜙1 = 0.6𝜙 and 𝜙2 = 1.4𝜙.  Also, to avoid assigning too many 
participants to an overly toxic dose, we use the dose elimination rule when implementing the 
BOIN design.  If pr(pj > 𝜙|mj,nj) > 0.95 and nj ≥ 3, then dose levels 𝑗 and higher are eliminated 
from the study, and the study is terminated if the first dose level is eliminated, where pj 
represents the toxicity rate, 𝜙 represents the target DLT rate, nj represents the total participants 
who have been treated, and mj represents the participants who have experienced toxicity at dose 
level 𝑗.  Table 3 (in the bottom row) provides the elimination boundaries for the target DLT rate 
of 33%, respectively.  For example, for the target DLT rate 33%, when the number of 
participants treated at the current dose nj = 4, we will eliminate that dose and higher doses if 3 or 
more participants experience toxicity. 
Based on the algorithm of the BOIN design, a minimum of 3 evaluable participants will be 
enrolled in each dose level with a maximum of 9 evaluable participants in each dose level. 
9.1.2. 
Interim Analyses for the Simon 2-Stage Design 
In Phase 2, there will be a planned interim analysis for futility in each of the 6 expansion cohorts.  
The Simon 2-stage design will be applied for each expansion cohort independently.  During 
Stage 1, n1 evaluable participants treated at the recommended dose and schedule will be enrolled 
(see Table 5), and if r1or fewer responses are observed, then the cohort will be discontinued.  The 
Simon 2-stage designs for each tumor type have design parameters determined by historical 
response rates and will have different sample sizes and different futility rules, depending on the 
historical response rate.  Based on this early termination rule, the probabilities of early 
termination under the assumption of treatment interruption response rates (H0) and desired 
response rates (HA) are summarized in Table 15. 


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Table 15: 
Probability of Early Termination for Simon 2-Stage Design 
Cohort (Tumor Type) 
p0 
p1 
Probability of Early Termination 
Under H0 
Under HA 
A1 (MSS-CRC)  
15%  
35%  
0.5995  
0.1211  
B1 (BTC)  
20%  
40%  
0.5583  
0.0834  
B2 (OC)  
15%  
35%  
0.5995  
0.1211  
C1 (GC)  
15%  
35%  
0.5995  
0.1211  
C2 (EC)  
15%  
35%  
0.5995  
0.1211  
C3 (OC)  
15%  
35%  
0.5995  
0.1211  
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 16.  
Table 16: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
26 JUL 2018 
Amendment 1 
08 MAR 2021 
10.1. 
Changes to Protocol-Defined Analyses 
Not applicable. 
10.2. 
Changes to the Statistical Analysis Plan 
10.2.1. 
Original to Amendment 1 
• 
 
 
• Section 5.3 was revised to change the general approach to display summary tables:  
for safety (exposure, AE, laboratory, ECG, and vital sign) analysis, Phase 1 and Phase 
2 FAS populations will be combined, and table summaries will be provided by 
treatment group and dose level; for disposition, baseline and demographic 
characteristics, prior and concomitant medication, medical history, and efficacy 
analysis, table summaries will be provided by treatment group and dose level for 
Phase 1 and by treatment group and expansion cohort (tumor type) for Phase 2. 
• Section 6.5 was added to include the description for the calculation of study drug 
compliance.  Planned tables for the summary of drug compliance were added to 
Appendix A. 
• 
  
  


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• Section 8.2.4 was updated to remove AE summary tables that were not important. 
• A summary table and a listing were planned for orotic acid, BUN/urea, and ammonia 
for potential urea cycle inhibition and added to Appendix A. 
In addition, other minor, administrative changes have been incorporated throughout the SAP and 
are noted in the redline version of the amendment. 
 
 
 


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11.
REFERENCES
 
 
Food and Drug Administration. Guidance for Industry: Clinical Trial Endpoints for the Approval 
of Cancer Drugs and Biologics. 2018.  
Food and Drug Administration. Guidance for Industry: Clinical Trial Endpoints for the Approval 
of Non-Small Cell Lung Cancer Drugs and Biologics. 2015.  
Koyama T, Chen H. Proper inference from Simon's two-stage designs. Stat Med 
2008;27:3145-3154. 
Liu S, Yuan Y. Bayesian optimal interval designs for phase I clinical trials. J R Stat Soc Ser C 
Appl Stat 2015;64:507-523. 


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APPENDIX A. PLANNED TABLES AND FIGURES 
This appendix provides a list of the planned tables and figures for the clinical study report.  
Standard tables will follow the conventions in the Standard Safety Tables version. 
The lists of tables, figures, and listings and the shells are to be used as guidelines.  Modifications 
to the list or shells that do not otherwise affect the nature of the analysis will not warrant an 
amendment to the SAP. 
Tables 
Table No. 
Title 
Population 
Standard 
In-Text 
1.1 Disposition 
1.1.1.1 
Summary of Participants Screened and Screen Failures 
All Enrolled 
X 
X 
1.1.1.2 
Analysis Populations  
Phase 1 FAS   
X 
X 
1.1.1.3 
Analysis Populations 
Phase 2 FAS   
X 
X 
1.1.2.1 
Summary of Participant Disposition 
Phase 1 FAS   
X 
X 
1.1.2.2 
Summary of Participant Disposition 
Phase 2 FAS   
X 
X 
1.1.3 
Summary of Number of Participants Enrolled by Country 
and Site 
FAS   
X 
 
1.2 Demography 
1.2.1 
Summary of Demographics  
Phase 1 FAS   
X 
X 
1.2.2 
Summary of Demographics  
Phase 2 FAS   
X 
X 
1.3 Baseline Characteristics 
1.3.1.1 
Summary of Baseline Disease Characteristics and Disease 
History – Solid Tumor Types 
Phase 1 FAS   
X 
 
1.3.1.2 
Summary of Baseline Disease Characteristics and Disease 
History – Solid Tumor Types 
Phase 2 FAS   
X 
 
1.3.3.2 
Summary of Baseline Disease Characteristics and Disease 
History – Colorectal Cancer 
Phase 2 FAS   
X 
 
1.3.4.2 
Summary of Baseline Disease Characteristics and Disease 
History – Endometrial Cancer 
Phase 2 FAS   
X 
 
1.3.5.2 
Summary of Baseline Disease Characteristics and Disease 
History – Gastric Cancer 
Phase 2 FAS   
X 
 
1.3.9.2 
Summary of Baseline Disease Characteristics and Disease 
History – Ovarian Cancer 
Phase 2 FAS   
X 
 
1.3.11.2 
Summary of Baseline Disease Characteristics and Disease 
History – Cholangiocarcinoma 
Phase 2 FAS   
X 
 
1.4 Prior Medication and Concomitant Medication 
1.4.1.1 
Summary of Prior Systemic Therapy 
Phase 1 FAS   
X 
 
1.4.1.2 
Summary of Prior Systemic Therapy 
Phase 2 FAS   
X 
 
1.4.2.1 
Summary of Prior Medications 
Phase 1 FAS   
X 
 
1.4.2.2 
Summary of Prior Medications 
Phase 2 FAS   
X 
 
1.4.3.1 
Summary of Prior Radiation  
Phase 1 FAS   
X 
 
1.4.3.2 
Summary of Prior Radiation  
Phase 2 FAS   
X 
 
1.4.4.1 
Summary of Prior Surgery 
Phase 1 FAS   
X 
 
1.4.4.2 
Summary of Prior Surgery 
Phase 2 FAS   
X 
 
1.4.5.1 
Summary of Concomitant Medications 
Phase 1 FAS   
X 
 
1.4.5.2 
Summary of Concomitant Medications 
Phase 2 FAS   
X 
 


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Table No. 
Title 
Population 
Standard 
In-Text 
1.5 Others 
1.5.1 
Summary of General Medical History 
Phase 1 FAS   
X 
 
1.5.2 
Summary of General Medical History 
Phase 2 FAS   
X 
 
1.5.3 
Summary of Protocol Deviations 
FAS 
 
X 
2.1 Efficacy 
2.1.1 
Summary of Confirmed Best Overall Response, Objective 
Response Rate, Duration of Response, and Disease Control 
Rate Under RECIST v1.1 – by Treatment Group and Dose 
Level 
Phase 1 Response 
Evaluable 
Population 
 
X 
2.1.2 
Summary of Confirmed Best Overall Response, Objective 
Response Rate, Duration of Response, and Disease Control 
Rate Under RECIST v1.1 – by Treatment Group and Tumor 
Type 
Phase 2 Response 
Evaluable 
Population 
 
X 
2.2.1 
Summary of Progression-Free Survival Under RECIST v1.1 
– by Treatment Group and Dose Level 
Phase 1 FAS 
 
X 
2.2.2 
Summary of Progression-Free Survival Under RECIST v1.1 
– by Treatment Group and Tumor Type 
Phase 2 FAS 
 
X 
3.1 Dose Exposure 
3.1.1.1 
Summary of INCB001158 Drug Exposure – by Treatment 
Group and Dose Level 
FAS 
X 
X 
3.1.1.2 
Summary of INCB001158 Drug Compliance – by Treatment 
Group and Dose Level 
FAS 
X 
X 
3.1.2.1 
Summary of Oxaliplatin Drug Exposure – by Treatment 
Group and Dose Level 
mFOLFOX6 FAS 
X 
X 
3.1.2.2 
Summary of Leucovorin Drug Exposure – by Treatment 
Group and Dose Level 
mFOLFOX6 FAS 
X 
X 
3.1.2.3 
Summary of 5-Fluorouracil Drug Exposure – by Treatment 
Group and Dose Level 
mFOLFOX6 FAS 
X 
X 
3.1.3.1 
Summary of Gemcitabine Drug Exposure – by Treatment 
Group and Dose Level 
Gemcitabine/ 
Cisplatin FAS 
X 
X 
3.1.3.2 
Summary of Cisplatin Drug Exposure – by Treatment Group 
and Dose Level 
Gemcitabine/ 
Cisplatin FAS 
X 
X 
3.1.4.1 
Summary of Paclitaxel Drug Exposure – by Treatment Group 
and Dose Level 
Paclitaxel FAS 
X 
X 
3.2 Adverse Events 
3.2.1 
Overall Summary of Treatment-Emergent Adverse Events – 
by Treatment Group and Dose Level 
FAS 
X 
X 
3.2.2 
Summary of Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term – by 
Treatment Group and Dose Level 
FAS 
X 
X 
3.2.3 
Summary of Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
– by Treatment Group and Dose Level 
FAS 
X 
X 
3.2.4 
Summary of Grade 3 or Higher Treatment-Emergent 
Adverse Events by MedDRA Preferred Term in Decreasing 
Order of Frequency – by Treatment Group and Dose Level 
FAS 
X 
X 
3.2.5 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
– by Treatment Group and Dose Level 
FAS 
X 
X 


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Table No. 
Title 
Population 
Standard 
In-Text 
3.2.6 
Summary of INCB001158 Treatment-Related Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency – by Treatment Group and Dose Level 
FAS 
X 
X 
3.2.7 
Summary of mFOLFOX6 Treatment-Related Adverse 
Events by MedDRA Preferred Term in Decreasing Order of 
Frequency – by Dose Level 
mFOLFOX6 FAS 
X 
X 
3.2.8 
Summary of Gemcitabine/Cisplatin Treatment-Related 
Adverse Events by MedDRA Preferred Term in Decreasing 
Order of Frequency – by Dose Level 
Gemcitabine/ 
Cisplatin FAS 
X 
X 
3.2.9 
Summary of Paclitaxel Treatment-Related Adverse Events 
by MedDRA Preferred Term in Decreasing Order of 
Frequency – by Dose Level 
Paclitaxel FAS 
X 
X 
3.2.10 
Summary of Grade 3 or Higher INCB001158 Treatment-
Related Adverse Events by MedDRA Preferred Term in 
Decreasing Order of Frequency – by Treatment Group and 
Dose Level 
FAS 
X 
X 
3.2.11 
Summary of Treatment-Emergent Adverse Events Leading to 
INCB001158 Dose Reduction by MedDRA Preferred Term 
in Decreasing Order of Frequency – by Treatment Group and 
Dose Level 
FAS 
X 
X 
3.2.12 
Summary of Treatment-Emergent Adverse Events Leading to 
INCB001158 Dose Interruption by MedDRA Preferred Term 
in Decreasing Order of Frequency – by Treatment Group and 
Dose Level 
FAS 
X 
X 
3.2.13 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of INCB001158 by MedDRA Preferred 
Term in Decreasing Order of Frequency – by Treatment 
Group and Dose Level 
FAS 
X 
X 
3.2.14 
Summary of fatal Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term – by 
Treatment Group and Dose Level 
FAS 
X 
X 
3.2.15 
Summary of Immune-Related Treatment-Emergent Adverse 
Events (Investigator-Identified) by MedDRA Preferred Term 
in Decreasing Order of Frequency – by Treatment Group and 
Dose Level 
FAS 
X 
X 
3.2.16 
Overall Summary of Immune-Related Treatment-Emergent 
Adverse Events (Investigator-Identified) – by Treatment 
Group and Dose Level 
FAS 
X 
X 
3.3 Laboratory 
3.3.1 
Summary of Laboratory Values – Hematology 
FAS 
X 
 
3.3.2 
Summary of Treatment-Emergent Worsening of Laboratory 
Abnormalities – Hematology 
FAS 
X 
 
3.3.3 
Summary of Laboratory Values – Chemistry 
FAS 
X 
 
3.3.4 
Summary of Treatment-Emergent Worsening of Laboratory 
Abnormalities – Chemistry 
FAS 
X 
 
3.3.5 
Summary of Clinical Laboratory Values Indicative of 
Potential Urea Cycle Inhibition  
 
FAS 
 
 
3.4 Vital Signs 
3.4.1 
Summary of Systolic Blood Pressure (mmHg) 
FAS 
X 
 
3.4.2 
Summary of Diastolic Blood Pressure (mmHg) 
FAS 
X 
 
3.5 ECGs 
3.5.8 
Summary of Outliers of QT, QTc, QTcB, and QTcF Interval 
Values (ms) from 12-Lead ECG by Visit 
FAS 
X 
X 


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Figures 
Figure No. 
Title 
Population 
2.1.1 
Kaplan-Meier Estimates of Progression-Free Survival 
Phase 1 FAS 
2.1.2 
Kaplan-Meier Estimates of Progression-Free Survival 
Phase 2 FAS 
2.3.1 
Swim Plot of Duration of Response (confirmed) – by 
Treatment Group and Dose 
Phase 1 FAS 
2.3.2 
Swim Plot of Duration of Response (confirmed) – by 
Treatment Group and Tumor Type 
Phase 2 FAS 
2.4.1 
Waterfall Plot of Percent Change from Baseline in Sum of 
Target Lesions – by Treatment Group and Dose Level 
Phase 1 FAS 
2.4.2 
Waterfall Plot of Percent Change from Baseline in Sum of 
Target Lesions – by Treatment Group and Tumor Type 
Phase 2 FAS 
2.5.1 
Spider Plot of Percent Change from Baseline in Sum of 
Target Lesions – by Treatment Group and Dose Level 
Phase 1 FAS 
2.5.2 
Spider Plot of Percent Change from Baseline in Sum of 
Target Lesions – by Treatment Group and Tumor Type 
Phase 2 FAS 
6.3.1 
Box-and-Whisker Plot of Maximum Orotic Acid Elevation 
FAS 
Listings 
Listing No. 
Title 
2.1.2 
Participant Enrollment and Disposition Status 
2.1.3 
Participant Inclusion and Exclusion Criteria Violations 
2.2.1 
Protocol Deviations and Violations 
2.3.1 
Analysis Populations 
2.4.1 
Demographics  
2.4.2.1 
Baseline Disease Characteristics – Solid Tumor Types 
2.4.2.2 
Baseline Disease Characteristics –Breast Cancer 
2.4.2.3 
Baseline Disease Characteristics – Colorectal Cancer 
2.4.2.4 
Baseline Disease Characteristics – Endometrial Cancer 
2.4.2.5 
Baseline Disease Characteristics – Gastric Cancer 
2.4.2.6 
Baseline Disease Characteristics – Non–Small Cell Lung Cancer 
2.4.2.7 
Baseline Disease Characteristics – Ovarian Cancer 
2.4.2.8 
Baseline Disease Characteristics – Pancreatic Cancer 
2.4.2.9 
Baseline Disease Characteristics – Cholangiocarcinoma 
2.4.4 
Prior Radiation Treatment 
2.4.5 
Prior Systemic Therapy 
2.4.6 
Prior Surgery or Surgical Procedure 
2.4.7 
Medical History 
2.4.8 
Prior and Concomitant Medication 
2.4.9 
Post-Treatment Anticancer Therapy 
2.5.1.1 
Study Drug Administration for INCB001158  
2.5.1.2 
Study Drug Compliance for INCB001158 
2.5.2 
Study Drug Administration for mFOLFOX6 
2.5.3 
Study Drug Administration for Gemcitabine/Cisplatin 
2.5.4 
Study Drug Administration for Paclitaxel 


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2.6.3.1.1 
Overall Response Assessment Under RECIST v1.1 – Phase 1 
2.6.3.1.2 
Overall Response Assessment Under RECIST v1.1 – Phase 2 
2.6.4.1 
Response Assessment:  Target Lesions – Phase 1 
2.6.4.2 
Response Assessment:  Target Lesions – Phase 2 
2.6.5.1 
Response Assessment:  Non-Target Lesions – Phase 1 
2.6.5.2 
Response Assessment:  Non-Target Lesions – Phase 2 
2.6.6.1 
Response Assessment:  New Lesions–  Phase 1 
2.6.6.2 
Response Assessment:  New Lesions – Phase 2 
2.6.7.1 
ECOG Status – Phase 1 
2.6.7.2 
ECOG Status – Phase 2 
2.6.8.1 
Confirmed Best Overall Response, Objective Response Rate, Duration of Response Under RECIST v1.1 
2.6.8.2 
Confirmed Best Overall Response, Objective Response Rate, Duration of Response Under RECIST v1.1 
2.7.1 
Adverse Events 
2.7.2 
Dose-Limiting Toxicities 
2.7.3 
Serious Adverse Events 
2.7.4 
Fatal Adverse Events 
2.7.5 
Adverse Events Leading to Discontinuation of INCB001158 
2.7.6 
Investigator-Identified Immune-Related Adverse Events 
2.8.1.1 
Clinical Laboratory Values – Hematology 
2.8.1.2 
Clinical Laboratory Values – Chemistry 
2.8.1.3 
Clinical Laboratory Values – Orotic Acid, BUN/Urea, and Ammonia for Potential Urea Cycle Inhibition 
2.8.1.4 
Abnormal Clinical Laboratory Values – Hematology 
2.8.1.5 
Abnormal Clinical Laboratory Values – Chemistry 
2.8.1.6 
PK Blood Sampling Times 
2.8.2.1 
Vital Signs 
2.8.2.2 
Abnormal Vital Sign Values 
2.8.3.1 
12-Lead Local ECG Values 
2.8.3.2 
Abnormal 12-Lead Local ECG Values