Clinical trial NCT02166905
Conditions: Fallopian Tube Carcinoma Ovarian Carcinoma Primary Peritoneal Carcinoma
Sponsor: Roswell Park Cancer Institute
Start date: 2014-10-10; Completion date: 2020-08-20
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This partially randomized phase I/IIb trial studies the side effects and best dose of IDO1 inhibitor INCB024360 in combination with DEC-205/NY-ESO-1 fusion protein CDX-1401 and poly ICLC and to see how well they work in treating patients with ovarian, fallopian tube, or primary peritoneal cancer who no longer have evidence of disease. Antigens (such as cancer/testis antigen \[NY-ESO-1\] protein) are found on many cancer cells. Vaccines made from NY-ESO-1 protein may cause the immune system to produce immune cells and antibodies that may help locate the NY-ESO-1 and/or cancer/testis antigen 2 (LAGE-1) antigens on cancer cells. By finding them, the immune system may then work to control or eliminate the remaining cancer cells. INCB024360 is an inhibitor of an enzyme called indoleamine 2,3 dioxygenase (IDO). This enzyme is produced by tumor cells to disable immune cells, and limit the efficacy of immune attack. Giving DEC-205/NY-ESO-1 fusion protein CDX-1401 with poly ICLC and IDO1 inhibitor INCB024360 may generate stronger and more long lasting anti-cancer immune responses in patients with ovarian, fallopian tube, and primary peritoneal cancer in remission.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety of fixed doses of DEC205mAb-NY-ESO-1 fusion protein (DEC-205/NY-ESO-1 fusion protein CDX-1401) with adjuvant poly-ICLC given as a vaccine in combination with INCB024360 (IDO1 inhibitor INCB024360). (Phase I) II. To evaluate toxicity as defined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. (Phase I) III. To determine the progression free survival (PFS) (primary endpoint) using standard immune-related response criteria (irRC) criteria. (Phase IIb)

SECONDARY OBJECTIVES:

I. To determine the effectiveness of INCB024360 on enhancing vaccine efficacy by assessing cancer-testis antigen (NY-ESO-1) specific cellular and humoral immunity.

II. To determine the effectiveness of Sirolimus on enhancing vaccine efficacy by assessing NY-ESO-1 specific cellular and humoral immunity (Exploratory Cohort ONLY) III. Peripheral blood NY-ESO-1 specific cluster of differentiation (CD)8+ and CD4+ T cells. (Exploratory Cohort ONLY) IV. Peripheral blood NY-ESO-1 specific antibodies.(Exploratory Cohort ONLY) V. Peripheral blood frequency of CD4+CD25+forkhead box P3 (FOXP3)+ regulatory T cells. (Exploratory Cohort ONLY) VI. Pharmacokinetics of INCB02360 in relation to T cell frequency and function in correlation with PFS. (Exploratory Cohort ONLY)

OUTLINE:

PHASE I:

Patients receive DEC-205/NY-ESO-1 fusion protein CDX-1401 via intracutaneous injection on day 1, poly ICLC subcutaneously (SC) on days 1 and 2, and IDO1 inhibitor INCB024360 orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. Patients receive IDO1 inhibitor INCB024360 for up to 7 courses.

PHASE IIb: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive DEC-205/NY-ESO-1 fusion protein CDX-1401 and poly ICLC as in Phase I.

ARM II: Patients receive DEC-205/NY-ESO-1 fusion protein CDX-1401, poly ICLC, and IDO1 inhibitor INCB024360 as in Phase I.

After completion of study treatment, patients are followed up for 30 days and then at 3, 6, and 12 months.

Arms: arm 1: Patients receive DEC-205/NY-ESO-1 fusion protein CDX-1401 and poly ICLC as in Phase I. arm 2: Patients receive DEC-205/NY-ESO-1 fusion protein CDX-1401, poly ICLC, and IDO1 inhibitor INCB024360 as in Phase I.
Interventions: intervention 1: DEC-205/NY-ESO-1 Fusion Protein CDX-1401 intervention 2: Epacadostat intervention 3: Laboratory Biomarker Analysis intervention 4: Pharmacological Study intervention 5: Poly ICLC
Intervention descriptions: intervention 1: Given via intracutaneous injection intervention 2: Given PO intervention 3: Correlative studies intervention 4: Correlative studies intervention 5: Given SC

Protocol documents:
Prot_SAP_000.pdf: 
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK
07/13/18, SRC 07/30/2018
Page 1 of 102
TITLE: A Phase I/IIb Study of DEC205mAb-NY-ESO-1 Fusion Protein 
(CDX-1401) Given with Adjuvant Poly-ICLC in Combination with INCB024360 
for Patients in Remission with Epithelial Ovarian, Fallopian Tube, or Primary 
Peritoneal Carcinoma Whose Tumors Express NY-ESO-1 or LAGE-1 Antigen
Roswell Park 
Study Number:
I 248613
NCT02166905
Roswell Park 
Study Number:
I 248613
Initial Submission Date:
December 6 2013
Amendment 1:
May 1, 2014
Amendment 2:
June 20, 2014
Amendment 3:  July 15, 2014
Amendment 4:
August 15, 2014
Amendment 5:  
Amendment 6:
Amendment 7:   
Amendment 8:   
Amendment 9:   
Amendment 10:
December 2, 2014
April 10, 2015
May 6, 2015
July 13, 2015
October 26, 2015
December 15, 2015
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                                                Amendment 11:
Amendment 12:
Amendment 13:
Amendment 14:
Amendment 15:
Amendment 16:
November 15, 2016
July 27, 2017
September 6, 2017
November 14, 2017
January 25, 2018
February 5, 2018
Amendment 17:
Amendment 18: 
July 13, 2018
April 14, 2021
Principal Investigator:
Emese Zsiros, MD
Roswell Park Cancer Institute
d/b/a Roswell Park Comprehensive Cancer 
Center
Elm & Carlton Streets
Buffalo, New York 14263
716-845-5855
Emese.Zsiros@RoswellPark.org
Confidentiality Statement
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of the parties mentioned above. The use of such confidential 
information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, 
in any form whatsoever without the prior written consent of the parties above.
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SYNOPSIS
Title / Phase
A Phase I/IIb Study of DEC205mAb-NY-ESO-1 Fusion Protein (CDX-1401) Given 
with Adjuvant Poly-ICLC in Combination with INCB024360 for Patients in Remission 
with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Carcinoma Whose 
Tumors Express NY-ESO-1 or LAGE-1 Antigen
Roswell Park Study 
Number
I 248613
Roswell Park Clinical 
Investigator
Emese Zsiros, MD
Study Drugs
DEC205mAb-NY-ESO-1 fusion protein given with adjuvant poly-ICLC 
INCB024360
Exploratory Cohort at Roswell Park ONLY: Sirolimus
Objectives
Phase I Primary Objectives:

To determine the safety of fixed doses of DEC205mAb-NY-ESO-1 fusion protein 
with adjuvant poly-ICLC given as a vaccine in combination with INCB024360.

To evaluate toxicity as defined by NCI Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0.
Phase IIb Primary Objective:

To determine the progression free survival (PFS) (primary endpoint) using irRC 
criteria.
Phase I and Phase IIb Secondary Objectives

To determine the effectiveness of INCB024360 on enhancing vaccine efficacy by 
assessing NY-ESO-1 specific cellular and humoral immunity.

Exploratory Cohort at Roswell Park ONLY: To determine the effectiveness of 
Sirolimus on enhancing vaccine efficacy by assessing NY-ESO-1 specific cellular 
and humoral immunity.
o
Peripheral blood NY-ESO-1 specific CD8+ and CD4+ T cells.
o
Peripheral blood NY-ESO-1 specific antibodies.
o
Peripheral blood frequency of CD4+CD25+FOXP3+ regulatory T cells.
o
Pharmacokinetics of INCB024360 in relation to T cell frequency and function 
in correlation with PFS.
Study Design
This is an open-label, Phase I/IIb study of the IDO inhibitor, INCB024360, in 
combination with DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) given with 
adjuvant poly-ICLC in patients with NY-ESO-1 or LAGE-1 expressing epithelial 
ovarian, fallopian tube, or primary peritoneal cancer who are in remission.
For the Phase I component of the study, eligible patients will receive a fixed 
intracutaneous dose of DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) (Day 1) 
given with subcutaneous adjuvant poly-ICLC (Day 1 and Day 2) for each 28 day cycle 
for a total of 5 cycles; and Cohort 1 patient enrollment will begin INCB024360 at a 
fixed daily dose of 300 mg BID orally (Cohort 1) for a total of 7 cycles. Based on the 
decision rules for DLTs, patients may be enrolled into Cohort -1. Cohort -1 will receive 
DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) (Day 1) given with adjuvant 
poly-ICLC (Day 1 and Day 2) for each 28 day cycle for a total of 5 cycles, and daily 
oral INCB024360 100 mg BID (Cohort -1) starting on Day 1 for 7 cycles. Based on the 
decision rules for DLTs, patients may be enrolled into Cohort -2. Cohort -2 will receive 
DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) (Day 1) given with adjuvant 
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poly-ICLC (Day 1 and Day 2) for each 28 day cycle for a total of 5 cycles, and daily 
oral INCB024360 50 mg BID (Cohort -1) starting on Day 1 for 7 cycles.
Phase IIb:
The Phase IIb component of this trial will consist of a randomized parallel design of
 n=25+25=50 patients =50 patients with treatment arms: (i) DEC205mAb-NY-ESO-
1
 fusion protein (CDX-1401) with adjuvant poly-ICLC alone and (ii) INCB024360 in
 combination with the DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) with
 adjuvant poly-ICLC. Stratification will be on clinical site (Roswell Park, U. of 
Pittsburgh).
 The primary endpoint will be progression free survival. Baseline is defined as the
 time following the treatment free interval, which can span 0 - 2 months, as described
 in Iasonos et al.[1] The primary analysis will be carried forth using a Cox
 proportional hazards model with factors corresponding to treatment and a 
continuous
 covariate adjustment for the length of the treatment free interval and a stratification
 factor for clinical site.
Exploratory Cohort Roswell Park site ONLY:
       An additional exploratory cohort (N=6) receiving 4 cycles of sirolimus in 
combination with DEC205mAb-NY-ESO-01 fusion protein (CDX-1401) with 
adjuvant poly-ICLC will be added to supplement the secondary objectives, which 
will aid in planning the next phase of the investigation. This will not affect the 
randomized component of the study as enrollment to the randomized Phase IIb at 
Roswell Park only will be suspended temporarily until the 6 patients are enrolled.
Accrual 
Target / Duration
Phase I: 3 – 12 patients
Phase IIb: 50 patients
Exploratory Cohort: 6 patients
The duration of patient enrollment is expected to be 8 years. Patients in Phase I and Phase 
IIb are expected to participate in the study for approximately 28 weeks of active therapy.  
Patients in the exploratory cohort are expected to participate in the study for 
approximately 20 weeks of active therapy.
Study Procedures 
and Observations
Patients will have regularly scheduled study visits at the clinical site including physical 
exam, hematology, chemistry, and performance status-refer to Table 3 and Table 4 
schedule of procedures and observations for specific time points..
Disease Assessment: Baseline, Cycle 4 Day 1, treatment discontinuation, and 3 and 
6 months after last study drug dose.
Adverse Events: From first dose of study drug until 30 days (± 3 days) after the last dose 
of study drug.
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Statistical Analysis

Phase I: The following decision rules will be followed: (i) If 0/3 dose limiting 
toxicities (DLTs) are observed proceed to enroll 3 more patients (ii) If 1/3 DLTs are 
observed enroll 3 more patients at the same treatment regimen. If 0/6 or 1/6 DLTs are 
observed, declare the regimen safe and as the maximum tolerated dose combination 
(MTD) of INCB024360 in combination with the vaccine. If at least 2/3 or 2/6 DLTs 
are observed in Cohort 1, stop and de-escalate INCB024360 to 100 mg BID in 
Cohort -1. If at least 2/3 or 2/6 DLTs are observed in Cohort -1, stop and de-escalate 
INCB024360 to 50 mg BID in Cohort -2.

Phase IIb: 

The Phase IIb component of this trial will consist of a randomized parallel design of 
n=25+25=50 patients =50 patients with treatment arms: (i) DEC205mAb-NY-ESO-1 
fusion protein (CDX-1401) with adjuvant poly-ICLC alone and (ii) INCB024360 in 
combination with the DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) with 
adjuvant poly-ICLC. Stratification will be on clinical site (Roswell Park, U. of 
Pittsburgh). The primary endpoint will be progression free survival. Baseline is 
defined as the time following the treatment free interval, which can span 0 - 2 months, 
as described in Iasonos et al.[1] The primary analysis will be carried forth using a Cox 
proportional hazards model with factors corresponding to treatment and a continuous 
covariate adjustment for the length of the treatment free interval and a stratification 
factor for clinical site.

Phase I/IIb: The secondary analysis of continuous immunological response 
endpoints [antibody titers; NY-ESO-1 specific CD8+ and CD4+ frequency and 
function (IFN-γ ELISPOT and tumor recognition by CTL)] will be analyzed in a 
straightforward analysis-of-covariance (ANCOVA) fashion modeling post-treatment 
levels as a function of pre-treatment levels with factors corresponding to INCB024360 
(yes/no) and DEC205mAb-NY-ESO-1 fusion protein with adjuvant poly-ICLC 
(yes/no).

Exploratory Cohort: The analysis of continuous immunological response endpoints 
(e.g., antibody titers; NY-ESO-1 specific CD8+ and CD4+ frequency and function; 
frequency of memory T cell populations; TCR avidity) will be analyzed via an 
analysis-of-covariance (ANCOVA) fashion modeling post-treatment levels as a 
function of pre-treatment levels with factors corresponding to Sirolimus (yes/no) and 
DEC205mAb-NY-ESO-1 fusion protein with adjuvant poly-ICLC (yes/no).
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Patient Name: (Network sites use subject initials) : 
_____________________________________________
Medical Record No.: (Network sites use subject ID) :  
_____________________________________
Title: A Phase I/IIb Study of DEC205mAb-NY-ESO-1 Fusion Protein (CDX-1401) Given 
with Adjuvant Poly-ICLC in Combination with INCB024360 for Patients in 
Remission with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal 
Carcinoma Whose Tumors Express NY-ESO-1 or LAGE-1 Antigen
INCLUSION CRITERIA
Yes
No
N/A
All answers must be “YES” or “N/A” for patient enrollment.
Date
1.
Eligible patients will be women with epithelial ovarian, fallopian tube, or 
primary peritoneal carcinoma after chemotherapy with no evidence of 
disease or minimal residual disease for primary or recurrent disease.  
This may or may not be measurable. These patients would normally 
enter a period of observation after standard management.
2.
Any HLA type. (Historic HLA typing is permitted.)
3.
Tumor expression of NY-ESO-1 or LAGE-1 by IHC and/or RTPCR.
4.
Life expectancy > 6 months.
5.
Hematology and biochemistry laboratory results within the limits 
normally expected for the patient population, without evidence of major 
organ failure. Have the following clinical laboratory values:

ANC ≥ 1,000/µL

PLT ≥ 100,000/µL

Hgb ≥ 8 g/dL

Total bilirubin ≤ 1.5 x ULN

Serum aspartate aminotransferase (SGOT/AST) or serum alanine 
aminotransferase (SGPT/ALT) ≤ 3 x ULN

Serum creatinine ≤ 2 x ULN
6.
Have been informed of other treatment options.
7.
Age ≥ 18 years of age.
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INCLUSION CRITERIA
Yes
No
N/A
All answers must be “YES” or “N/A” for patient enrollment.
Date
8.
Patient or legal representative must understand the investigational nature 
of this study and sign an Independent Ethics Committee/Institutional 
Review Board approved written informed consent form prior to receiving 
any study related procedure.
9.
Have an ECOG Performance Status of ≤ 2. Refer to Appendix A.
10. The ability to swallow and retain oral medication.
11. Patients of child-bearing potential must agree to use acceptable 
contraceptive methods (e.g., double barrier) during treatment.
12. Patients may have received previous NY-ESO-1 vaccine therapy. 
Patients who received maintenance paclitaxel or bevacizumab are 
eligible for enrollment provided they have discontinued therapy (at least 
4 weeks for prior taxane or prior bevacizumab) prior to randomization 
and recovered from toxicities to less than Grade 2.
Investigator Signature: ___________________________________
Date: ____________
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INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM
Patient Name: (Network sites use subject initials) : 
_____________________________________________
Medical Record No.: (Network sites use subject ID) :  
_____________________________________
Title: A Phase I/IIb Study of DEC205mAb-NY-ESO-1 Fusion Protein (CDX-1401) Given 
with Adjuvant Poly-ICLC in Combination with INCB024360 for Patients in 
Remission with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal 
Carcinoma Whose Tumors Express NY-ESO-1 or LAGE-1 Antigen
EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for patient enrollment.
Date
1.
Metastatic disease to the central nervous system for which other 
therapeutic options, including radiotherapy, may be available.
2.
Other serious illnesses (e.g., serious infections requiring antibiotics, 
bleeding disorders).
3.
History of severe autoimmune disorders requiring use of steroids or other 
immunosuppressives. 
4.
Concomitant systemic treatment with chronic use (based on the 
investigator’s judgement) of corticosteroids, anti-histamine or non-
steroidal anti-inflammatory drugs, and other platelet inhibitory agents 
(See also Section 6.4 for restrictions/recommendations on ancillary 
therapy).
5.
Chemotherapy, radiation therapy, or immunotherapy within 4 weeks 
prior to first dosing of study drug (6 weeks for nitrosoureas). 
Concomitant hormonal therapies for breast cancers are allowed.
6.
Subjects being treated with a monoamine oxidase inhibitor (MAOI), or 
drug which has significant MAOI activity (e.g., meperidine, linezolid, 
methylene blue) within 3 weeks prior to screening.
7.
Subjects who are currently receiving therapy with a potent CYP3A4 
inducer or inhibitor (e.g. clarithromycin, telithromycin, nefazodone, 
itraconazole, ketoconazole, atazanavir).
8.
Use of UGT1A9 inhibitor including: diclofenac, imipramine, and 
ketoconazole.
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EXCLUSION CRITERIA
Yes
No
N/A
All answers must be “No” or “N/A” for patient enrollment.
Date
9.
Participation in any other clinical trial involving another investigational 
agent within 4 weeks prior to first dosing of study drug.
10. Known hepatitis B, hepatitis C, or HIV.
11. Mental impairment that may compromise the ability to give informed 
consent, and comply with the requirements of the study.
12. Lack of availability of a patient for immunological, and clinical follow-
up assessment.
13. Evidence of current drug or alcohol abuse or psychiatric impairment, 
which in the Investigator’s opinion will prevent completion of the 
protocol therapy or follow-up.
14. Pregnant or nursing female patients.
15. Unwilling or unable to follow protocol requirements.
16. Any condition which in the Investigator’s opinion deems the patient an 
unsuitable candidate to receive study drug (i.e., any significant medical 
illness or abnormal laboratory finding that would, in the investigator’s 
judgment, increase the patient’s risk by participating in this study).
17. Known hypersensitivity to any of the study drugs that will be given to 
the participant.
18. Additional exclusion criteria for exploratory cohort ONLY: Known 
pulmonary hypertension.
Patient meets all entry criteria:
 Yes
 No
If “NO”, do not enroll patient in study.
Investigator Signature: ___________________________________
Date: ____________
Investigator Printed Name:________________________________
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TABLE OF CONTENTS
1
Background........................................................................................................................15
1.1  Study Disease:  Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer............................15
1.2  NY-ESO-1 as a Target for Immunotherapy............................................................................15
1.3   NY-ESO-1 and Ovarian Cancer ............................................................................................16
1.4  LAGE-1 and Ovarian Cancer .................................................................................................16
1.5  Clinical Studies with NY-ESO-1 Vaccines ............................................................................17
1.6 Study Drugs .............................................................................................................................18
1.6.1 DEC205mAb-NY-ESO-1 Fusion Protein (CDX-1401) with Adjuvant Poly-ICLC ............18
1.6.1.1 DEC205mAb-NY-ESO-1 Fusion Protein (CDX-1401) ....................................................18
1.6.1.2 Clinical Studies with CDX-1401 and Adjuvants...............................................................18
1.6.1.3 POLY-ICLC ......................................................................................................................19
1.6.2 INCB024360 (4-amino-1,2,5-oxadiazole-3-carboximidamide) Inhibitor of Indoleamine 2,3 
Dioxygenase (IDO)............................................................................................................19
1.6.2.1 INCB024360 Preclinical Pharmacology............................................................................20
1.6.2.1.1 In Vitro Pharmacology....................................................................................................20
1.6.2.1.2 In Vivo Pharmacology.....................................................................................................21
1.6.2.2 INCB024360 Preclinical Pharmacokinetics ......................................................................22
1.6.2.3 INCB024360 Preclinical Safety ........................................................................................23
1.6.2.4 INCB024360 Clinical Studies ...........................................................................................23
1.6.3 Sirolimus (used in Exploratory Cohort at Roswell Park ONLY).........................................25
1.6.4
Potential Risks and Benefits ..............................................................................................26
1.6.4.1 INCB024360 Potential Risks.............................................................................................26
1.6.4.2 INCB024360 Benefits .......................................................................................................27
1.6.4.3 Sirolimus Potential Risks...................................................................................................27
1.7 Rationale for the Use of DEC205mAb-NY-ESO-1 Fusion Protein (CDX-1401) with 
Adjuvant Poly-ICLC in Combination with INCB024360.................................................28
2
Objectives ..........................................................................................................................29
2.1 Phase I Primary Objectives......................................................................................................29
2.2 Phase IIb Primary Objectives ..................................................................................................30
2.3 Secondary Objectives (Phase I, Phase IIb and Exploratory Cohort).......................................30
3
Methodology......................................................................................................................30
3.1 Study Design............................................................................................................................30
3.1.1
Target Accrual and Study Duration...................................................................................31
4
Patient Selection ................................................................................................................31
4.1 Inclusion Criteria .....................................................................................................................31
4.2 Exclusion Criteria ....................................................................................................................32
4.3 Inclusion of Women and Minorities........................................................................................33
5
Investigational agents ........................................................................................................33
5.1 DEC205mAb-NY-ESO-1 Fusion Protein (CDX-1401) ..........................................................33
5.2 Poly-ICLC Adjuvant................................................................................................................34
5.3 INCB024360............................................................................................................................34
5.4
Sirolimus (exploratory cohort at Roswell Park only)........................................................35
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5.4.1
Active Substance and Source.............................................................................................35
5.4.2
Packaging and Labeling.....................................................................................................35
5.5
Storage and Stability..........................................................................................................35
5.6
Handling and Disposal of Investigational Products...........................................................35
6
Treatment Plan...................................................................................................................36
6.1 Dosing and Administration......................................................................................................36
6.1.1
CDX-1401..........................................................................................................................36
6.1.2
Poly-ICLC..........................................................................................................................37
6.1.3
INCB024360......................................................................................................................37
6.1.4
Sirolimus (Exploratory cohort at Roswell Park ONLY) ...................................................38
6.1.5
Compliance........................................................................................................................38
6.2 Cohort Management ................................................................................................................40
6.3 Dose Modification ...................................................................................................................40
6.3.1 Definition of Dose-Limiting Toxicity ..................................................................................42
6.3.2 Management of Delayed Events...........................................................................................43
6.4 Ancillary Therapy and Supportive Care..................................................................................43
6.4.1 Permitted Treatment .............................................................................................................43
6.5 Prohibited Treatment ...............................................................................................................44
6.6 Duration of Treatment .............................................................................................................45
6.7 Treatment Discontinuation ......................................................................................................45
7
Study Procedures ...............................................................................................................46
7.1 Vaccination Site Care ..............................................................................................................46
7.2 Unscheduled Visit....................................................................................................................46
7.3 Schedule of Procedures and Observations...............................................................................47
1.1.1.1
Treatment discontinuation13.................................................................................48
1.1.1.2
Treatment discontinuation12.................................................................................51
2
Positive by either PCR or immunohistochemistry ((archived tissue (Appendix F) 
and/or frozen/fresh tumor tissue (Appendix G)). Documented historical NY ESO 1 
positive results by IHC or PCR or serum antibody reactive with ESO are acceptable..53
7.4 Pathology .................................................................................................................................54
7.4.1 Baseline Tumor Tissue Requirements..................................................................................54
7.4.2 Recurrence Tumor Tissues Requirements............................................................................54
7.5 Immunological Response.........................................................................................................55
7.5.1 Humoral Immunity ...............................................................................................................56
7.5.2 Cellular Immunity.................................................................................................................56
7.6 Additional Exploration of the T cell response.........................................................................56
7.7 Pharmacokinetic/Pharmacodynamic Blood Sample Collection and Processing.....................57
7.7.1 INCB024360 Levels .............................................................................................................57
7.7.2
Sirolimus Levels ................................................................................................................59
8
Efficacy Evaluations..........................................................................................................59
8.1
Objective Tumor Response................................................................................................59
8.2
Target Lesions – PHASE 1................................................................................................59
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8.3
Non-Target Lesions ...........................................................................................................60
8.4
Evaluation of Response .....................................................................................................62
8.5 Guidelines for Evaluation of Measurable Disease...................................................................64
9
Safety Evaluation...............................................................................................................66
9.1 Adverse Events ........................................................................................................................66
9.1.1
Definition...........................................................................................................................66
9.1.1.1 Diagnosis Versus Signs and Symptoms ............................................................................66
9.1.1.2 Adverse Events Occurring Secondary to Other Events.....................................................66
9.1.1.3 Abnormal Laboratory Values ............................................................................................66
9.1.1.4 Preexisting Medical Conditions (Baseline Signs and Symptoms) ....................................67
9.1.2
Grading and Relationship to Drug.....................................................................................67
9.1.3
Reporting Adverse Events .................................................................................................68
9.2 Serious Adverse Events ...........................................................................................................68
9.2.1 Definition..............................................................................................................................68
9.2.2 Reporting Serious Adverse Events .......................................................................................69
9.2.3 Follow-Up for Serious Adverse Events................................................................................70
9.3 Unanticipated Problems...........................................................................................................70
9.3.1 Definition..............................................................................................................................70
9.3.2 Reporting Unanticipated Problems.......................................................................................70
9.3.3 Notifying the Study Drug Provider.......................................................................................71
9.4 FDA Reporting ........................................................................................................................71
10
Data and Safety Monitoring...............................................................................................72
11
Statistical Methodology.....................................................................................................73
11.1 Primary Objective..................................................................................................................73
11.1.1 Sample Size Justification...................................................................................................73
11.2 Secondary Objectives ............................................................................................................74
11.3 Toxicity..................................................................................................................................74
11.4 Immune Response..................................................................................................................74
11.5 Interim Analysis and Criteria for Early Termination of the Study........................................75
12
Correlative Data Analysis..................................................................................................75
12.1 Pharmacokinetic or Pharmacokinetic/Pharmacodynamic Analysis ......................................75
13
Ethical and Regulatory Standards......................................................................................75
13.1 Ethical Principles...................................................................................................................75
13.2 Informed Consent ..................................................................................................................76
14
Study Responsibilities .......................................................................................................76
14.1 Data Collection ......................................................................................................................76
14.2 Monitoring .............................................................................................................................77
14.3 Maintenance of Study Documents.........................................................................................77
15
Administrative Rules .........................................................................................................78
15.1 Revisions to the Protocol.......................................................................................................78
15.2 Termination of the Study.......................................................................................................78
15.3 Confidentiality .......................................................................................................................78
16
Appendices ........................................................................................................................79
17
References..........................................................................................................................99
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IN-TEXT TABLES
Table 1.
Dosing Schedule for INCB024360 and DEC205mAb-NY-ESO-1 Fusion Protein 
(CDX-1401) Given with Adjuvant Poly-ICLC .............................................................................38
Table 2
Exploratory Cohort Dosing Schedule for Sirolimus and DEC205mAb-NY-ESO-1 
Fusion Protein (CDX-1401) Given with Adjuvant Poly-ICLC.....................................................40
Table 3.
Schedule of Procedures and Observations (INCBO24360 cohorts) ...........................48
Table 4
Schedule of Procedures/Observations (Exploratory cohort with Sirolimus-Roswell 
site ONLY) ....................................................................................................................................51
Table 5.
Time Point Response Criteria (+/- non-target disease) ...............................................63
Table 6.
Time Point Response Criteria (non-target disease only).............................................63
Table 7.
Guidelines for Routine Adverse Event Reporting for Phase I Studies (Regardless of 
Expectedness) ................................................................................................................................68
Table 8.
Guidelines for Routine Adverse Event Reporting for Phase IIb Studies (Regardless of 
Expectedness) ................................................................................................................................68
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APPENDICES
Appendix A.
ECOG Performance Status Scores.......................................................................79
Appendix B
Sirolimus Drug Interaction List ...........................................................................80
Appendix C.
Diary for Medication (Poly-ICLC Subcutaneous Injection)................................81
Appendix D.
Diary for Medication (INCB024360) ..................................................................82
Appendix E
Diary for Medication (Sirolimus) ........................................................................84
Appendix F.
Immunohistochemistry to Determine NY-ESO-1 Tumor Expression.................85
Appendix G.
Nucleic Acid Determination of NY-ESO-1 and LAGE-1 Tumor Expression.....86
Appendix H.
Shipping Information for HLA Testing ...............................................................90
Appendix I.
Assessment of T cell Responses ..........................................................................91
Appendix J
Instructions for Network Sites .............................................................................92
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1
BACKGROUND
1.1  Study Disease:  Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer
Ovarian cancer is the leading cause of death from gynecologic malignancies [2]. More than 
23,000 cases occur annually in the United States, and 14,000 women can be expected to succumb 
to the disease [3]. Despite advances in surgery, and chemotherapy over the past 20 years, only 
modest progress has been made in improving the time to disease progression [4, 5], and the overall 
survival for patients with ovarian cancer has not changed significantly. Although the majority of 
women with advanced stage ovarian cancer respond to first-line chemotherapy, most of these 
responses are not durable and more than 70% of patients die of recurrent disease within 5 years of 
diagnosis. By contrast, patients with early stage ovarian cancer have excellent prognosis with 
currently available treatment modalities. The poor survival in advanced disease is due both to late 
diagnosis and lack of effective second-line cytotoxic therapy for the majority of patients who 
relapse following initial clinical complete response to platinum-based chemotherapy. The inability 
to “cure” ovarian cancer is attributed to intrinsic or acquired resistance to drug therapy which is 
combated with high-dose chemotherapeutic regimens complicated by significant drug related 
morbidity and mortality. Moreover, effective strategy for the prevention of recurrence in complete 
responders is lacking. Therefore, new treatment modalities and paradigms are needed before a 
significant impact can be expected in the prognosis of women diagnosed with epithelial ovarian 
cancer. Fallopian tube and primary peritoneal cancers are clinically and biologically similar to 
ovarian cancer, and are treated in the same fashion.
1.2  NY-ESO-1 as a Target for Immunotherapy
There is increasing evidence that the immune system has the ability to recognize tumor-associated 
antigens expressed in human malignancies and to induce antigen-specific humoral and cellular 
immune responses to these targets. Importantly, evidence from correlative human studies indicate 
that the presence of tumor-infiltrating lymphocytes may be associated with improved clinical 
outcome in several human cancers, including ovarian, melanoma, colon, gastric, liver, brain, lungs, 
kidney and prostate cancers. In addition, encouraging results from large-scale clinical trials of 
immune system-provoking therapies [1-4] have re-kindled the promise of harnessing the power of 
the immune system to attack cancers. Therefore, the development of strategies to enhance the 
potential of tumor antigen-specific CD8+ T cells and CD4+ T cells is urgently needed for 
extending remission rates in several cancer types. In this regard, cancer-testis antigens, a unique 
class of antigens that demonstrate high levels of expression in adult male germ cells but generally 
not in other normal adult tissues and aberrant expression in a variable proportion of a wide range 
of different cancer types, are promising candidates for immunotherapy. Among cancer-testis 
antigens, NY-ESO-1 is one of the most spontaneously immunogenic tumor antigens described so 
far [5, 6]. The NCI antigen prioritization panel has recently ranked NY-ESO-1 in the top 
10 antigens for further development of human cancer vaccines [7].
The NY-ESO-1 antigen was initially identified by serological analysis of recombinant cDNA 
expression libraries (SEREX), using tumor mRNA and autologous serum from a patient with 
squamous cell carcinoma of the esophagus. The full-length NY-ESO-1 cDNA was cloned, 
encoding a protein of 180 amino acids [5]. The function of this protein is unknown. The gene 
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encoding NY-ESO-1 has been mapped to chromosome Xq28 [5]. A gene LAGE-1, encoding an 
antigen closely related to NY-ESO-1, has also been mapped to chromosome Xq28 [8].
NY-ESO-1 showed restricted mRNA expression in normal tissues, with high-level mRNA 
expression found only in the germ line cells in testis [5, 9]. Reverse transcription-polymerase chain 
reaction (RT-PCR) analysis showed NY-ESO-1 mRNA expression in a variable proportion of a 
wide array of human cancers, including melanoma, breast cancer, prostate cancer, lung cancer, 
hepatocellular carcinoma, ovarian cancer, thyroid cancer and bladder cancer [9]. Expression of 
LAGE-1 parallels the expression of NY-ESO-1 in most cases [8]. The pattern of NY-ESO-1 and 
LAGE-1 expression indicates that NY-ESO-1 family belongs to a growing family of immunogenic 
testicular antigens that are aberrantly expressed in a wide range of human cancers. These antigens, 
initially detected by either cytotoxic T cells (MAGE, BAGE, GAGE-1) or antibodies [HOM-
MEL-40 (SSX2), NY-ESO-1], represent a pool of antigenic targets for cancer vaccination [10]. 
The expression of these genes in many different types of cancer suggests that immunization against 
the antigens encoded by these genes could be applied to a large proportion of cancer patients.
NY-ESO-1 has 2 characteristics that make it a viable candidate as a tumor vaccine; [1] testis-
restricted expression in normal tissues and; [2] its immunogenicity. The first characteristic also 
applies to MAGE and other genes with a similar expression pattern (see above). A serological 
survey has shown that patients with melanoma, ovarian cancer, lung cancer, or breast cancer 
produced antibodies against NY-ESO-1 more often (19 of 209) than antibodies against MAGE-1 
(3 of 209) or MAGE-3 (2 of 209). Antibodies were not detected in 70 healthy blood donors [11]. 
This is evidence for NY-ESO-1 immunogenicity in patients with cancer, supporting the 
expectation that immunity can be enhanced or induced by vaccination.
1.3   NY-ESO-1 and Ovarian Cancer
Data from 8 ovarian tumors by Chen et al. [6] showed aberrant expression of NY-ESO-1 in 25% 
(2 of 8) of epithelial ovarian cancers. Using a combination of RT-PCR and immunohistochemistry, 
data indicates aberrant expression of NY-ESO-1 in up to 43% (82 of 190) of patients with 
epithelial ovarian cancer [7]. In the current protocol, patients with NY-ESO-1 or LAGE-1 
expressing epithelial ovarian, primary peritoneal, and fallopian tube tumors will be candidates for 
antigen-specific immunotherapy.
1.4  LAGE-1 and Ovarian Cancer
The LAGE-1 cancer/testis antigen was identified by using representational difference analysis 
comparing testicular versus nontesticular mRNA from a melanoma patient [8]. The antigen is 
aberrantly expressed in a wide variety of tumors including melanomas, sarcomas, breast, lung, 
head and neck, prostate and bladder cancers [8]. The 180 amino acid protein encoded by the fully 
spliced LAGE-1 mRNA shares 94% nucleotide and 89% amino acid homology to NY-ESO-1 [8, 
9]. Using RT-PCR analysis, we have found aberrant expression of LAGE-1 in 22/107 (21%) of 
epithelial ovarian tumors [7]. Since many NY-ESO-1 epitopes are also shared by LAGE-1, in the 
current protocol, patients with LAGE-1 expressing epithelial ovarian, primary peritoneal, and 
fallopian tube tumors will also be candidates for immunotherapy.
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1.5  Clinical Studies with NY-ESO-1 Vaccines
In the first human study of NY-ESO-1 vaccination, ESO157–165 peptide in conjunction with 
granulocyte/macrophage colony-stimulating factor was shown to induce HLA-A2-restricted CD8+ 
T cell responses in patients without preexisting NY-ESO-1 immunity [12], although these peptide-
induced CD8+ T cell responses were generally of low affinity and did not recognize naturally 
processed NY-ESO-1 [13]. Subsequently, recombinant NY-ESO-1 protein in a saponin-based 
adjuvant (ISCOMATRIX) was used to immunize Stage III and Stage IV melanoma patients after 
tumor resection [14]. More recently, patients with a range of tumor types were immunized with 
recombinant vaccinia NY-ESO-1 and recombinant fowlpox NY-ESO-1 [15], and recombinant 
protein with CpG adjuvant [16]. These vaccine strategies were found to be safe, and induced high-
titered NY-ESO-1 Ab, CD4+, and CD8+ T cell responses in a high proportion of patients.
A number of studies targeting NY-ESO-1 have been conducted at Roswell Park. Protocol RP02-
28, a Phase I clinical trial of immunization with an NY-ESO-1 derived long peptide of dual MHC 
Class I/II specificities, mixed with incomplete Freund's adjuvant (Montanide ISA51) in 18 ovarian 
cancer patients [17]. Protocol I 13303, a Phase II clinical trial of recombinant vaccinia-NY-ESO-1 
(rV-NY-ESO-1) and recombinant fowlpox-NY-ESO-1 (rF-NY-ESO-1) in ovarian cancer patients 
whose tumors express NY-ESO-1 or LAGE-1. One serious adverse event (SAE) was reported to 
be unlikely due to rV-NY-ESO-1 or rF-NY-ESO-1. Toxicity and immunological results are 
currently being evaluated. Protocol I 27008 is an on-going Phase I study testing epigenetic 
modulation of NY-ESO-1 with 5-Azacytidine in combination with recombinant NY-ESO-1 
protein admixed with GMCSF and IFA in ovarian cancer patients receiving liposomal doxorubicin 
for recurrent disease. Nine out of 12 planned patients have been enrolled; and no treatment related 
Grade 3 adverse events (AEs) have been noted.
Protocol I 125207, a Phase I study testing (ALVAC)-NY-ESO-1/TRICOM (recombinant 
canarypox expressing NY-ESO-1 and a triad of co-stimulatory molecules, TRICOM). Planned 
accrual of 12 patients has been completed and no Grade 3 toxicities attributable to the vaccine 
were noted. Collective experiences from these studies indicate that NY-ESO-1 vaccines are safe. 
Moreover, NY-ESO-1 specific antibody responses and/or CD8+ and CD4+ T cell responses were 
induced by vaccinations in a high proportion of patients. Vaccine-induced CD8+ and CD4+ T cell 
clones were shown to recognize NY-ESO-1 -expressing tumor targets. However, inhibitory 
networks such as the indole-amine 2,3 dioxygenase (IDO), PD-1/PDL-1, CTLA4 pathways act to 
restrict the efficacy of anti-tumor immune responses.
Recently, protocol I191511 "A Phase I Clinical Trial of mTOR Inhibition With Rapamycin for 
Enhancing Intranodal Dendritic Cell Vaccine Induced Anti-Tumor Immunity In Patients With NY- 
ES0 -1 Expressing Solid Tumors" was completed and the 4 mg/day Sirolimus dosing was tolerated 
well. This same dose is proposed in the exploratory cohort of this protocol. 
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1.6 Study Drugs
1.6.1 DEC205mAb-NY-ESO-1 Fusion Protein (CDX-1401) with Adjuvant Poly-ICLC
The investigational vaccine is composed of DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) 
with adjuvant poly-ICLC.
1.6.1.1 DEC205mAb-NY-ESO-1 Fusion Protein (CDX-1401)
The DEC-205 receptor has been shown to be an efficient mAb-based target to enhance the 
induction of strong Ag-specific immune responses and cross-presentation in mice [10] and humans 
[11]. The receptor is also expressed on human monocyte-derived dendric cells along with other 
endocytic receptors, such as the mannose receptor/CD206 and DC-SIGN/CD209 (reviewed in 
ref[12]). In order to enhance the efficiency of NY-ESO-1 presentation to CD4+ and CD8+ T cells 
in vivo, exogenous NY-ESO-1 protein will be targeted to the DEC-205 endocytosis receptor on 
dendric cells for cross-presentation in this clinical trial. In a recent study, full-length NY-ESO-1 
was fused to the C terminus of human anti-DEC-205 (DEC205mAb-NY-ESO-1 fusion protein). 
Whereas non-targeted and Ab-targeted NY-ESO-1 proteins similarly activated CD4+ T cells, 
cross-presentation to CD8+ T cells was only efficiently induced by targeted NY-ESO-1 [13]. In 
addition, DEC-205 targeting elicited specific CD4+ and CD8+ T cells from PBLs of cancer 
patients. In this study, the DEC-205 mAb-NY-ESO-1 fusion protein will be directly injected 
intracutaneously in an effort to prime endogenous dendric cells with full length NY-ESO-1 protein 
and thereby prime specific CD4+ and CD8+ T cells to NY-ESO-1.
DEC205mAb-NY-ESO-1 fusion protein has been developed by Celldex Therapeutics, Inc, under 
the code designation CDX-1401. CDX-1401 is a fusion protein consisting of a fully human 
monoclonal antibody (HuMab) of IgG1 (kappa) isotype with specificity for the DC receptor, DEC-
205, genetically linked to the full length NY-ESO-1 tumor antigen (Ag) protein (10). A detailed 
discussion of the preclinical pharmacology, pharmacokinetics, and toxicology of Anti DEC-205-
NYESO-1 Fusion Protein can be found in the Investigator’s Brochure.
1.6.1.2 Clinical Studies with CDX-1401 and Adjuvants
As of February 4, 2011, safety data are available for 21 patients who have received CDX-1401 
(0.1 mg, 1 mg or 3 mg) plus topical resiquimod (0.5 mg; delivered as 250 mg of 2% gel) or poly 
ICLC (2 mg flat dose given SQ). There have been no dose-limiting toxicities, treatment-related 
Grade 3 or Grade 4 AEs, treatment-related SAEs or AEs requiring discontinuation of treatment. 
Injection site reactions, all Grade 1 in severity, have occurred in 76% of treated patients. These 
reactions have included rash, erythema, pruritus, pain, induration and swelling. Additional 
treatment-related toxicities have all been mild to moderate in severity, and have included, fatigue 
(24%), decreased appetite (14%), nausea (10%), arthralgia (10%), headache (10%) and pruritus 
(10%). Six patients with stable disease (range: 4.7 to 11.5 + months) have been retreated for more 
than one cycle, including 4 who received ≥ 3 cycles. Poly-ICLC has been the adjuvant chosen for 
further studies of this protein based upon preliminary data on induction of anti-NY-ESO-1 specific 
immune responses.
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1.6.1.3 POLY-ICLC
Poly-ICLC (Hiltonol, Oncovir by Dalton, Inc. 3203 Cleveland Ave, NW Washington, DC, 20008) 
is an experimental viral mimic and broad activator of innate immunity. While initially developed 
as an interferon inducer, poly-ICLC has much broader biological effects in humans, including 
specific antiviral, immune activating, vaccine adjuvant, and antitumor actions.
Synthetic double stranded RNA (dsRNA) such as poly-IC, which consists of a pair of strands of 
poly-inosinic and poly-cytidylic acids, are not normally found in mammalian cells, but they are 
the basic genetic material or are replication byproducts of many viruses (29). Plain poly-IC itself 
proved to be ineffective in primates because it is rapidly inactivated by natural enzymes in the 
blood. However, stabilized poly-IC with poly-lysine is a very stable dsRNA that is a potent 
interferon inducer in man. Early, short term, high dose cancer trials showed that high dose 
poly-ICLC could induce very large amounts of interferon production in man, but with only modest 
therapeutic effects and moderate transient toxicity (29). Low dose poly-ICLC is a potent clinical 
activator of a variety of host defense mechanisms that go well beyond simple induction of 
interferons and which include reversal or preemption of certain viral or tumor induced inhibitions, 
broad immune stimulation, gene regulatory and specific antiviral, and anticancer effects, with little 
or no toxicity (29,30).
In this study low dose poly-ICLC will be used as a direct immune-enhancer in order to activate T-
cells, natural killer cells, and, dendritic cells, release of cytokines such as interferons, interleukins, 
corticosteroids, and tumor necrosis factor (TNF). Its recently demonstrated effect on dendritic cells 
through Toll-like receptors (TLR3) may be especially important since CDX-1401 directly targets 
these cells (31). As described above, dendritic cells play a critical role in the immune response by 
recognizing pathogens and presenting their antigens to the immune system. The poly-ICLC used 
in this study will provide an adjuvant effect for the CDX-1401 and lead to increased antibody and 
cellular immune response to NY-ESO-1antigen found on antigen-presenting cells. 
1.6.2 INCB024360 (4-amino-1,2,5-oxadiazole-3-carboximidamide) Inhibitor of Indoleamine 
2,3 Dioxygenase (IDO)
Recent interest has focused on the role of indoleamine 2,3–dioxygenase (IDO) as a mechanism of 
induction of tolerance to malignancy. IDO is a heme-containing, monomeric oxidoreductase that 
catalyzes the degradation of the essential amino acid tryptophan (Trp) to N-formylkynurenine 
(Kyn). Kynurenine can be subsequently metabolized through a series of enzymatic steps to NAD+. 
IDO is the first rate-limiting enzyme in one of the breakdown pathways of Trp. In an alternative 
pathway for Trp metabolism, Trp hydroxylase leads to the formation of serotonin and melatonin.
The expression and activity profiles of IDO are distinct from those of Trp dioxygenase (TDO), an 
enzyme predominantly expressed in liver that catalyzes the same enzymatic reaction as IDO and 
maintains proper Trp balance in response to dietary uptake. In contrast to TDO, IDO is expressed 
in a variety of tissues, with particularly high levels found in areas of contact with potential sources 
of immune challenge (e.g., gut, respiratory tract, placenta, spleen), consistent with a role for 
regulating Trp metabolism in a local microenvironment. The IDO-driven oxidation of Trp results 
in a strongly inhibitory effect on the development of T cell mediated responses by blocking T cell 
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activation and inducing T cell apoptosis. Both the reduction in local Trp levels and the production 
of Trp catabolites that are inhibitory to cells contribute to the immunosuppressive effects [14].
IDO activity also promotes the differentiation of naïve T cells to cells with a regulatory phenotype 
(Treg) [15]. Since increased Treg activity has been shown to promote tumor growth and Treg depletion 
has been shown to allow an otherwise ineffectual anti-tumor immune response to occur [16], IDO 
expansion of Tregs may provide an additional mechanism whereby IDO could promote an 
immunosuppressive environment.
Preliminary data clearly supports the role of IDO in contributing to the profound immune 
suppressive environment in ovarian cancer. There are currently 2 on-going clinical trials testing 
IDO 
inhibition 
in 
patients 
with 
solid 
tumors 
(NCT01792050; 
NCT01685255, 
http://www.cancer.gov/search/ViewClinicalTrials). One trial is testing the IDO inhibitor, dextro -
1-methyl-tryptophan (D1-MT) in combination with chemotherapy. In contrast to the levo-isoform 
(L-INCB024360) that blocks IDO1, D1-MT, which is used in the clinical trials inhibits IDO2, and 
exhibits little IDO blockade in some in vitro test systems [17]. Emerging data indicate that IDO2 
is NOT affected by D-1-MT [18, 19]. In studies conducted at Roswell Park, it has been found that, 
L-1-MT and D/L-1-MT can restore proliferation of tumor and peripheral blood T cell subsets of 
ovarian cancer patients, D-1-MT does not effectively restore IDO-induced arrest of human T cell 
proliferation [20]. Given the controversy surrounding D-1MT, we have focused on INCB024360 
(4-amino-1,2,5-oxadiazole-3-carboximidamide), a novel, potent and selective inhibitor of IDO1 
enzyme activity [21, 22]. INCB024360 was recently identified by high throughput screening and 
was shown to be a reversible and competitive inhibitor of IDO1, resulted in efficient and durable 
suppression of IDO1 activity in mice to levels seen in Ido1-deficient mice, and impedes tumor 
growth in a dose- and lymphocyte-dependent fashion [21, 23, 24].
Published literature and preliminary data indicate that INCB024360 is the most potent inhibitor of 
human IDO1 reported to date, more than 10,000-fold more potent than 1-methyl-tryptophan when 
tested in the same assays. The compound also exhibits more than 100-fold selectivity over TDO, 
IDO2, and tryptophan transporters [22]. Moreover, INCB024360 significantly promotes 
proliferation, survival, and functions of T cells and abrogates generation of CD4+ Tregs.
Extensive preclinical pharmacologic, pharmacodynamic, pharmacokinetic and toxicology studies 
have been performed with INCB024360. There is emerging clinical data on the administration of 
INCB024360 in humans. Consequently, any information about specific risks and the potential for 
AEs is based on emerging results from an on-going Phase I study.
1.6.2.1 INCB024360 Preclinical Pharmacology
1.6.2.1.1 In Vitro Pharmacology
INCB024360 represents a novel, potent, and selective inhibitor of the enzyme IDO. In cell-based 
assays, INCB024360 potently inhibits IDO in both human tumor cells and human dendritic cells 
resulting in reduced Trp to Kyn conversion (IC50 values = 7.1 nM - 12.7 nM). INCB024360 does 
not significantly inhibit other proteins that could impact Trp catabolism and demonstrates 
selectivity against a broad panel of G-protein coupled receptors (GPCRs), ion channels, 
transporters and enzymes. As described above, IDO driven oxidation of Trp results in a strong 
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inhibitory effect on the development of T cell mediated responses by blocking T cell activation 
and inducing G1 arrest and apoptosis. INCB024360 reverses the inhibition of the development of 
T cell mediated responses that IDO activity imparts, resulting in enhanced T cell and NK cell 
proliferation, enhanced interferon-gamma (IFN-γ) production, reduced Treg differentiation, 
reduced DC apoptosis and enhanced expression of DC activation markers. INCB024360 reversal 
of the IDO-mediated suppression of T cell proliferation is dose-dependent with a potency 
consistent with its inhibition of Trp to Kyn conversion (EC50 = 17.7 nM). Ex vivo, INCB024360 
inhibits IFN-γ induced IDO activity in human whole blood with an IC50 value of 125 nM ± 26 nM. 
This value is consistent with the predicted value of 130 nM, based on the in vitro potency in cell-
based assays and the measured free fraction of INCB024360 in human serum.
1.6.2.1.2 In Vivo Pharmacology
The in vivo data demonstrate that INCB024360 can inhibit IDO systemically and, importantly, in 
tumors and tumor draining lymph nodes. INCB024360 was efficacious in multiple mouse models 
of cancer and its ability to reduce tumor growth was dependent on a functional immune system – 
consistent with its proposed mechanism of action. Moreover, INCB024360 enhanced lymphocyte 
function in tumors and tumor draining lymph nodes. Finally, INCB024360 improved the tumor 
growth control of cytotoxic chemotherapy when used in combination.
In order to examine regulation of IDO activity by INCB024360 in vivo, naïve C57BL/6 mice were 
administered a single oral dose of INCB024360 and blood samples were analyzed to determine 
the amount of Kyn and INCB024360 in plasma over time. Plasma Kyn levels decreased within 
1 hour and stayed at their minimum levels for as long as plasma levels of INCB024360 exceed the 
mouse protein binding adjusted EC50 of 1.2 = μM (approximately 8 hours). Consistent with 
specific inhibition of IDO by INCB024360, no reduction in Kyn levels were observed in mice 
lacking IDO expression even though compound exposures were similar between mouse strains. 
These data suggest that monitoring Kyn levels in plasma may be a useful pharmacodynamic 
marker of the activity of INCB024360.
Orally dosed INCB024360 was evaluated in immune competent and compromised mouse tumor 
models to characterize the effects of IDO inhibition on tumor growth and to determine if any 
observed effect was mediated by the immune system. Balb/c mice bearing well established 
subcutaneous syngeneic CT26 colon carcinomas, which had previously been demonstrated to 
express IDO, were treated orally with INCB024360. As a single agent, INCB024360 inhibits 
CT26 tumor growth in a dose dependent fashion, with 46% and 66% tumor growth control (TGC) 
at doses of 30 mg/kg and 100 mg/kg, respectively. Similar results were seen in the PAN02 
pancreatic cancer model in C57BL/6 mice, with twice daily oral doses of INCB024360 of 25, 50, 
or 100 mg/kg resulted in 61%, 63% and 83% TGC, respectively. Consistent with the proposed 
mechanism, there was no effect of 30 mg/kg or 100 mg/kg INCB024360 on the growth of CT26 
tumors in immunocompromised Balb/c nu/nu mice. These data imply that INCB024360 can 
impede tumor growth as a single agent and indicate that T cells are required for antitumor activity.
In summary, pharmacological data obtained in both in vitro and in vivo model systems support the 
potential utility of orally administered INCB024360 in the treatment of malignant disease.
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1.6.2.2 INCB024360 Preclinical Pharmacokinetics
The in vitro permeability of INCB024360 was considered moderate. In the presence of various P-
glycoprotein inhibitors, the bi-directional transport ratio was partially decreased suggesting that 
INCB024360 is likely a P-glycoprotein substrate and perhaps other apically localized transporters. 
In single oral dose pharmacokinetics studies in mice, rats, cynomolgus monkeys, and dogs, the 
Tmax values for INCB024360 ranged from 0.25 hours to 2.0 hours. The absolute oral bioavailability 
ranged from low to moderate and was consistent with the moderate clearance and the limited 
aqueous solubility of INCB024360 (< 100 μg/mL). In mice, rats, cynomolgus monkeys, and dogs, 
the apparent steady-state volume of distribution values of INCB024360 suggested that 
INCB024360 is distributed beyond the total volume of body water in mice, rats, and monkeys 
while apparently limited to body water in dogs. The reason for lower volume of distribution in 
dogs relative to the other species studied is not clear. In rats, INCB024360 exhibits limited 
penetration across the blood-brain barrier.
The in vitro serum and plasma protein binding of INCB024360 in mice and dogs was high with 
mean unbound fractions ranging from 3.1% to 4.1%. The ex vivo unbound fraction determined in 
plasma from mice and dogs given INCB024360 was 2.5% and 3.8%, respectively. The mean 
in vitro unbound fraction of INCB024360 in human plasma was 3.1%, and the compound binds 
predominantly to human serum albumin.
The potential for INCB024360 to inhibit human cytochrome P450s was studied in vitro. The 
inhibitory IC50 values for INCB024360 were > 25 μM for CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, and CYP2D6 while the IC50 values for CYP2C19 and CYP3A4 were greater than and 
equal to 12.5 μM, respectively. Based on this data, the potential for INCB024360 to cause drug-
drug interactions through CYP inhibition is considered low. In addition, the potential for 
INCB024360 to induce CYP3A isozymes was studied in vitro using the human pregnane X 
receptor reporter gene assay, and results show that the potential for INCB024360 to induce 
CYP3A4 in clinical studies is low.
INCB024360 exhibits low to moderate intrinsic clearance in vitro following incubation with 
hepatic S9 fractions prepared from mice, rats, dog, cynomolgus monkeys, and humans. Consistent 
with the in vitro data, INCB024360 exhibited moderate systemic clearance (ranging from 24% to 
58% of hepatic blood flow) in pharmacokinetic studies. Based on studies with recombinant CYP 
isozymes, INCB024360 is metabolized primarily by CYP3A4 in vitro. A major route of 
INCB024360 in vivo metabolism is via glucuronidation. Based on studies with recombinant UGT 
isozymes, INCB024360 is metabolized by UGT1A9 in vitro. Glucuronidation is the proposed 
primary metabolic pathway in human based on in vitro studies. After IV administration, 
INCB024360 had a moderate half-life in mice (2.5 hours), rats (male 1.4 hours, female 1.7 hours), 
monkeys (3.3 hours), and dogs (3.1 hours). In single intravenous dose pharmacokinetics studies in 
mice, monkeys, and dogs, less than 3% of INCB024360 was excreted as parent in urine.
1.6.2.3 INCB024360 Preclinical Safety
INCB024360 was studied in a variety of in vitro binding and enzyme assays against a panel of 
receptors, channels, transporters, and non-kinase enzymes to evaluate its specificity. INCB024360 
demonstrated cross reactivity at the vasopressin 1a receptor, with an IC50 value of 0.67 μM. Weak 
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activity was also noted for the dopamine transporter (71% inhibition at a concentration of 10 μM) 
and for carbonic anhydrase II (IC50 5.3 μM). Given that INCB024360 is a potent inhibitor of IDO 
with an IC50 value of 72 nM, the risk of unintended pharmacological activity is expected to be 
low. Evaluation of the potential interaction of INCB024360 with the hERG channel was evaluated 
using voltage-clamped human embryonic kidney cells (HEK293). There was no significant 
inhibition of the hERG potassium current at 10 μM.
A preliminary assessment of the potential genotoxicity of INCB024360, using a non-GLP bacterial 
mutagenicity assay, with and without metabolic activation, indicated that INCB024360 lacks the 
potential to be genotoxic. Oral administration studies in both mice and beagle dogs were conducted 
in order to assess the potential systemic toxicity of INCB024360. In single dose studies in mice, 
no mortality or adverse changes in parameters evaluated were noted at doses up to 4000 mg/kg. 
Single doses of up to 540 mg/kg were well tolerated in the dog.
Toxicological data from 2 repeat oral dose administration studies in the mouse (8-day non-GLP 
and 28-day GLP) revealed no adverse findings in any parameter evaluated. The NOEL for the 28-
day study in mice was defined as 2000 mg/kg/day. Two repeat dose oral administration studies 
were conducted in the dog (7-day non-GLP and 28-day GLP). All dose levels in both studies were 
well tolerated, resulting in the NOAEL being identified as 500 mg/kg/day. INCB024360-related 
changes included an increased incidence of diarrhea in 500 mg/kg/day dogs as well as sporadic 
emesis. In dogs, pharmacodynamic analysis determined that all dose levels used in the 28-day 
study were pharmacologically active with almost 100% inhibition of tryptophan conversion to 
kynurenine being achieved at 1 hour post-dose for all dose levels.
The projected clinical dose is 550 mg QD, a dose estimated to be associated with achieving IC90 
at trough. The projected unbound AUC associated with this dose is 0.72 μM*h. Safety margins 
calculated by comparing the clinical projected AUC versus the unbound no-observed-adverse-
effect level (NOAEL) dose of 500 mg/kg/day in the dog 28-day study are 11- and 17-fold for male 
and female dogs, respectively. For the unbound no-observed-effect level (NOEL) dose of 
2000 mg/kg/day in the mouse, the safety margins are 20- and 37-fold for male and female mice, 
respectively. Based on the planned clinical starting dose of 50 mg, the lack of any apparent 
INCB024360-related toxicity and the large safety margins associated with the predicted clinically 
efficacious dose, the potential risk associated with clinical administration of INCB024360 is 
expected to be low.
1.6.2.4 INCB024360 Clinical Studies
INCB24360-101 has been evaluated in Phase I study conducted by Incyte Corporation in subjects 
with refractory solid tumors. The study has used a 3+3 dose escalation design, with doses of 
INCB024360 ranging from 50 mg once daily (QD) to 700 mg twice daily (BID). Three subjects 
have initiated treatment at 50 mg QD, 4 subjects at 50 mg BID, 3 subjects at 100 mg BID, 
6 subjects at 300 mg BID, 11 subjects at 400 mg BID, 5 subjects at 500 mg BID and 4 subjects at 
700 mg BID.
INCB024360 has generally been well tolerated. The most common Grade 1 or Grade 2 AEs in 
≥ 20% reported have been fatigue, nausea, decreased appetite, vomiting, constipation, abdominal 
pain, diarrhea, dyspnea, back pain, and cough. The most common Grade 3 or Grade 4 AEs were 
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abdominal pain, hypokalemia, and fatigue (9.6% each). Despite 1 patient reporting a dose-limiting 
toxicity (DLT) of radiation pneumonitis at 300 mg BID, additional subjects were enrolled at this 
dose and no additional DLTs were reported. At 400 mg BID, 1 patient reported a DLT of Grade 3 
fatigue, with no additional DLTs at this dose level. Another patient at 400 mg BID developed 
asymptomatic and transient hypopituitarism after 1 cycle of therapy and was able to continue 
dosing with INCB024360. Among the 18 subjects treated at either 600 mg or 700 mg BID, no 
DLTs were observed. Dose escalation was completed based on preliminary pharmacokinetic and 
pharmacodynamic data, which demonstrated that doses of INCB024360 above 300 mg BID 
achieved exposures exceeding the IC90 determined in nonclinical models and, in 
pharmacodynamic assays, reached a plateau for Kyn/Trp levels and ratios. In the final cohort of 
600 mg BID, the effect of food on INCB024360 absorption was evaluated. No objective responses 
were reported. At 2 months, stable disease was seen in 15 patients and lasted ≥ 4 months in 
7 patients. The main AE reported in subjects receiving more than 2 cycles of INCB024360 has 
been Grade 1 or Grade 2 fatigue.
In a combination study conducted by Incyte Corporation of INCB024360 and ipilimumab in 
metastatic melanoma patients, 5 of 7 subjects enrolled at a dose of 300 mg BID of INCB024360 
plus 3 mg/kg of ipilimumab, developed Grade 3 or Grade 4 AST and ALT elevations between 
2 and 4 cycles of treatment. Only one of these subjects had a bilirubin elevation of Grade 1.
Plasma levels of INCB024360 and plasma levels of Kyn were measured in serial samples. Steady-
state linear pharmacokinetics were obtained on or before Day 8 and there was achievement of 
steady-state on Day 15. The half-life was 2.3 to 4 hours. Pharmacodynamic correlates suggest that 
significant target inhibition was achieved at BID doses greater than or equal to 300 mg BID, 
resulting in steady state exposures that exceeded the IC90. Blood samples for tryptophan and 
kynurenine levels as a pharmacodynamic effect show significant target inhibition with doses of 
50 mg BID or greater. BID doses greater than or equal to 300 mg BID result in normalization of 
kynurenine levels in those patients who show elevations at baseline. Immunohistochemical 
staining of 11 patients demonstrated that IDO1 tumor expression could be observed in tumor cells 
and/or infiltrating inflammatory cells in 10/11 samples, and CD3+ T cells and Foxp3+ 
T regulatory cells were present in all of the samples examined.
In unpublished preliminary data from Incyte, Kynurenine concentrations and the Kyn/Trp ratio 
were higher in the serum of most patients compared to controls and normalized following 
treatment with inhibitor when treated with doses that exceeded the IC90 (i.e., > 300 mg BID 
(n = 19 patients)).
Data for All Patients

Kynurenine concentrations:
o
Normal individuals:
median, 2.0 µM
o
Cancer patients:
median, 2.1 µM (1.3 µM - 4.2 µM)
o
Post inhibitor:
median, 0.97 µM (0.5 µM - 1.7 µM)

Kyn/Try ratios:
o
Normal individuals:
median, 29.9 nmol/µmol
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o
Cancer patients:
median, 37.4 nmol/mmol (17.8 - 68.9 nmol/µmol)
o
Post inhibitor:
median, 18.3 nmol/µmol
Data for Patients with Kyn levels > 2 µM (n = 8) or K/T > 30 nmol/µmol (n = 14)

Kynurenine concentrations:
o
Normal individuals: median, 2.0 µM
o
Cancer patients:
median, 2.7 µM (2.1 µM - 4.2 µM)
o
Post inhibitor:
median, 1.1 µM (0.5 µM - 1.7 µM)

Kyn/Try ratios:
o
Normal individuals:
median, 29.9 nmol/µmol
o
Cancer patients:
median, 42.0 nmol/µmol (34 – 69 nmol/µmol)
o
Post inhibitor:
median, 18.6 nmol/µmol (8 - 43 nmol/µmol)
1.6.3 Sirolimus (used in Exploratory Cohort at Roswell Park ONLY)
Sirolimus is a specific inhibitor of the mammalian target of sirolimus (mTOR complex 1) and is 
the active metabolite of temsirolimus, which is the first in class mTOR inhibitor approved for use 
in RCC mTOR inhibitor approved for the treatment of renal cell cancer [25-27].  Sirolimus binds 
to an intracellular protein (FKBP-12), and the protein–drug complex binds to mTOR to inhibit its 
kinase activity [25].  In preclinical tumor models, sirolimus inhibited cell proliferation, cell growth, 
survival pathways, and tumor angiogenesis [28, 29].  Initial clinical studies in cancer patients 
investigated IV sirolimus administered at dosages that were corrected for body surface area 
(mg/m2) and were designed to establish tolerability, safety, and pharmacokinetic parameters [30, 
31].  When administered as a 30-minute infusion once weekly, sirolimus was well tolerated over 
a wide range of doses (7.5 mg/m2 – 165 mg/m2) [31].  Rash and mucositis/stomatitis were the 
most frequent drug-related AEs, and thrombocytopenia was the main dose-limiting toxicity. 
Antitumor activity was observed in heavily pretreated patients, including patients with advanced 
RCC, who received different doses and schedules) [30, 31]. Overall, the most frequent Grade 3 or 
Grade 4 mTOR inhibition-related AEs (n = 110) were hyperglycemia (17%), hypophosphatemia 
(13%), anemia (9%), and hypertriglyceridemia (6%).
The major limitation for combining sirolimus and immunotherapy is that mTOR inhibitors are 
generally regarded as immunosuppressive via several mechanisms, including the induction of 
regulatory T-cells. Although sirolimus is thought to have immunosuppressive effects, its effects 
on the potential inhibition of T-lymphocyte function after repeated daily administrations in 
euthymic mice showed that T-lymphocyte activity recovered within 24 hours after the 
discontinuation of treatment.
Sirolimus has been used in patients with HIV and hepatitis undergoing solid organ transplant. In 
several reports no increased incidence of reactivation of HIV or any other viral infection have 
occurred.
Recent studies by our group and others show that mTOR inhibition appears to significantly 
condition tumor bearing hosts for augmented vaccine induced T-cell mediated tumor control) [32, 
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33]. It has been observed that mTOR inhibition selectively switches the transcriptional program in 
effector CD8+ T-cells from T-bet to Eomes expression. Eomes expression has been known to 
increase in the CD8+ precursor memory T-cells. The observations will imply that sirolimus 
conditions CD8+ T-cells to have greater capacity for lymph node homing and retention.
Since sirolimus is cytostatic, the potential for therapeutic synergy with immunotherapy is likely to 
include (1) increase the dose of antigens delivered for presentation (2) enhanced anti-tumor T-cell 
response in the draining lymph node through cross-priming (3) effects on T-cell trafficking (4) 
generation of immunological memory. Taken together, we propose that sirolimus and 
immunotherapeutic strategies might be combined to control tumor growth, and the vaccine- 
induced memory immune responses would still be available to delay time to disease relapse.
1.6.4
Potential Risks and Benefits
1.6.4.1 INCB024360 Potential Risks
There have been no adverse findings in toxicology or safety pharmacology assessments described 
herein. INCB024360-related changes included an increased incidence of diarrhea in 
500 mg/kg/day dogs as well as sporadic emesis. Weak cross reactivity of INCB024360 to the 
human vasopressin 1a receptor, dopamine receptor and carbonic anhydrase II is not expected to 
pose a risk to humans. Blood pressure will be monitored in this clinical study and blood electrolytes 
will also be assessed. In 28-day toxicology studies, Cmax values have exceeded the IC50 for the 
IDO enzyme (72 nM) by up to 37-fold and the IC50 for the vasopressin 1a receptor by up to 4-
fold (13-fold in single dose studies) in the absence of any toxicity, so the risk of unintended 
pharmacological activity is expected to be low.
Hypothetically, IDO represents an important immune control enzyme and cells expressing IDO 
are capable of suppressing amplified immune effector responses and promoting immune tolerance 
under various physiological conditions. Inhibition of IDO using 1-MT has been shown to induce 
fetal allograft rejection in mice (Munn et al, 1998). Syngeneic, pluripotent bone marrow stem cells, 
transferred to mice with experimental autoimmune encephalomyelitis, a model of multiple 
sclerosis, enhanced recovery, prevented relapses and promoted myelin repair through their 
expression of IDO and this was blocked by administration of 1-MT (Matysiak et al, 2008) and 
inhibition of IDO by systemic administration of 1-MT at clinical onset significantly exacerbated 
disease scores in this model (Sakurai et al, 2002). Blocking IDO with 1-MT also aggravated the 
severity of arthritis and enhanced the immune responses in mice with collagen-induced arthritis 
(Szántó et al, 2007). Taken together, these studies imply that IDO may be a negative inhibition 
pathway to control autoimmune diseases. For these reasons, patients with autoimmune disease are 
excluded from participation in this study and study participants will be closely monitored for signs 
or symptoms of developing autoimmune or inflammatory disease.
Recent studies with the anti-CTLA-4 antibody ipilimumab have shown dysregulation of mucosal 
immunity and gastrointestinal toxicity which manifests as diarrhea (Berman et al, 2008). The 
immune related AEs are distinct from classic inflammatory bowel diseases and graft-versus-host 
disease in terms of histologic features but respond to treatment with steroids. Since IDO targets 
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immune regulation differently from the anti-CTLA-4 antibodies, it is unknown whether similar 
toxicities may be observed with IDO inhibition. There is no evidence of gastrointestinal toxicity 
in the IDO knockout mouse.
1.6.4.2 INCB024360 Benefits
Patients may experience improvement in their disease status during the study. It is unknown if 
there will be significant benefit for the patients enrolled in this study.
1.6.4.3 Sirolimus Potential Risks
Sirolimus is metabolized primarily by CYP3A4 in human liver microsomes, and may influence 
substrate transport via P-glycoprotein. Since there are many agents that affect the metabolic 
activity of CYP3A4 and P-glycoprotein, there is a potential for drug-drug interactions to occur 
between sirolimus and co-administered drugs. Current knowledge and available data suggest 
caution when combining sirolimus with strong CYP3A4 inhibitors. Strong CYP3A4 inhibitors are 
to be avoided unless there is no alternative available. Co-administration of ketoconazole should be 
avoided if possible. Patients would be strongly encouraged to avoid herbal supplements including, 
but not limited to St. John’s Wort, during active treatment. Sirolimus may inhibit CYP2D6 and 
potentially interact with drugs that are substrates for CYP2D6.

Interstitial Pneumonitis/Alveolitis
There have been a number of reports of a non-specific interstitial pneumonitis/alveolitis among 
oncology patients who received sirolimus. Some are asymptomatic and detected on CT scan or 
chest x-ray, while symptoms such as dyspnea, cough, and fever were noted in others. Some cases 
resulted in discontinuation of sirolimus and treatment with corticosteroids and/or antibiotics, while 
others did not require intervention. In most cases to date, where outcome is known, there was 
improvement or resolution following such interventions. There have been some occurrences of 
rechallenge with subsequent recurrence of the pneumonitis. This type of event has also been 
reported in association with the closely-related compound sirolimus (when given orally to 
transplant patients) and other agents. 

Pulmonary Hypertension
To date, there have been sporadic reports of pulmonary hypertension in oncology patients 
receiving sirolimus. A causal relationship to sirolimus cannot be determined based on the available 
information. These reports will continue to be monitored.

Renal Impairment
Renal impairment, insufficiency, and failure have been reported in some oncology patients 
receiving sirolimus. A causal relationship to sirolimus cannot be determined based on the available 
information. These reports will continue to be monitored.

Thrombotic Events
Thrombotic events, including thromboembolism, thrombosis, arterial thrombosis limb, venous 
thrombosis deep limb, venous thrombosis, vena cava thrombosis, and pulmonary embolism, have 
been reported in patients receiving sirolimus. Although most events were considered unrelated to 
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sirolimus, it should be noted that sirolimus is associated with increased fibrinogen levels. The 
clinical significance of this association is not yet known.

Central Nervous System Bleeding
Central nervous system (CNS) bleeding has been observed in some oncology patients receiving 
sirolimus. While a relationship to sirolimus is not suspected, it cannot be ruled out. Most of these 
patients had CNS tumors and most were receiving anticoagulants (low molecular weight heparin, 
warfarin, etc). It is not clear if there could have been a drug-drug interaction between sirolimus 
and the anticoagulant. Patients receiving anticoagulants should be monitored closely.

Immunosuppression with Continuous Sirolimus Dosing
Patients treated with a continuous dose of sirolimus may have immunosuppressant. As such, these 
patients should be carefully observed for occurrence of infections, especially opportunistic 
infections.
1.7 Rationale for the Use of DEC205mAb-NY-ESO-1 Fusion Protein (CDX-1401) with 
Adjuvant Poly-ICLC in Combination with INCB024360
In previous experimental studies, we have observed that (i) the beneficial prognostic effect of 
CD8+ tumor infiltrating lymphocytes (TILs) in ovarian cancer is modulated by CD25+FOXP3+ 
subpopulation of CD4+ T cells with immunosuppressive properties [34] (ii) tumor and dendritic 
cell expression of indoleamine 2,3 dioxygenase (IDO) mediate preferential accumulation of 
CD4+CD25+FOXP3+ T cells in human ovarian cancer (iii) NY-ESO-1 peptide vaccination failed 
to modulate the suppressive effect of Tregs on high-avidity NY-ESO-1-specific T cell precursors 
[35]. Therefore, the ideal strategy for improving anti-tumor efficacy should combine (i) abrogation 
of Treg induction and (ii) augmentation of clonal expansion of high avidity effector T cells. In this 
clinical trial, we have focused on targeting a valid, immunogenic ovarian tumor antigen 
NY-ESO-1; along with enhancement of T cell clonal expansion and abrogation of Tregs with the 
IDO inhibitor, INCB024360.
The survival of patients with Stage III/IV ovarian cancer has been strongly correlated with the 
presence or absence of intratumoral T cells [34, 36]. Additionally, high levels of intratumoral IDO 
expression in ovarian cancer have been found to correlate with a reduced number of tumor 
infiltrating lymphocytes [37]. This high level of IDO expression was found to correlate with 
disease stage as well as with decreased survival, a finding that has been described by a number of 
investigators [38-41]. Thus, there is a strong rationale to utilize IDO inhibition as a strategy to 
restore antitumor immunity in advanced ovarian cancer.
Based on the safety profiles in Phase I and on-going Phase II studies, there is an extremely low 
potential for toxicity of the treatment combination. The vaccine (CDX-1401 with adjuvant 
polyICLC) has been shown to be safe in Phase I studies, with virtually no dose limiting toxicities, 
treatment-related Grade 3 or Grade 4 AEs, treatment-related SAEs or AEs requiring 
discontinuation of treatment. INCB024360 has been tested in Phase I trials, and is currently 
undergoing Phase II evaluation. INCB024360 was shown to be safe at doses as high as 600 mg 
bid. This is much lower than the maximum 300 mg bid that we propose in this clinical trial.
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1.8
Rationale for Exploratory Cohort at Roswell Park ONLY (DEC205mAb-NY-ESO-1 
Fusion Protein (CDX-1401) with Adjuvant Poly-ICLC in Combination with Sirolimus)
A major limitation of current cancer vaccines is the ineffective generation of memory T-cell 
precursors. This issue will be addressed in the current clinical trial via the use of sirolimus to 
promote the generation of effector/memory T-cells.
The induction of memory T-cell responses is a key to prevent tumor recurrence, but has been a 
major challenge for all tumor immunotherapy approaches. Recently, we have reported that 
rapamycin mediated inhibition of mammalian target of rapamycin (mTOR) switches effector 
CD8+ T cells to memory precursor like phenotype [33].  Our data indicate that (i) inhibition of 
mTOR activity switches T-bet for Eomesodermin expression, facilitating transition of type 1 
effector cells for memory (ii) mTOR inhibition post-immunization enhances tumor control in EOC 
bearing hosts (iii) rapamycin mediated mTOR inhibition is reversed over time, (iv) varying the 
duration (0-8, 0-20 or 0-40 days) of mTOR inhibition after immunization produces memory CD8+ 
T cells with varying extent of type 1 effector functions. Collectively, these findings encourage us 
to exploit the use of mTOR inhibition to generate durable CD8+ T cell responses and test its ability 
to prolong EOC remission rates in a clinical trial.
Based on our observations, we propose to test the hypothesis that mTOR inhibition will condition 
vaccine induced T cells for enhanced persistence, antigen recall and durable tumor immunity in a 
human clinical trial. We plan to use rapamycin, a clinically available mTOR inhibitor that has not 
been previously used in this fashion, for our “Proof-of-Principle” studies. The regimen of mTOR 
inhibition that can optimally combine with NY-ESO-1 protein with CDX-1401 vaccination to 
generate memory T-cells in cancer patients is not established. As varying the duration and timing 
of mTOR inhibition in relation to vaccination leads to distinct functional outcomes in T-cells, the 
dose and schedule for sirolimus in this study has been based on our completed clinical trial 
(NCT01522820), titled “A phase I clinical trial of mTOR inhibition with rapamycin for enhancing 
intranodal dendritic cell vaccine induced anti-tumor immunity in patients with NY-ESO-1 
expressing solid tumors”.
2
OBJECTIVES
2.1 Phase I Primary Objectives

To determine the safety of fixed doses of DEC205mAb-NY-ESO-1 fusion protein with 
adjuvant poly-ICLC given as a vaccine in combination with INCB024360.

To evaluate toxicity as defined by NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0.
2.2 Phase IIb Primary Objectives

To determine the progression free survival (PFS) (primary endpoint) using standard irRC 
criteria.
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2.3 Secondary Objectives (Phase I, Phase IIb and Exploratory Cohort)

To determine the effectiveness of INCB024360 on enhancing vaccine efficacy by assessing 
NY-ESO-1 specific cellular and humoral immunity.

Exploratory Cohort at Roswell Park ONLY: To determine the effectiveness of Sirolimus 
on enhancing vaccine efficacy by assessing NY-ESO-1 specific cellular and humoral 
immunity.
o
Peripheral blood NY-ESO-1 specific CD8+ and CD4+ T cells.
o
Peripheral blood NY-ESO-1 specific antibodies.
o
Peripheral blood frequency of CD4+CD25+FOXP3+ regulatory T cells.
o
Pharmacokinetics of INCB02360 in relation to T cell frequency and function in 
correlation with PFS.
3
METHODOLOGY
3.1 Study Design
This is an open-label, Phase I/IIb study of the IDO inhibitor, INCB024360, in combination with 
DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) given with adjuvant poly-ICLC in patients 
with NY-ESO-1 or LAGE-1 expressing epithelial ovarian, fallopian tube, or primary peritoneal 
cancer who are in remission.
For the Phase I component of the study, eligible patients will receive a fixed intracutaneous dose 
of DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) (Day 1) given with subcutaneous 
adjuvant poly-ICLC (Day 1 and Day 2) for each 28 day cycle for a total of 5 cycles; and Cohort 1 
patient enrollment will begin INCB024360 at a fixed daily dose of 300 mg BID orally (Cohort 1) 
for a total of 7 cycles. Based on the decision rules for DLTs, patients may be enrolled into 
Cohort -1. Cohort -1 will receive DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) (Day 1) 
given with adjuvant poly-ICLC (Day 1 and Day 2) for each 28 day cycle for a total of 5 cycles, 
and daily oral INCB024360 100 mg BID (Cohort -1) starting on Day 1 for 7 cycles. Based on the 
decision rules for DLTs, patients may be enrolled into Cohort -2. Cohort -2 will receive 
DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) (Day 1) given with adjuvant poly-ICLC 
(Day 1 and Day 2) for each 28 day cycle for a total of 5 cycles, and daily oral INCB024360 50 mg 
BID (Cohort -1) starting on Day 1 for 7 cycles.
After completing 1 cycle of treatment in the last patient from Cohort 1 (or Cohort -1 or Cohort -2), 
accrual into the randomized Phase IIb study (Cohort 2) will begin at the dose of INCB024360 that 
is determined to be safe in the Phase I trial (300 mg BID versus 100 mg BID versus 50 mg BID) 
in combination with CDX-1401. This is a randomized parallel design employing randomization 
for each patient enrolled to 1 of 2 groups (Table 1). Treatment cohorts include (i)  DEC205mAb-
NY-ESO-01 fusion protein (CDX-1401) given with adjuvant poly-ICLC alone and (ii) 
INCB024360 plus DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) given with adjuvant 
poly-ICLC.
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An additional exploratory cohort (N=6) receiving 4 cycles of sirolimus in combination with 
DEC205mAb-NY-ESO-01 fusion protein (CDX-1401) with adjuvant poly-ICLC will be added to 
supplement the secondary objectives, which will aid in planning the next phase of the 
investigation. This will not affect the randomized component of the study as enrollment to the 
randomized Phase IIb at Roswell Park only will be suspended temporarily until the 6 patients are 
enrolled. Data will be included as described in Section 11.4 for immune response. 
3.1.1
Target Accrual and Study Duration
The Phase I component of this study will enroll 3 -18 patients and 50 patients for the Phase IIb 
component. Six patients will be enrolled in the additional exploratory cohort.  Patients will be 
enrolled at Roswell Park and participating sites. The exploratory cohort applies to the Roswell 
Park site only.  Accrual is expected to take approximately 8 years. Patients in Phase I and Phase 
IIb are expected to participate in this study for approximately 28 weeks of active therapy.  Patients 
in the exploratory cohort are expected to participate in this study for approximately 20 weeks of 
active therapy.
4
PATIENT SELECTION
4.1 Inclusion Criteria
To be included in this study, patients must meet the following criteria:
1.
Eligible patients will be women with epithelial ovarian, fallopian tube, or primary 
peritoneal carcinoma after chemotherapy with no evidence of disease or minimal residual 
disease for primary or recurrent disease. This may or may not be measurable. These 
patients would normally enter a period of observation after standard management.
2.
Any HLA type. (Historic HLA typing is permitted.)
3.
Tumor expression of NY-ESO-1 or LAGE-1 by IHC and/or RTPCR.
4.
Life expectancy > 6 months.
5.
Hematology and biochemistry laboratory results within the limits normally expected for 
the patient population, without evidence of major organ failure. Have the following 
clinical laboratory values:

ANC ≥ 1,000/µL

PLT ≥ 100,000/µL

Hgb ≥ 8 g/dL

Total bilirubin ≤ 1.5 x ULN

Serum aspartate aminotransferase (SGOT/AST) or serum alanine aminotransferase 
(SGPT/ALT) ≤ 3 x ULN

Serum creatinine ≤ 2 x ULN
6.
Have been informed of other treatment options.
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7.
Age ≥ 18 years of age.
8.
Patient or legal representative must understand the investigational nature of this study 
and sign an Independent Ethics Committee/Institutional Review Board approved written 
informed consent form prior to receiving any study related procedure.
9.
Have an ECOG Performance Status of ≤ 2. Refer to Appendix A.
10. The ability to swallow and retain oral medication.
11. Patients of child-bearing potential must agree to use acceptable contraceptive methods 
(e.g., double barrier) during treatment.
12. Patients may have received previous NY-ESO-1 vaccine therapy. Patients who received 
maintenance paclitaxel or bevacizumab are eligible for enrollment provided they have 
discontinued therapy (at least 4 weeks for prior taxane or prior bevacizumab) prior to 
randomization and recovered from toxicities to less than Grade 2.
4.2 Exclusion Criteria
Patients will be excluded from this study for the following:
1.
Metastatic disease to the central nervous system for which other therapeutic options, 
including radiotherapy, may be available.
2.
Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders).
3.
History of severe autoimmune disorders requiring use of steroids or other 
immunosuppressives.
4.
Concomitant systemic treatment with chronic use (based on the investigator’s judgment) 
of corticosteroids, anti-histamine or non-steroidal anti-inflammatory drugs, and other 
platelet inhibitory agents (See also Section 6.4 for restrictions/recommendations on 
ancillary therapy).
5.
Chemotherapy, radiation therapy, or immunotherapy within 4 weeks prior to first dosing 
of study drug (6 weeks for nitrosoureas). Concomitant hormonal therapies for breast 
cancers are allowed.
6.
Subjects being treated with a monoamine oxidase inhibitor (MAOI), or drug which has 
significant MAOI activity (e.g., meperidine, linezolid, methylene blue) within 3 weeks 
prior to screening.
7.
Subjects who are currently receiving therapy with a potent CYP3A4 inducer or inhibitor 
(e.g. clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir). 
8.
Use of UGT1A9 inhibitor including: diclofenac, imipramine, and ketoconazole. 
9.
Participation in any other clinical trial involving another investigational agent within 
4 weeks prior to first dosing of study drug.
10. Known hepatitis B, hepatitis C, or HIV.
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11. Mental impairment that may compromise the ability to give informed consent and 
comply with the requirements of the study.
12. Lack of availability of a patient for immunological and clinical follow-up assessment.
13. Evidence of current drug or alcohol abuse or psychiatric impairment, which in the 
Investigator’s opinion will prevent completion of the protocol therapy or follow-up.
14. Pregnant or nursing female patients.
15. Unwilling or unable to follow protocol requirements.
16. Any condition which in the Investigator’s opinion deems the patient an unsuitable 
candidate to receive study drug (i.e., any significant medical illness or abnormal 
laboratory finding that would, in the investigator’s judgment, increase the patient’s risk 
by participating in this study).
17. Known hypersensitivity to any of the study drugs that will be given to the participant
18. Additional exclusion criteria for exploratory cohort ONLY: Known pulmonary 
hypertension.
4.3 Inclusion of Women and Minorities
Women and members of all races and ethnic groups are eligible for this study.
5
INVESTIGATIONAL AGENTS
5.1 DEC205mAb-NY-ESO-1 Fusion Protein (CDX-1401)
Detailed technical information regarding CDX-1401 can be found in the Investigator’s Brochure. 
CDX-1401 is a fusion protein consisting of a fully human monoclonal antibody (HuMab) of IgG1 
(kappa) isotype with specificity for the dendritic cell receptor, DEC-205, genetically linked to the 
full length NY-ESO-1 tumor antigen.
The clinical trial product will be formulated as a sterile solution intended for parenteral use. 
CDX-1401 will be provided in 2 mL vials containing approximately 1 mL of solution, at a 
concentration of 1 mg/mL. CDX-1401 vials should be stored at -20˚C ± 5˚C the in pharmacy 
department.
Source:
Celldex Therapeutics, Inc, Fall River, MA.
Intended Dose:
1 mg on Day 1 of each cycle.
5.2 Poly-ICLC Adjuvant
Poly-ICLC 
(polyinosinic-polycytidylic 
acid 
stabilized 
with 
poly-L-lysine 
and 
carboxymethylcellulose) is a synthetic double-stranded ribonucleic acid (dsRNA) with broad 
immune-enhancing effects mediated through TLR-3 activation.
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Poly-ICLC will be provided in single-dose vials containing 1 mL of opalescent solution. Poly-
ICLC drug product used to be labeled as 2 mg/mL but as per IB V14 (1/25/2018), this is being 
changed to 1.8 mg/mL to incorporate for the water content in the lyophilized components (Poly I 
and Poly C). This represents no change in the product or formulation, but simply a calculation 
correction and therefore, irrespective of being labeled differently (older lots 2.0 mg/mL label and 
newer lots 1.8 mg/mL label) dosing volume for this study remains unchanged. In effect, the prior 
2.0 mg/mL label represented the “wet” Poly-IC concentration which is equivalent to the current 
1.8 mg/mL label representing the “dry” Poly-IC concentration. The current lot labeled 2.0 mg/mL 
will expire on 2/28/18 and pharmacy will start using the new lot with the new labels (1.8 mg/ml) 
effective 3/1/18.
The poly-ICLC vials should be refrigerated at about 40ºF (2 ºC  - 8ºC) but should not be frozen. 
Poly-ICLC is also stable at room temperature for brief periods (days).
Because the product is not formulated with a preservative, once the sterile vials are entered or the 
poly-ICLC is drawn into a syringe, the drug should be used as soon as possible (typically within 
6 hours if kept at room temperature or within 24 hours if refrigerated and the syringe(s) had been 
filled under aseptic conditions) or in accordance with any applicable institutional guidance. 
Poly-ICLC is to be withdrawn from the vial under sterile conditions and administered 
subcutaneously as supplied. 
Source: Poly-ICLC is an Investigational Product manufactured by Oncovir for Dalton, 
Washington, DC, USA; will be supplied by Celldex Therapeutics, Inc, Fall River, MA.
Intended Dose: 1 ml on Day 1 and Day 2 of each cycle.
All synthesis, production, formulation, and packaging of the investigational agents are in 
accordance with applicable current Good Manufacturing Practices and meet applicable criteria for 
use in humans.
5.3 INCB024360
INCB024360 drug substance is a white to off white powder and is referred to herein as 
INCB024360. INCB024360 drug product will be provided as 25 mg, 100 mg, and 300 mg tablets. 
The tablet formulation contains the active ingredient along with commonly used excipients. The 
tablets contain the active drug (INCB024360) along with commonly used excipients Lactose 
Monohydrate, Microcrystalline Cellulose, Povidone, Croscarmellose Sodium Colloidal Silicon 
Dioxide, and Magnesium Stearate. All excipients are of compendial grade.
Source:
Incyte Corporation Wilmington, DE 19880
Intended Dose:
50 mg, 100 mg, and 300 mg BID, depending on the cohort.
5.4
Sirolimus (exploratory cohort at Roswell Park only)
5.4.1
Active Substance and Source
Each tablet of sirolimus contains either 1 mg or 2 mg. Sirolimus will be purchased by Roswell 
Park Investigational Drug Services with grant funding.
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5.4.2
Packaging and Labeling
 Either generic or brand name Sirolimus can be used in this study at a dose of 4 mg/day.
5.5
Storage and Stability
The Investigator or designate is responsible to store and dispense the investigational product and 
will be responsible for ensuring that study drug is securely maintained in a locked, limited-access 
facility, in accordance with the applicable regulatory requirements. Drug storage temperature will 
be maintained, recorded, dated, and initialed daily, as applicable.
Sirolimus is chemically stable at room temperature.
5.6
Handling and Disposal of Investigational Products
The Investigator or designate will be responsible for dispensing and accounting for all 
investigational drug provided by Roswell Park exercising accepted medical and pharmaceutical 
practices. Study drugs must be handled as cytotoxic agents and appropriate precautions taken per 
the institution’s environmentally safe handling procedures. All investigational drugs will be 
dispensed in accordance with the Investigator’s prescription or written order.
Study drug accountability records will be available for verification by the Clinical Research 
Monitor appointed from the CRS office at each monitoring visit. At the completion of the study, 
there will be a final reconciliation of all study drug.
An investigational agent dispensing record will be kept current and will contain the following 
information:

Patient’s identification information (i.e., patient number and initials).

Date and quantity of drug dispensed.

Date and quantity of drug returned to the Investigator/pharmacy (if any).

Date and quantity of accidental loss of study drug (if any).
These inventories must be made available for inspection by the CRS study monitor. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained.
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol.
6
TREATMENT PLAN
6.1 Dosing and Administration
Treatment will be administered on an outpatient basis.
For the Phase I component of the study, eligible patients will receive a fixed intracutaneous dose 
of DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) (Day 1) given with subcutaneous 
adjuvant poly-ICLC (Day 1 and Day 2) for each 28 day cycle for a total of 5 cycles; and Cohort 1 
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patient enrollment will begin INCB024360 at a fixed daily dose of 300 mg BID orally (Cohort 1) 
for a total of 7 cycles. Based on the decision rules for DLTs, patients may be enrolled into 
Cohort -1. Cohort -1 will receive DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) (Day 1) 
given with adjuvant poly-ICLC (Day 1 and Day 2) for each 28 day cycle for a total of 5 cycles, 
and daily oral INCB024360 100 mg BID (Cohort -1) starting on Day 1 for 7 cycles. Based on the 
decision rules for DLTs, patients may be enrolled into Cohort -2. Cohort -2 will receive 
DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) (Day 1) given with adjuvant poly-ICLC 
(Day 1 and Day 2) for each 28 day cycle for a total of 5 cycles, and daily oral INCB024360 50 mg 
BID (Cohort -1) starting on Day 1 for 7 cycles.
After completing 1 cycle of treatment in the last patient from Cohort 1 (or Cohort -1 or Cohort -2), 
accrual into the randomized Phase IIb study (Cohort 2) will begin at the dose of INCB024360 that 
is determined to be safe in the Phase I trial (300 mg BID versus 100 mg BID versus 50 mg BID) 
in combination with CDX-1401. This is a randomized parallel design employing randomization 
for each patient enrolled to 1 of 2 groups. Treatment cohorts include (i) DEC205mAb-NY-ESO-1 
fusion protein (CDX-1401) given with adjuvant poly-ICLC alone and (ii) INCB024360 plus 
DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) given with adjuvant poly-ICLC. 
An additional exploratory cohort (N=6) receiving 4 cycles of sirolimus in combination with 
DEC205mAb-NY-ESO-01 fusion protein (CDX-1401) with adjuvant poly-ICLC will be added to 
supplement the secondary objectives, which will aid in planning the next phase of the 
investigation. This will not affect the randomized component of the study as enrollment to the 
randomized Phase IIb at Roswell Park only will be suspended temporarily until the 6 patients are 
enrolled. Data will be included as described in Section 11.4 for immune response. 
6.1.1
CDX-1401
CDX-1401 will be administered as a total dose of 1 mg based on the safety and immunogenicity 
assessment in the Phase I study of CDX-1401. CDX-1401 will be supplied at a concentration of 
1 mg/mL. A 1 mL volume is to be administered and should be split into 2 intracutaneous injections 
given within the 5 cm x 5 cm administration site.
Intracutaneous injection is a combination of intradermal and subcutaneous administration. The 
maximum volume which can be administered intradermally is 0.1 ml and the maximum volume 
administered subcutaneously is considered to be 1-2 ml.  Each injection will be given 
intracutaneously (0.1 ml intradermally and the remainder subcutaneously) within the identified 5 
cm X 5 cm treatment site.
Intracutaneous injection should be performed as follows: Small gauge needles (5/8 inch-1 inch by 
25 gauge or smaller) are recommended for intracutaneous injections. A region of skin including 
the 5 cm x 5 cm administration site should be cleaned with an alcohol prep pad and allowed to air 
dry. Each of the 2 injections should consist of a combination of intradermal and subcutaneous 
administration. Beginning with the intradermal administration, the needle is advanced at least 1 cm 
into the dermis at a shallow angle, ensuring that the needle tip remains within the dermis. The 
injection should then begin; assuring that a skin bleb begins to form. If a bleb is not formed, the 
needle should be repositioned within the skin without being withdrawn, and the injection can be 
attempted again. Approximately 0.1 ml of each planned injection should be injected intradermally. 
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The needle is then backed away so that the tip is outside the bleb but still within the skin. It can 
then be advanced at a sharper angle to reach the superficial subcutaneous space underneath the 
bleb at a depth of approximately 5 mm. Provided no blood is aspirated, the remaining planned 
injection volume is administered. This procedure is repeated for the remaining injection until the 
total planned volume of 1 mL is administered.
The administration site should be free of potentially complicating dermatologic conditions, and 
should not be located in an area where integrity of the draining lymph node bed is potentially 
compromised (i.e., an extremity where a nodal resection was previously performed). For each 
subsequent administration cycle, a new administration site should be selected, with the aim of 
stimulating a new draining lymph node bed for each administration. All nurses administering this 
vaccine will be trained to administer the doses intracutaneously prior to study implementation.
6.1.2
Poly-ICLC
Poly-ICLC dosing will consist of 1 subcutaneous injection of 1 mL administered by the clinic 
personnel within 5x5 cm area of CDX-1401. Adjuvant poly-ICLC will be administered as soon as 
possible after each CDX-1401 injection, with the goal to administer the vaccine and adjuvant 
within a 1 hour period. The second poly-ICLC administration for each cycle may be self-
administered by the patient 24 hours (± 6 hours) later for Cycle 2 onward. Patients will be properly 
educated and instructed regarding the storage of poly-ICLC; when, how, and where to self-
administer the product; and to maintain the patient diary.  (Appendix C).
6.1.3
INCB024360
INCB024360 is administered at varying dose levels depending on the cohort a patient is assigned 
(Table 1). Patients will be instructed on the dose and schedule of INCB024360 for the cohort to 
which they have been assigned. Tablets will be taken in the morning and evening, approximately 
12 hours apart and at least 2 hours after a meal. Patients will abstain from food for 1 hour after 
dosing. Each cycle is a period of 28 days.
6.1.4
Sirolimus (Exploratory cohort at Roswell Park ONLY)
Sirolimus is administered to patients enrolled in the exploratory cohort at Roswell Park ONLY.  A 
fixed dose of Sirolimus 4mg/day for the first 2 weeks of each 28 day cycle will be given for four 
cycles as described in Table 2 and Table 4.  Sirolimus will not be taken with the 5th vaccine.
6.1.5
Compliance
CDX-1401 and poly-ICLC will be administered by the study staff on the CDX-1401 dosing dates, 
and may be self-administered by the patient for the remaining doses. Compliance with self-
administration of adjuvants and INCB024360 (or Sirolimus for exploratory cohort) will be 
assessed via patient-reported dosing diaries (Appendix C and Appendix D).
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Table 1.
Dosing Schedule for INCB024360 and DEC205mAb-NY-ESO-1 Fusion 
Protein (CDX-1401) Given with Adjuvant Poly-ICLC
Treatment 
Cohorts
Number of 
Patients
DEC205mAb-NY ESO 1 Fusion Protein (CDX 
1401) Given with Adjuvant Poly-ICLCa
INCB024360 (Oral)
Phase I
Cohort -2
3 – 6 patients

DEC205mAb-NY-ESO-1 fusion protein (1 mg, 
intracutaneous injection) on Day 1 of each 28 day 
cycle for a total of 5 cycles.

Adjuvant poly-ICLC (1 ml, subcutaneous) on 
Day 1 and Day 2 of each 28 day cycle for a total of 
5 cycles.
50 mg BID for a total of 
7 cycles
Cohort -1
3 – 6 patients

DEC205mAb-NY-ESO-1 fusion protein (1 mg, 
intracutaneous injection) on Day 1 of each 28 day 
cycle for a total of 5 cycles.

Adjuvant poly-ICLC (1 ml, subcutaneous) on 
Day 1 and Day 2 of each 28 day cycle for a total of 
5 cycles.
100 mg BID for a total 
of 7 cycles
Cohort 1 
(start)
3 – 6 patients

DEC205mAb-NY-ESO-1 fusion protein (1 mg, 
intracutaneous injection) on Day 1 of each 28 day 
cycle for a total of 5 cycles.

Adjuvant poly-ICLC (1 ml, subcutaneous) on 
Day 1 and Day 2 of each 28 day cycle for a total of 
5 cycles.
300 mg BID for a total 
of 7 cycles
Randomized Phase IIb (parallel groups design)
Cohort 2a
25 patients
DEC205mAb-NY-ESO-1 fusion protein (1 mg. 
intracutaneous injection) on Day 1 of each 28 day 
cycle for a total of 5 cycles
Adjuvant poly-ICLC (1 ml. subcutaneous) on Day 1 
and Day 2 of each 28 day cycle for a total of 5 cycles..
None
Cohort 2b
25 patients

DEC205mAb-NY-ESO-1 fusion protein (1 mg, 
intracutaneous injection) on Day 1 of each 28 day 
cycle for a total of 5 cycles.

Adjuvant poly-ICLC (1 ml, subcutaneous) on 
Day 1 and Day 2 of each 28 day cycle for a total of 
5 cycles.
300 mg BID for a total 
of 7 cycles
1
Refer to Section 11 statistical considerations and additional decision rules.
Based on phase 1 safety review, INCB024360 300 mg. po BID for a total of 7 cycles was determined the phase IIb 
dose level.
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Table 2
Exploratory Cohort Dosing Schedule for Sirolimus and DEC205mAb-
NY-ESO-1 Fusion Protein (CDX-1401) Given with Adjuvant Poly-ICLC
NOTE: Exploratory Cohort enrollment at Roswell Park site ONLY.
6.2 Cohort Management
A patient will be considered to have completed treatment with study medications following 
completion of 7 cycles of treatment and the final assessments at treatment discontinuation. An 
eligible patient receiving at least 1 dose of the investigational agents, DEC205mAb-NY-ESO-1 
fusion protein (CDX-1401) given with adjuvant poly-ICLC with or without INCB024360, will be 
considered evaluable for safety. A patient that completes 2 or more cycles of treatment will be 
eligible for the analysis of immune response. Patients who do not complete the study through 
Day 29 for reasons other than dose limiting toxicities (DLTs) will be replaced. All patients will be 
included in the analysis of results.
6.3 Dose Modification
No dose adjustments during this study are planned for the DEC205mAb-NY-ESO-1 fusion protein 
(CDX-1401) given with adjuvant poly-ICLC vaccine.
In the event of excessive discomfort, skin breakdown or desquamation, or a Grade 3 treatment-
related systemic toxicity following CDX-1401 and poly-ICLC dosing, administration of adjuvant 
(poly-ICLC) on the subsequent day should be omitted. Provided the toxicity has resolved to 
Grade 2 or less, the next monthly treatment may be administered as scheduled at a new 
administration site.
Refer to Section 11.1 for the Phase I parameters and decisions rules for INCB024360 dose 
adjustments.
Dose adjustments for hematological toxicity will be based on the blood counts obtained at baseline 
and after each 28-day cycle of DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) given with 
adjuvant poly-ICLC and with or without INCB024360.
If at least 2/3 or 2/6 DLT’s are observed in cohort one, the dose of INCB024360 will be reduced 
from 300 mg to 100 mg BID. If at least 2/3 or 2/6 DLT’s are observed in Cohort 1, the dose of 
INCB024360 will be reduced from 100 mg to 50 mg BID in Cohort 2. The study will continue at 
this dose level.
Treatment 
Cohorts
Number of 
Patients
DEC205mAb-NY ESO 1 Fusion Protein (CDX 1401) 
Given with Adjuvant Poly-ICLCa
Sirolimus
Exploratory Cohort
Cohort 3
6 patients

DEC205mAb-NY-ESO-1 fusion protein (1 mg, 
intracutaneous injection) on Day 1 of each 28 day 
cycle for a total of 5 cycles.

Adjuvant poly-ICLC (1 ml, subcutaneous) on Day 1 
and Day 2 of each 28 day cycle for a total of 
5 cycles.
4 cycles of 4 mg/day for 
2 weeks followed by 2 
weeks off 
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Dose modification for INCB024360 are based on decision rules in Section 11.1.
Patients will be withdrawn from the study if they fail to recover to Grade 2, CTCAE Version 4.0, 
from a treatment-related toxicity within 4 weeks (leading to treatment delay of ≥ 4 weeks. For 
patients that recover in < 4 weeks, when toxicities have resolved to Grade 2 or lower, INCB024360 
may be restarted. In patients that recover from toxicity in less than 4 weeks and who restart therapy, 
the next treatment cycle will be scheduled for 4 weeks later. Additional cycles will also follow at 
4 weeks intervals. 
Dose modification for Phase IIB (INCBO24360 cohorts)
When an INCBO24360 toxicity is observed, dose administration may be delayed/interrupted to 
allow for recovery from toxicity.  INCB024360 may be restarted at a reduced dose of 100 mg. po 
BID.  Please contact the PI for attribution. 

Febrile neutropenia with standard of care treatment for ≥ 7 days. Growth factors may be used 
according to American Society of Clinical Oncology guidelines.

Platelets ≤ 50 x 109/L

Grade 3 or greater non-hematologic toxicity

Serum bilirubin > 3.0 mg/dL

AST / ALT > 3.5 x ULN
o
AST normal range: 15 U/L – 46 U/L
o
ALT normal range: 11 U/L - 66 U/L

Serum creatinine  > grade 3 (equal or greater) will be considered a DLT

Grade 3 or greater hypersensitivity reaction.  If the hypersensitivity reaction is determined to 
be related to INCB024360 alone, the INCB024360 will be discontinued and patient may 
continue on treatment with CDX-1401 with Poly-ICLC at the discretion of the investigator.
Dose modification for exploratory cohort with Sirolimus (Roswell site ONLY):
Based on the completed trial (I 191511 “A Phase 1 Clinical Trial of mTOR Inhibition With 
Rapamycin for Enhancing Intranodal Dendritic Cell Vaccine Induced anti-Tumor Immunity In 
Patients with NY-ESO-1 Expressing Solid Tumors”), the 4 mg/day Sirolimus dose was safely used 
in combination with DEC205 and therefore dose modification is not expected.  However, in the 
event of an unexpected toxicity attributed to Sirolimus, a lower dose of Sirolimus may be 
considered.
Based on the phase I safety review, INCBO24360 300 mg. po BID x 7 cycles has been selected 
for the phase IIB dose. Dose modification criteria will be defined as any Grade 3 or higher 
treatment-related (i.e. definitely, probably, or possibly related) toxicity that occurs outside the 
DLT evaluation period including: 
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6.3.1 Definition of Dose-Limiting Toxicity
Patients who do not complete the study through Day 29 for reasons other than dose limiting 
toxicities (DLTs) will be replaced. All patients will be included in the analysis results.
All AEs (as defined in Section 9) will be graded according to the NCI-CTCAE scale Version 4.0. 
Patients who experience a DLT will not receive any additional treatment ( i.e., will be removed 
from the study and followed until resolution of their toxicity) and will not receive continued 
treatment even at a reduced dosage of the INCB024360 product.  Patients with dose limiting 
toxicities requiring drug discontinuation (specified below) will be removed from the study (see 
exception for hypersensitivity reaction). The DLT period will be defined as 28 days after the first 
dose of vaccine. Late developing toxicities, occurring between Day 29 and Day 183 will be 
monitored throughout the study and according to the schedule of procedures and observations. 
Patients may be withdrawn from study even if DLT is due to INCB024360 or sirolimus alone. 
Safety monitoring will include careful assessment and appropriate reporting of AEs, as well as the 
construction and implementation of a data and safety-monitoring plan (Auditing, Monitoring, and 
Inspecting). Medical monitoring will include a regular assessment of the number and type of SAEs. 
Refer to the stopping rules for this study in Section 6.3.2. Any event(s) that might appear to trigger 
a treatment discontinuation rule or trial stopping rule will be discussed with the FDA review team.  
For phase IIb dose reductions for INCB024360 will be allowed (see section 6.3)
Management and dose modifications associated with AEs are outlined in Section 6.3. Refer to 
Section 11 for statistical considerations and additional decision rules.
These events should be deemed to be possibly, probably or definitely related to study drugs. DLT 
criteria will be defined as any Grade 3 or higher treatment-related (i.e. definitely, probably, or 
possibly related) toxicity that occurs during the DLT evaluation period, including:

Febrile neutropenia with standard of care treatment for ≥ 7 days. Growth factors may be used 
according to American Society of Clinical Oncology guidelines.

Platelets ≤ 50 x 109/L

Grade 3 or greater non-hematologic toxicity

New onset pulmonary hypertension, interstitial pneumonitis or, CNS bleeding

Serum bilirubin > 3.0 mg/dL

AST / ALT > 3.5 x ULN
o
AST normal range: 15 U/L – 46 U/L
o
ALT normal range: 11 U/L - 66 U/L

Serum creatinine  > grade 3 (equal or greater) will be considered a DLT

Grade 3 or greater hypersensitivity reaction.  If the hypersensitivity reaction is determined to 
be related to INCB024360 alone, the INCB024360 will be discontinued and patient may 
continue on treatment with CDX-1401 with Poly-ICLC at the discretion of the investigator.
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6.3.2 Management of Delayed Events
Late-developing toxicities, occurring between Day 29 and Day 143 will be monitored throughout 
the study and according to the schedule of procedures and observations.
Study Stopping Rules
Any Grade 4 event will trigger a study pause for data review prior to further enrollment. In 
addition, the following stopping rule for treatment-related SAEs will be used:

Accrual to study will be suspended to allow protocol review with institutional IRB, the Early 
Phase Clinical Trials (EPCT) Committee, and the FDA review team if any of the following 
occurs among patients who receive experimental agents:
o
Any treatment-related death, judged to be possibly, probably, or definitely related 
to INCB024360 or DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) given 
with adjuvant poly-ICLC.
o
Exploratory cohort at Roswell Park ONLY: Any treatment-related death, judged to 
be possibly, probably, or definitely related to sirolimus or DEC205mAb-
NY-ESO-1 fusion protein (CDX-1401) given with adjuvant poly-ICLC.
o
Grade 4 events considered to be possibly, probably, or definitely related to the 
experimental agents.
6.4 Ancillary Therapy and Supportive Care
Patients may not receive chronic treatment during the period of study with systemic corticosteroids 
or other immunosuppressive agents including chemotherapeutic agents. A brief course of systemic 
corticosteroids can be used to manage immune based toxicities, if deemed appropriate by the 
treating physician. Treatment with NSAIDs should be avoided during the study.  Investigators may 
prescribe all other concomitant medications or treatments deemed necessary to provide adequate 
patient care.
Concurrent non-cytotoxic anti-cancer therapy (e.g., hormone therapy) is permitted.
The electronic case report form (eCRF) must capture the concurrent use of all other drugs, over-
the-counter medications, or alternative therapies, listing drug name, indication, dose, route of 
administration, and dates of administration.
Patients may be pretreated for nausea and vomiting with appropriate anti-emetics.
6.4.1 Permitted Treatment

Any medication for concurrent medical condition.

Inhaled corticosteroids, if indicated.

If clinically indicated, use of growth factors according to American Society of Clinical 
Oncology guidelines.

Antiemetics for breakthrough nausea and vomiting:
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o
Metoclopramide 1 mg - 2 mg/kg IV every 3 to 4 hours p.r.n. nausea/vomiting.
o
Prochlorperazine 10 mg IV/PO every 4 to 6 hours p.r.n. nausea/vomiting.
o
Lorazepam 0.5 mg - 2 mg PO/SL/IV every 4 to 6 hours p.r.n nausea/vomiting.
o
Olanzepine 2.5 mg - 5 mg PO twice daily.

Use of coumarin-based anticoagulants (e.g. Coumadin) is discouraged.  Low-dose coumadin 
(1 mg) is acceptable; however, doses that increase the INR are discouraged and will require 
dose modification.  If an alternative to coumarin-based anticoagulants cannot be used, dose 
adjustment of the Coumadin may be needed.  Based on the observed magnitude of 
epacadostat/warfarin PK interaction and PK/PD modeling results, for an epacadostat dose of 
300 mg BID, the dose of warfarin should be reduced by approximately one-third after initiation 
of epacadostat administration based on approximately 30% to 40% reduction in S- and R-
warfarin oral clearance values.  Close INR monitoring is recommended for patients on a stable 
dose of warfarin who are starting treatment with epacadostat.  Based on PK/PD modeling, 
recommendations for warfarin dose modifications for subjects receiving other epacadostat 
doses, are summarized below based on the INR prior to starting epacadostat.
Stable Baseline INR
Epacadostat Dose
                                      < 100 mg BID          200 mg BID                 300 mg BID  
INR <2.5                   Close INR monitoring        Close INR monitoring          Reduce warfarin by~33%
                                                                                                             and monitor INR
                                                                                                             
                                                                                                                                   
INR >2.5                   Close INR monitoring         Reduce warfarin by 20-      Reduce warfarin by ~33%/
                                                                        25%/monitor INR                monitor INR
6.5 Prohibited Treatment
Chemotherapy, radiation, surgery, immunosuppressive therapies are prohibited throughout this 
study. Patients being treated with a monoamine oxidase inhibitor (MAOI), or drug which has 
significant MAOI activity (e.g., meperidine, linezolid, methylene blue) within 3 weeks prior to 
screening is prohibited.  Patients who are currently receiving therapy with a potent CYP3A4 
inducer or inhibitor is prohibited. Use of UGT1A9 inhibitor including:  diclofenac, imipramine, 
and ketoconazole is prohibited. Inhaled corticosteroids or short course of systemic corticosteroids 
are permitted.  Daily nonsteroidal anti-inflammatory drugs for more than 2 weeks are not 
permitted.
Sirolimus Exploratory Cohort: At the investigator’s discretion full dose anti-coagulation therapy 
may need to be adjusted for study procedures. Daily nonsteroidal anti-inflammatory drugs for more 
than 2 weeks are not permitted. The use of posaconazole and voriconazole are contraindicated 
because of drug-drug interactions. An additional list of drugs that have theoretical or probable 
interaction with sirolimus is provided in Appendix B.    Patients taking any of these drugs will be 
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monitored clinically. Treatment with corticosteroids should be avoided during this study. 
However, a short duration (≤ 2 weeks) with systemic corticosteroids will be allowed for treatment 
of acute events.
                                       
                
                                                
6.6 Duration of Treatment
The duration of patient enrollment is expected to be 8 years. 
INCB groups: Patients are expected to participate in the study for approximately 28 weeks of 
active therapy and follow-up assessments at 3 months, 6 months, and 12 months after the last dose 
of study drug. Patients may return to standard of care after completing all assessments at follow-
up.
Exploratory Cohort with Sirolimus: Patients are expected to participate in the study for 
approximately 20 weeks of active vaccine therapy and follow-up assessments at 3 months, 6 
months and 12 months after the last dose of study drug. Patients may return to standard of care 
after completing all assessments at End of Treatment.
6.7 Treatment Discontinuation
Upon treatment discontinuation all end of study evaluations and tests will be conducted. All 
patients who discontinue due to an AE must be followed until the event resolves or stabilizes. 
Appropriate medical care should be provided until signs and symptoms have abated, stabilized, or 
until abnormal laboratory findings have returned to acceptable or pre-study limits. The final status 
of the AE will be reported in the patient’s medical records and the appropriate eCRF.  If patient 
terminates study participation prior to study completion, all efforts will be made to complete an 
early termination visit (within approximately 30 days of last dose).  Assessment will include 
physical exam, vital signs and weight, performance status, labs (CBC/diff, CMP, LDH, Coag if on 
anticoagulants, con med/AE assessment.
Reasons for treatment discontinuation should be classified as follows:

Death

Progressive disease

Treatment-related toxicity
o
Subjects who experience a DLT will not receive any additional treatment ( i.e., will be 
removed from the study and followed until resolution of their toxicity) and will not 
receive continued treatment even at a reduced dosage of the INCB024360 product.
o
Persistent toxicity that is unresolved to a grade 2 toxicity, where subsequent treatment 
cannot be given.

Toxicity unrelated to treatment

Investigator judgment
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o
The Investigator may withdraw a patient if, in his/her judgment, it is in the patient’s 
best interest to do so.

Noncompliance

Patient voluntary withdrawal
o
A patient may withdraw from the study at any time, for any reason. If a patient 
discontinues treatment, an attempt should be made to obtain information regarding the 
reason for withdrawal.

Roswell Park’s decision.
Patients who are unavailable for follow-up evaluations should be classified as lost to follow-up for 
1 of the following reasons:

Lost to follow-up: For a patient to be considered lost to follow-up, the Investigator must make 
2 attempts to re-establish contact with the patient. The attempts to re-establish patient contact 
must be documented (e.g., certified letter).

Death: Date and cause of death will be recorded for those patients who die within 30 days after 
last dose of study drug (telephone contact is acceptable).
7
STUDY PROCEDURES
Eligibility of each patient will be established prior to enrollment. Informed consent MUST be 
completed prior to receiving any study related procedures.  Details regarding the schedule of 
procedures and observations are outlined below and in Table 3.
7.1 Vaccination Site Care
After the administration of the vaccine to the patient, the vaccination site will be covered loosely 
with a gauze bandage, using first aid adhesive tape to keep it in place.
The patient will be instructed as follows:

Keep the vaccination site dry and cover the vaccination site with a waterproof bandage 
when bathing.

Change bandage to the loose gauze bandage after bathing.

DO NOT use a bandage that blocks all air from the vaccination site. This may cause the 
skin at the vaccination site to soften and wear away. Use loose gauze secured with medical 
tape to cover the site.

DO NOT put salves or ointments on the vaccination site.
7.2 Unscheduled Visit
The Investigator may, at his/her discretion, arrange for a patient to have an unscheduled visit, 
especially in the case of AEs that require follow-up. If a patient is experiencing an AE considered 
by the Investigator to be possibly related to the study drug, an unscheduled visit should be 
performed; the unscheduled visit pages for the eCRF must be completed.
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7.3 Schedule of Procedures and Observations
Clinical assessments will be performed every 4 weeks. Imaging with computed tomography (CT) 
or magnetic resonance imaging (MRI) will be performed according to standard of care. 
Performance status and AEs will be assessed at each clinical assessment until disease progression.
The schedule of procedures and observations for the INCB024360 cohorts in this study is 
summarized in Table 3 below. Approximately ± 3 days are allowed for the schedule of procedures.
The schedule of procedures and observations for the exploratory cohort (with sirolimus) at Roswell 
Park site ONLY is summarized in Table 4.
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Table 3.
Schedule of Procedures and Observations (INCB024360 cohorts)
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Cycle 7
Study Event
Baseline1
Day 1
Day 2
Day 15
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 1
± 3 days
1.1.1
Treatment 
discontinuation13
3 Months, 6 Months, 
and 12 Months After 
Last Vaccine or dose of 
INCB 
Informed Consent
X
Medical History
X
X
X
X
X
X
X
X
X
Physical Examination, vital signs and 
weight 
X
X
X
X
X
X
X
X
X
NY-ESO-1, TIL, PD-L1, and/or 
LAGE-1 Expression in Tumor Tissue2
X
HLA Typing (Historic HLA Typing is 
Permitted-low resolution)3
X
Disease Assessment4
X
X
X
X5
Hematology, PT/INR6
X
X
X
X
X
X
X
X
Chemistry7
X
X
X
X
X
X
X
X
Pharmacokinetic/Pharmacodynamic 
Sampling8
X
X
X
Performance Status (Appendix A)
X
X
X
X
X
X
X
X
X
Tumor Markers9
X
X
X
X
X
X
X
X
X
Vaccination: 
DEC205mAb-NY-ESO-1 Fusion 
Protein (CDX-1401) given with 
Adjuvant Poly-ICLC
X
X
X
X
X


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Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Cycle 7
Study Event
Baseline1
Day 1
Day 2
Day 15
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 1
± 3 days
.1.1
Treatment 
discontinuation13
3 Months, 6 Months, 
and 12 Months After 
Last Vaccine or dose of 
INCB 
Adjuvant Poly-ICLC (administered in 
clinic or at home by the patient)
X
X
X
X
X
X
X
X
X
X
INCB02436010
X
X
X
X
X
X
X
X
X
X
X
X
X
Antibody Response: NY-ESO-1 
ELISA and NY-ESO-1 Cellular 
Immune Response (T cell): ELISPOT 
and ICS11
X
X
X
X
X
X
X
Urinary Pregnancy Test in Females of 
Childbearing Potential
X
Concomitant Medications
X12
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X


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Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Cycle 7
Study Event
Baseline1
Day 1
Day 2
Day 15
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 1
± 3 days
.1.1
Treatment 
discontinuation13
3 Months, 6 Months, 
and 12 Months After 
Last Vaccine or dose of 
INCB 
1
To be performed within 28 days prior to the first vaccination.
2
Positive by either PCR or immunohistochemistry ((archived tissue (Appendix F) and/or frozen/fresh tumor tissue (Appendix G)). Documented historical NY 
ESO 1 positive results by IHC or PCR or serum antibody reactive with ESO are acceptable.
3
 Refer to Appendix H 
4
Including CT scan abdomen and pelvis, or PET/CT as described in Section 8.5; within 28 days prior to first vaccination. If patient early terms, CT will be 
performed at the PI’s discretion.
5
Only 3 months and 6 month for those patients who have not experienced disease progression.
6
Hematology includes: CBC with auto differential, platelets. PT/INR for patients on anticoagulants.
7
Chemistry includes: glucose, urea nitrogen, creatinine, calcium, protein, albumin, bilirubin, AST, ALT, LDH, alkaline phosphatase.
8
Pharmacokinetic sampling is dependent upon cohort. Refer to Section 7.7 for details.
9
Tumor markers to be obtained as per standard of care.
10
INCB024360 will be administered daily for 7 cycles.
11
Refer to Section 7.5.
12
Medications ongoing within 1 week prior to first dose of study drug.
13
Approximately 30 days after last.study drug, con meds and AE’s will be followed. Telephone contact is allowed.


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Table 4
Schedule of Procedures/Observations (Exploratory cohort with Sirolimus-Roswell site ONLY)
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Study Event
Baseline1
Day 1
Day 2
Day 15
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
1.1.2
Treatment 
discontinuation12
3 Months, 6 Months, 
and 12 Months After 
Last Vaccine or dose of 
Sirolimus 
Informed Consent
X
Medical History
X
X
X
X
X
X
X
X
Physical Examination, vital signs and 
weight 
X
X
X
X
X
X
X
X
NY-ESO-1, TIL, PD-L1, and/or 
LAGE-1 Expression in Tumor 
Tissue2
X
HLA Typing (Historic HLA Typing is 
Permitted-low resolution)3
X
Disease Assessment4
X
X
X
X5
Hematology, PT/INR6
X
X
X
X
X
X
X
X
Chemistry7
X
X
X
X
X
X
X
X
Performance Status (Appendix A)
X
X
X
X
X
X
X
Tumor Markers8
X
X
X
X
X
X
X


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Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Study Event
Baseline1
Day 1
Day 2
Day 15
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
.1.2
Treatment 
discontinuation12
3 Months, 6 Months, 
and 12 Months After 
Last Vaccine or dose of 
Sirolimus 
Vaccination: 
DEC205mAb-NY-ESO-1 Fusion 
Protein (CDX-1401) given with 
Adjuvant Poly-ICLC
X
X
X
X
X
Adjuvant Poly-ICLC (administered 
in clinic or at home by the patient)
X
X
X
X
X
X
X
X
X
X
Sirolimus9
X
X
X
X
X
X
X
X
Antibody Response: NY-ESO-1 
ELISA and NY-ESO-1 Cellular 
Immune Response (T cell): ELISPOT 
and ICS10
X
X
X
X
X
X
X
Urinary Pregnancy Test in Females 
of Childbearing Potential
X
CMV PCR, Qualitative
X
X
X
Lipid profile13
X
X
X
X
Concomitant Medications
X11
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X


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Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Study Event
Baseline1
Day 1
Day 2
Day 15
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
Day 1
± 3 days
Day 2
.1.2
Treatment 
discontinuation12
3 Months, 6 Months, 
and 12 Months After 
Last Vaccine or dose of 
Sirolimus 
1
To be performed within 28 days prior to the first vaccination.
2
Positive by either PCR or immunohistochemistry ((archived tissue (Appendix F) and/or frozen/fresh tumor tissue (Appendix G)). Documented 
historical NY ESO 1 positive results by IHC or PCR or serum antibody reactive with ESO are acceptable.
3
 Refer to Appendix H 
4
Including CT scan abdomen and pelvis, or PET/CT as described in Section 8.5; within 28 days prior to first vaccination. If patient early terms, CT will 
be performed at the PI’s discretion.
5
Only 3 months and 6 month for those patients who have not experienced disease progression.
6
Hematology includes: CBC with auto differential, platelets. PT/INR for patients on anticoagulants.
7
Chemistry includes: glucose, urea nitrogen, creatinine, calcium, protein, albumin, bilirubin, AST, ALT, LDH, alkaline phosphatase.
8
Tumor markers to be obtained as per standard of care.
9
4 cycles of Sirolimus 4mg/day will be given for 2 weeks, followed by 2 weeks off (each cycle = 28 days).
10
Refer to Section 7.5.
11
Medications ongoing within 1 week prior to first dose of study drug.
12
Approximately 30 days after last study drug, Con meds and AE’s will be followed. Telephone contact is allowed.
13
Patients known from clinical history to have elevation of lipids and triglycerides will be followed per standard guidelines.  Lipid profile will be 
obtained as lipid panel including: Cholesterol, triglycerides, LDL, HDL.


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7.4 Pathology
7.4.1 Baseline Tumor Tissue Requirements
Tumor tissue requirements for IDO, NY-ESO-1, TIL, PD-1, PD-L1 and/or LAGE-1, Expression 
in Tumor are as follows:

Evaluation of NY-ESO-1 will occur at OmniSeq.
o
5 unstained sections (5μm thick) and 8 tissue curls (10 μm thick) cut with molecular 
precautions.

Evaluation of all other biomarkers will occur in the Pathology Network Shared Resource 
at Roswell Park.
o
8 unstained sections (5μm thick) on plus glass

Evaluation by PCR will occur in Immune Analysis Facility at the Center for 
Immunotherapy at Roswell Park. The director of the center is Junko Matsuzaki, Cancer 
Cell Center, Roswell Park, Room C-410, phone number 716-845-8459, e-mail address, 
junko.matsuzaki@roswellpark.org. Refer to Appendix G.
o
This will be performed when fresh/frozen tumor tissue is available.

Documented historical NY ESO 1 positive results by IHC or PCR or serum antibody reactive 
with ESO are acceptable.
Network Site see Appendix J for specific instruction.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. The 
Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process in 
place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
7.4.2 Recurrence Tumor Tissues Requirements
The standard of care in patients who develop recurrent cancer, for the most part, is an additional 
cytotoxic chemotherapy. In order to ascertain whether treatment failure is a consequence of 
antigenic loss or represents failure of this strategy, it will be important to analyze tissue specimens 
from patients with recurrent disease. In a subset of patients, surgical resection of 
recurrent/progressive disease will be indicated as part of standard care. Specimens obtained at the 
time of surgery for recurrent/progressive disease will be analyzed for antigen expression and 
antigen-specific tumor infiltrating lymphocytes. The basic panel of markers noted in Section 7.4.1 
will also be tested. Up to 25 unstained sections of formalin-fixed paraffin-embedded recurrent 
tumors cut at 5 µm thickness on plus slides from the same population of patients will be used. The 
paraffin-embedded archival specimens will be obtained from the paraffin-archive resource in 
Roswell Park’s Department of Pathology. Fresh or frozen tumor tissue will be obtained from 
Roswell Park Protocol I 115707 titled “Roswell Park Remnant Clinical Biospecimen Storage, 
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Collection, and Distribution for Research Purposes”, or I 215512 titled “Analysis of Tumor 
Antigens, Immunity, and Genetic Changes in Gynecological Cancer Patients”.
7.5 Immunological Response
INCB024360 Cohorts:
70 mL of blood for immunological analysis (humoral and cellular immunity) will be collected via 
venipuncture using 6 green top and 1 red top collection tube. Sample collection will be obtained 
at the following visits:

Cycle 1 Day 1

Cycle 2 Day 1

Cycle 3 Day 1

Cycle 4 Day 1

Cycle 5 Day 1

 Treatment discontinuation

3 Months, 6 Months, and 12 Months After Last Vaccine or last dose of INCB 
Assays of samples to determine immune responses will be performed in the Immune Analysis 
Facility at the Center for Immunotherapy at Roswell Park.
Network Site see Appendix H for specific instruction.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. The 
Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process in 
place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
Sirolimus Cohorts:
Blood samples will be collected via venipuncture for antibody response and cellular (T cell) 
immune response using ELISA for NY-ESO-1 and ELISPOT/ ICS (intracellular staining) 
respectively. Samples (70 ml) will be collected using 6 green top and 1 red top collection tube. 
These samples for immunological analyses will be collected at the following visits:

Cycle 1 Day 1

Cycle 2 Day 1

Cycle 3 Day 1

Cycle 4 Day 1

Cycle 5 Day 1
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
 Treatment discontinuation

3 Months, 6 Months, and 12 Months After Last Vaccine or last dose of sirolimus.
Samples will be kept at room temperature prior to processing. All samples to be sent to Immune 
Analysis Facility at Center for Immunotherapy:
Director: Dr. Junko Matsuzaki
CCC building, 4th floor
Phone 716-845-8459
Junko.Matsuzaki@RoswellPark.org 
Note: All laboratories housing research samples need to maintain current, study-specific 
Temperature 
Logs 
and 
Sample 
Tracking 
and 
Shipping 
Logs. 
The 
Principal 
Investigator/Laboratory Manager must ensure that the stated lab(s) have a process in place to 
document the receipt/processing/storage/shipping of study-related samples/specimens. This is 
required for both observational and interventional clinical studies collecting clinical samples.
7.5.1 Humoral Immunity
Specific antibody against NY-ESO-1 will be measured by ELISA (see Reference [7] for 
methodology).
7.5.2 Cellular Immunity
NY-ESO-1 specific CD4+ and CD8+ T cells will be measured by IFNγ release ELISPOT and 
Intracellular 
Cytokine 
Staining 
(ICS). 
Peripheral 
blood 
frequency 
of 
CD4+ CD25+ FOXP3+ regulatory T cells. Assays will be performed at the Immune Analysis 
Facility at the Center for Immunotherapy, Roswell Park, Buffalo, NY [42-44] for methodology). 
In order identify the DEC205mAb-NY-ESO-1 fusion protein with adjuvant poly-ICLC 
vaccination plus INCB024360 (or sirolimus for exploratory cohort) schedule that is associated 
with optimal biological activity, the following parameters will be determined (i) generation of 
effector and memory T cells with (ii) high avidity that are also (iii) resistant to Tregs.
7.6 Additional Exploration of the T cell response
The methods to analyze the T cell response to cancer antigens used in this study are well 
established. However, as T cell biology and immune regulation are very active fields of discovery, 
the opportunity exists to refine and extend the analysis of the T cell response. Therefore, although 
most of the blood drawn for the analysis of the immune response will be used for the assays listed 
above, a small part may be used to explore other aspects of the T cell response. In this regard, we 
will examine the evolution of memory CD8+ cells in the different patient cohorts. Using multi-
parameter flow cytometry we will determine CD8+ cell subsets as follows: (i) central memory 
CD45RA–CCR7+CD27+ cells, which have the ability to migrate to lymph nodes; (ii) early and 
intermediate effector memory CD45RA–CCR7–CD27+ cells, with high proliferative capacity and 
low cytolytic activity; (iii) CD45RA–CCR7–CD27– cells, so-called late effector memory cells, with 
strong effector functions such as cytolytic capacity; and (iv) CD45RA+CCR7–CD27– cells, known 
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as fully differentiated effector cells, which retain those functional capacities but are stably non-
replicative and apoptosis-resistant memory cells. On the basis of the distinct phenotypes of effector 
and memory CD8+ T cells generated by DEC205mAb-NY-ESO-1 fusion protein with adjuvant 
poly-ICLC vaccine in the presence or absence of IDO inhibition, we will determine whether the 
transition from an effector to a memory cell phenotype is an abrupt or gradual event, and whether 
this transition would occur simultaneously for different markers at the primary and secondary 
responses. This work may also involve establishing T cell lines and clones in culture, and 
collaborations with Investigators outside of Roswell Park.
7.7 Pharmacokinetic/Pharmacodynamic Blood Sample Collection and Processing
7.7.1 INCB024360 Levels
Whole blood samples for pharmacokinetic analysis of INCB024360 levels will be collected via 
venipuncture using (1) 4 mL purple-top EDTA collection tube per time point.
INCB024360 pharmacokinetic sample collection will be obtained on:

Cohort -2, Cohort -1, and Cohort 1
o
Cycle 1 Day 1 and Day 15: predose and 1, 2, 4, and 6 hours post dose of 
INCB024360
o
Cycle 2 Day 1: trough, prior to vaccination

Cohorts 2b 
o
Cycle 1 Day 15: predose and 2 hours post dose of INCB024360
o
Cycle 2 Day 1: trough, prior to vaccination
Plasma will be separated by centrifugation at 4°C from whole blood within 30 minutes following 
the extraction and aliquotted into (2) cryovials per time-point.
Network Site see Appendix H for specific instruction.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. The 
Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process in 
place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
Tryptophan and Kynurenine Levels:
Whole blood samples for pharmacokinetic analysis of tryptophan and kynurenine levels will be 
collected via venipuncture using (1) 4 mL purple-top EDTA collection tube per time point.
Tryptophan and kynurenine pharmacokinetic sample collection will be obtained on:

Cohort -2, Cohort -1, and Cohort 1
o
Cycle 1 Day 1 and Day 15: predose, 1, 2, 4, and 6 hours post dose of INCB024360
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o
Cycle 2 Day 1: trough, prior to vaccination

Cohorts 2b 
o
Cycle 1 Day 15: predose and 2 hours post dose of INCB024360
o
Cycle 2 Day 1: trough, prior to vaccination
Plasma will be separated by centrifugation at 4°C from whole blood within 30 minutes following 
the extraction and aliquotted into (2) cryovials per time-point.
Network Site see Appendix H for specific instruction.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. The 
Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process in 
place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
Sample Processing:
The screw cap polypropylene cryogenic tube will be labeled with the participant’s MR number(for 
Roswell Park participants), patient’s initials, patient’s study number, clinical study number, 
protocol time point, dose, and protocol day. The label for each patient’s sample will be supplied 
by Roswell Park. The samples will be immediately frozen at - 70ºC or below until analyzed at the 
Roswell Park’s Bioanalytics, Metabolomics & Pharmacokinetics Core Facility:
Roswell Park Bioanalytics, Metabolomics & Pharmacokinetics Core Facility, Center for Genetics 
and Pharmacology, Room L1-140, I 248613, Elm & Carlton Streets, Buffalo, New York 14262, 
BMPKCore@Roswell Park.org.
For additional information regarding the handling of pharmacokinetic samples, please contact 
Roswell Park’s Bioanalytics, Metabolomics & Pharmacokinetics Core Facility laboratory at 716-
845-3303 (Tel) or 716-845-1579 (Fax).  Joshua Prey (Joshua.Prey@roswellpark.org); John Wilton 
(John.Wilton@roswellpark.org)
 PK blood samples will be sent to procurement lab for processing and storage. After hours samples 
will be processed in Lab Medicine.
Network Site see Appendix H for specific instruction.
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. The 
Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process in 
place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples.
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7.7.2
Sirolimus Levels
Pharmacokinetic analysis of sirolimus levels will not be done for patients participating in the 
exploratory cohort. Based on the completed trial (I 191511 “A Phase 1 Clinical Trial of mTOR 
Inhibition With Rapamycin for Enhancing Intranodal Dendritic Cell Vaccine Induced anti-Tumor 
Immunity In Patients with NY-ESO-1 Expressing Solid Tumors”), the 4 mg/day Sirolimus dose 
was safely used in combination with DEC205. 
8
EFFICACY EVALUATIONS
8.1
Objective Tumor Response
All protocol-defined imaging studies must be performed at the investigative site or sponsor-
approved facility using protocol-defined parameters. The same method of assessment and the same 
technique should be used to characterize each identified and reported lesion at baseline and during 
follow-up. RECIST 1.1 will be used to assess objective tumor response.
8.2
Target Lesions – PHASE 1
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative 
of all involved organs, will be identified as target lesions and recorded and measured at baseline. 
Target lesions will be selected on the basis of their size. Lesions with the longest diameter (short 
axis for lymph nodes) and are ≥ 10 mm (CT and MRI), ≥ 15 mm lymph nodes, > 20 mm CXR and 
are for accurate repetitive measurements (either by imaging techniques or clinically) will be 
chosen. A sum of the longest diameter (short axis for lymph nodes) of all target lesions will be 
calculated and reported as the baseline sum diameters. This will be used as reference to further 
characterize the objective tumor response of the measurable dimension of the disease.

Complete Response (CR): Disappearance of all target lesions. Any lymph nodes must 
have a reduction in short axis to < 10 mm. Changes in tumor measurements must be 
confirmed by repeat studies performed no less than 6 weeks after the criteria for response 
are first met.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. Changes in tumor measurements must be 
confirmed by repeat studies performed no less than 6 weeks after the criteria for response 
are first met.

Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as references the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. The appearance of one or more new 
lesions is also considered progression.

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameter while on study. Patients 
having a documented response with no confirmation of the response will be listed with 
stable disease.
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8.3
Non-Target Lesions
All other small lesions (longest diameter < 10 mm or lymph nodes ≥ 10 mm to < 15 mm short 
axis) and non-measurable lesions (i.e., leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, blastic bone 
lesions, or abdominal masses / abdominal organomegaly identified by physical exam that is not 
measurable by imaging) should be identified as non-target lesions and indicated as present in the 
source documents at baseline. The general location will also be documented on the images drawing 
a regularly-shaped Region of Interest. Measurements of the non-target lesions will not be 
performed, but the presence or absence of each should be noted throughout follow-up and 
evaluation.
Those patients, who have no evidence of disease at the baseline, will be documented as no evidence 
of disease until progression of disease is documented per RECIST 1.1.

Complete Response: Disappearance of all non-target lesions and normalization of tumor 
marker level, if applicable. All lymph nodes must be non-pathological in size (< 10 mm 
short axis).

Non-Complete Response/Non-Progressive Disease: Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the upper limits of normal.

Progressive Disease: Appearance of 1 or more new lesions or the unequivocal progression 
of existing non-target lesions. Although a clear progression of non-target lesions is 
exceptional, in such circumstances, the opinion of the treating physician should prevail and 
the progression status should be confirmed at a later time.
o
TUMOR RESPONSE ASSESSMENT BY IRRC – PHASE 2

Tumor Response will be assessed by the Immune-related response criteria (irRC) as 
published by Wolchok et al. (68).  Response is defined as irCR, irPR or irSD over a period 
of at least 4 weeks.  Disease Control by irRC is defined as irSD or irPR or irCR.
PROGRESSION-FREE SURVIVAL (PFS)
Progression-free survival will be determined for each patient with time origin at the start of the 
treatment (day 1) until the first occurrence of confirmed progression by irRC or date of 
death if the patient dies from any causes before progression.  Every effort will be made to 
follow patients for progression after they discontinue the study.
OVERALL SURVIVAL (OS)
Overall survival (OS) will be measured for each patient with time origin at the start of the 
treatment (day 1) until recorded date of death.  Every effort will be made to follow patients 
for overall survival after they discontinue the study.
Antitumor response based on total measurable tumor burden:
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Only index and measurable new lesions are taken into account when evaluating total 
measurable tumor burden.  The longest diameter and longest perpendicular diameter should 
be recorded in millimeters (mm).  At the baseline tumor assessment, the sum of the 
products of the two largest perpendicular diameters (SPD) of all index lesion (> 10x10 mm; 
five lesions per organ, up to 10 visceral lesions and five cutaneous index lesions) is 
calculated.  At each subsequent tumor assessment, the SPD of the index lesions and of new, 
measurable lesions (> 5 x 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions 
and 10 visceral lesions) are added together to provide the total tumor burden.
Time-point response assessment:
Percentage changes in tumor burden per assessment time point describe the size and growth 
kinetics of both conventional and new, measurable lesions as they appear.  At each tumor 
assessment, the response in index and new, measurable lesions is defined based on the 
change in tumor burden (after ruling out irPD).  Decreases in tumor burden must be 
assessed relative to baseline measurements (i.e., the SPD of all index lesions at screening).
irCR
Disappearance of all lesions in two consecutive observations not less than 4 weeks apart.
irPR
>50% decrease in tumor burden compared with baseline in two observations at least 4 weeks 
apart.
irSD
50% decrease in tumor burden compared with baseline cannot be established nor 25% increase 
compared with nadir.
irPD
At least 25% increase in tumor burden compared with nadir (at any single time point) in two 
consecutive observations at least 4 weeks apart.
Overall response assessment:
The overall response is derived form time-point response assessment (based on tumor burden) 
as follows:
Index and new                      Non-index non-                    New non-measurable                         Overall
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Measurable lesions             measurable lesions                     lesions                                         Response
(Tumor Burden)
          100%                                Absent                                      Absent                                     irCR
          100%                                 Stable                                       Any                                         irPR
          100%                       Unequivocal Progression                   Any                                         irPR
          >50%                          Absent/Stable                                  Any                                         irPR
          >50%                       Unequivocal Progression                   Any                                         irPR
   <50% TO <25%                 Absent/Stable                                 Any                                         irSD
   <50% TO <25%              Unequivocal Progression                   Any                                        irSD
          >25%                                   Any                                          Any                                        irPD
        
8.4
Evaluation of Response
Response assessment is for measuring time to disease progression. Time point response 
assessments will be performed on Cycle 4 Day 1 and Treatment discontinuation (timed to coincide 
with mid-point and the end of study) with a confirmatory assessment (required for non-randomized 
trials) within 6 weeks after a PR or CR is deemed. Response assessment may also be based on 
tumor marker measurements. To determine time point response using imaging studies, refer to 
Table 5 and below.
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Table 5.
Time Point Response Criteria (+/- non-target disease)
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Table 6.
Time Point Response Criteria (non-target disease only)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD1
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
1
Non-CR/non-PD is preferred over SD for non-target disease since SD is used as endpoint for assessment of 
efficacy in trials so to assign this category when no lesions can be measured is not advised.
The best overall response is the best response recorded from the start of study treatment until end 
of treatment (taking into account any requirement for confirmation). In general, the patient’s best 
response assignment will depend on the achievement of both measurement and confirmation 
criteria and will be determined by combining the patient’s status of target lesions, non-target 
lesions, and new lesions.

Residual Disease: Patients with objective response but who continue to have residual 
measurable disease.

Symptomatic Deterioration: Patients with global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time, 
and not related to study treatment or other medical conditions should be reported as 
progressive disease due to “symptomatic deterioration.” Every effort should be made to 
document objective progression even after discontinuation of treatment due to 
symptomatic deterioration. Symptomatic deterioration that may lead to discontinuation of 
treatment include, but is not limited to, symptoms such as:
o
Weight loss > 10% of body weight.
o
Worsening of disease-related symptoms (e.g., worsening dyspnea, increasing 
pain/increasing requirement for narcotic analgesics).
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o
Decline in performance status of > 1 level on ECOG scale.
8.5 Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation. All baseline evaluations should 
be performed as closely as possible to the beginning of treatment and never more than 4 weeks 
before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.

Clinical Lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.

Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.

Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g., for body scans).
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible.

PET CT: At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements. However, if the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then 
the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time. 
Note, however, that the PET portion of the CT introduces additional data which may bias 
an Investigator if it is not routinely or serially performed.

Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
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independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances.

Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation 
is not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint.

Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.

Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease.

FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG PET imaging can be identified according to the following algorithm:
o
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.
o
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD.
o
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity.
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Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
9
SAFETY EVALUATION
9.1 Adverse Events
9.1.1
Definition
An adverse event or adverse experience (AE) is any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of ‘unrelated’, ‘unlikely’, 
‘possible’, ‘probable’, or ‘definite’).
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents.
9.1.1.1 Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the CRF rather than individual signs and symptoms 
(e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be clinically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event 
should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently established, it 
should be reported as follow-up information.
9.1.1.2 Adverse Events Occurring Secondary to Other Events
In general, AEs occurring secondary to other events (e.g., cascade events or clinical sequelae) 
should be identified by their primary cause. For example, if severe diarrhea is known to have 
resulted in dehydration, it is sufficient to record only diarrhea as an AE or SAE on the CRF.
However, clinically significant AEs occurring secondary to an initiating event that are separated 
in time should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to renal failure, both events should be recorded separately on 
the CRF.
9.1.1.3 Abnormal Laboratory Values
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, further 
diagnostic investigation, etc.).
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If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline 
phosphatase and bilirubin 5 x the upper limit of normal associated with cholecystitis), only the 
diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse Event CRF.
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory abnormality 
can be characterized by a precise clinical term, the clinical term should be recorded as the AE or 
SAE. For example, an elevated serum potassium level of 7 mEq/L should be recorded as 
“hyperkalemia”
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or 
etiology changes.
9.1.1.4 Preexisting Medical Conditions (Baseline Signs and Symptoms)
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such events on 
an Adverse Event CRF, it is important to convey the concept that the preexisting condition has 
changed by including applicable descriptors (e.g., “more frequent headaches”).
9.1.2
Grading and Relationship to Drug
The descriptions and grading scales found in the CTEP Version 4 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. CTEP 
Version 4 
of 
the 
CTCAE 
is 
identified 
and 
located 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. AEs not covered by 
specific criteria should be reported with common medical terminology and graded according to 
definitions provided in the CTCAE Version 4.
The relationship of event to study drug will be documented by the Investigator as follows:

Unrelated: The event is clearly related to other factors such as the patient’s clinical state, other 
therapeutic interventions or concomitant drugs administered to the patient.

Unlikely: The event is doubtfully related to investigational agent(s). The event was most likely 
related to other factors such as the patient’s clinical state, other therapeutic interventions, or 
concomitant drugs.

Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the patient’s clinical 
state, other therapeutic interventions or concomitant drugs.

Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot be 
reasonably explained by other factors such as the patient’s clinical state, therapeutic 
interventions or concomitant drugs.

Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
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explained by other factors such as the patient’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, improves 
upon stopping the drug, or reappears on re-exposure.
9.1.3
Reporting Adverse Events
Table 7.
Guidelines for Routine Adverse Event Reporting for Phase I Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
X
X
Unlikely
X
X
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
Table 8.
Guidelines for Routine Adverse Event Reporting for Phase IIb Studies 
(Regardless of Expectedness)
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Unrelated
X
X
Unlikely
X
X
Possible
X
X
X
X
Probable
X
X
X
X
Definite
X
X
X
X
All new routine AEs occurring between the start date of intervention until 30 days after the last 
intervention or until the event has resolved, stabilized, death, or a new treatment is started, 
whichever comes first, will be reported.
9.2 Serious Adverse Events
9.2.1 Definition
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following:

Death.

A life-threatening adverse event (experience). Any AE that places a patient in the view of the 
Investigator or sponsor, at immediate risk of death from the reaction as it occurred. It does 
NOT include an AE that, had it occurred in a more severe form, might have caused death.

Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours).

A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions.
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
A congenital anomaly or birth defect.

Important Medical Event (IME) that, based upon medical judgment, may jeopardize the patient 
and may require medical or surgical intervention to prevent one of the outcomes listed above.
9.2.2 Reporting Serious Adverse Events
All new SAEs occurring from the start of treatment until 30 days after the last intervention or a 
new treatment is started, whichever comes first, will be reported. SAE’s occurring after this time 
that the investigator determines to be possibly, probably or definitely related to the study 
intervention, should be reported.
The Roswell Park SAE Source Form is to be completed with all available information, including 
a brief narrative describing the SAE and any other relevant information. The site Investigator or 
designated research personnel will report all SAEs, whether related or unrelated, to the 
investigational agent(s) to the IRB in accordance with their local institutional guidelines.
INCB024360 Cohorts:
Investigators MUST report (within 1 business day), upon becoming aware, to Incyte, Sentrx, and 
Celldex ANY SAEs, whether or not they are considered related to the investigational 
agent(s)/intervention.
    Incyte Pharmacovigilance
Route 141 and Henry Clay Road
              Wilmington, DE  19880
     Phone:  302-498-6727
                           All SAE reports are to be sent via e-mail to:  PhVpHVOpsIST@incyte.com     
Sentrx
Overlook at Great Notch
150 Clove Road
Little Falls, NJ 07424
SAE Facsimile Number: Sentrx: 866-726-9234
Sentrx Helpdesk Phone (Helpdesk support available 8am – 8 pm EST):
866-278-6759 (toll free in US)
973-812-7575 Ext: 250
Celldex Therapeutics, Inc.
SAE Reporting
Fax No:  781-644-6434
Email:  SAE@celldex.com
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Exploratory Cohort with sirolimus (Roswell Park site ONLY):
Similarly as above, investigators MUST report (within 1 business day), upon becoming aware, to 
Sentrx, and Celldex ANY SAEs, whether or not they are considered related to the investigational 
agent(s)/intervention.
SAE’s identified as an Unanticipated Problem by the Investigator must be reported. Please refer 
to Section 9.3 for details on reporting Unanticipated Problems.
9.2.3 Follow-Up for Serious Adverse Events
All related SAEs will be followed to their resolution, until the study participant is lost to follow-
up, the start of new treatment, or until the study investigator assesses the event(s) as stable or 
irreversible. New information will be reported when it is received.
9.3 Unanticipated Problems
9.3.1 Definition
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria:

Unexpected (in terms of nature, severity, or frequency) given:
a) The research procedures that are described in the study-related documents, including 
study deviations, as well as issues related to compromise of patient privacy or 
confidentiality of data.
b) The characteristics of the patient population being studied.

Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research).

Suggests that the research places patients or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized and if in relation to an AE is also deemed Serious per Section 9.2.
9.3.2 Reporting Unanticipated Problems
The Reportable New Information (RNI) Form will be submitted to CRS Quality Assurance Office 
within 1 business day of becoming aware of the Unanticipated Problem. After review, CRS 
Quality Assurance will submit the RNI to the IRB.
When becoming aware of new information about the Unanticipated Problem, submit the updated 
information to CRS Quality Assurance with an updated Reportable New Information Form. The 
site Investigator or designated research personnel will report all unanticipated problems, whether 
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related or unrelated to the investigational agent(s) to the IRB in accordance with their local 
institutional guidelines.
9.3.3 Notifying the Study Drug Provider
INCB024360 cohorts:
Expedited reporting by investigator to Celldex, Incyte, and Sentrx.  Contact information can be 
found in section 9.2.2.
The investigator must inform Celldex, Incyte, and Sentrx in writing using an SAE form or 
MEDWATCH 3500A form of any SAE within 24 hours of being aware of the event.  The written 
report must be completed and supplied by facsimile within 24 hours/1 business day.  The initial 
report must be as complete as possible, including an assessment of the causal relationship between 
the event and the investigational product(s), if available.  Information not available at the time of 
the initial report (e.g., an end date for the adverse event or laboratory values received after the 
report) must be documented on a follow-up report.  An SAE is considered to be any adverse event 
that is life-threatening or that results in any of the following outcomes: death; inpatient 
hospitalization or prolongation of existing hospitalization; persistent or significant disability or 
incapacity; or a congenital anomaly or birth defect.  Completed SAE reports are to be submitted 
to:
Celldex Therapeutics, Inc.
SAE Reporting
Fax No: 781-644-6434
Email: SAE@celldex.com
Exploratory Cohort with Sirolimus:
Similarly as above, expedited reporting by investigator to Celldex and Sentryx.
9.4 FDA Reporting
When Roswell Park is the IND holder the following describes the FDA reporting requirements by 
timeline for AEs and new safety findings that meet the criteria outlined below:
Within 7 Calendar Days
Any adverse event that meets ALL the following criteria:

Related or possibly related to the use of the study drug;

Unexpected; and

Fatal or life-threatening.
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Within 15 Calendar Days
Any adverse event that meets ALL the following criteria:

Related or possibly related to the use of the study drug;

Unexpected; and

Serious but not fatal or life-threatening.
Or meets ANY of the following criteria:

A previous adverse event that is not initially deemed reportable but is later found to fit the 
criteria for reporting (report within 15 days from when event was deemed reportable).

Any findings from other studies, including epidemiological studies, pooled analysis of 
multiple studies, or other clinical studies conducted with the study drug that suggest a 
significant risk in humans exposed to the drug.

Any findings from animal or in vitro testing that suggest a significant risk for human 
patients including reports of mutagenicity, teratogenicity, or carcinogenicity or reports of 
significant organ toxicity at or near the expected human exposure.

Any clinically important increase in the rate of occurrence of a serious, related or possibly 
related adverse event over that listed in the protocol or investigator brochure.
Sponsors are also required to identify in IND safety reports, all previous reports concerning similar 
adverse events and to analyze the significance of the current event in the light of the previous 
reports.
Reporting Process
The principal investigator or designee will complete and submit a FDA Form 3500A Medwatch 
for any event that meets the above criteria. Forms will be submitted to the CRS Quality Assurance 
Office via email to CRSQAGroup@RoswellPark.org.
10 DATA AND SAFETY MONITORING
Phase I studies will be reviewed at the scheduled Roswell Park Early Phase Clinical Trials (EPCT) 
meetings and the minutes are forwarded to the IRB for review.
The Roswell Park Data Safety Monitoring Committee will assess the progress of the Phase IIb 
portion of the study, the safety data, and critical efficacy endpoints. The DSMC will review the 
study annually and will make recommendations that include but not limited to; (a) continuation of 
the study, (b) modifications to the design (c) or termination of the study.
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11 STATISTICAL METHODOLOGY
11.1 Primary Objective
For the Phase I component of the study 2 cohorts will be examined as described in the body of the 
project description. The following decision rules will be followed: (i) If 0/3 dose limiting toxicities 
(DLTs) are observed proceed to enroll 3 more patients (ii) If 1/3 DLTs are observed enroll 3 more 
patients at the same treatment regimen. If 0/6 or 1/6 DLTs are observed, declare the regimen safe 
and as the maximum tolerated dose combination (MTD) of INCB024360 in combination with the 
vaccine. If at least 2/3 or 2/6 DLTs are observed in Cohort 1, stop and de-escalate INCB024360 to 
100 mg BID in Cohort -1. If at least 2/3 or 2/6 DLTs are observed in Cohort -1, stop and de-
escalate INCB024360 to 50 mg BID in Cohort -2. It is anticipated that the probability of a DLT is 
rare in this setting. A Monte Carlo study using 10,000 replications was conducted. If the 
Prob(DLT) = 0.2 for Cohort 1 and Prob(DLT) = 0.1 for Cohort -1 or Cohort -2 then the expected 
sample size for the Phase I component of this study is 5.1 patients and the probability of declaring 
Cohort 1 as the MTD is 0.71 and the probability of declaring Cohort -1 or Cohort -2 as the MTD 
is 0.22. If the Prob(DLT) = 0.1 for Cohort 1 and Prob(DLT) = 0.05 for Cohort -1 or Cohort -2 then 
the expected sample size for the Phase I component of this study is 4.0 patients and the probability 
of declaring Cohort 1 as the MTD is 0.91 and the probability of declaring Cohort -1 or Cohort -2as 
the MTD is 0.08. If the Prob(DLT) = 0.5 for Cohort 1 and Prob(DLT) = 0.1 for Cohort -1 or 
Cohort -2 then the expected sample size for the Phase I component of this study is 6.1 patients and 
the probability of declaring Cohort 1 as the MTD is 0.17 and the probability of declaring Cohort -1 
or Cohort -2 as the MTD is 0.47.
The Phase IIb component of this trial will consist of a randomized parallel  design of 
n = 25 + 25 = 50 patients with  treatment arms (i) DEC205mAb-NY-ESO-1 fusion protein (CDX-
1401) with adjuvant poly-ICLC and (ii)  INCB024360 in combination with the DEC205mAb-
NY-ESO-1 fusion protein (CDX-1401) with adjuvant poly-ICLC . Stratification will be on clinical 
site (Roswell Park, U. of Pittsburgh). The primary endpoint will be progression free survival. 
Baseline is defined as the time following the treatment free interval, which can span 0 - 2 months, 
as described in Iasonos et al.[1] The primary analysis will be carried forth using a Cox proportional 
hazards model with factors corresponding to treatment and  a continuous covariate adjustment for 
the length of the treatment free interval and a stratification factor for clinical site.Permuted blocked 
random assignment with block sizes of 4 and an allocation ratio of 1:1 for DEC205mAb-NY-ESO-
1 fusion protein (CDX-1401) with adjuvant poly-ICLC  alone versus INCB024360 in combination 
with the DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) with adjuvant poly-ICLC stratified 
by clinical site..
11.1.1 Sample Size Justification
We assume a median PFS of 8 months for the INCB024360 alone arm. For the purpose of our 
simulation study we utilized the simplifying assumption that the covariate adjustment for time 
between treatment and clinical site are not significant. We also assume a constant hazard rate and 
a 9 month accrual period with up to 5 years of follow-up. The detectable effect size for the 
INCB024360 in combination with the DEC205mAB-NY-ESO-1 fusion protein (CDX-1401) arm 
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different from the INCB024360 alone arm is a PFS of 16 months (or a 2 to 1 risk ratio) with a 
power estimated from simulation of 0.70. From a practical consideration n = 25 patients per arm 
is anticipated to be the maximum for which we can accrue during the timeframe of this study.
An additional exploratory cohort (N=6) receiving the same DEC205mAb-NY-ESO-01 fusion 
protein (CDX-1401) with adjuvant poly-ICLC but in combination with sirolimus in place of  
INCB024360 will be added to supplement the secondary objectives, which will aid in planning the 
next phase of the investigation. 
11.2 Secondary Objectives
The secondary analysis of continuous immunological response endpoints [antibody titres; 
NY-ESO-1 specific CD8+ and CD4+ frequency and function (IFN-γ ELISPOT and tumor 
recognition by CTL)] will be analyzed in a straightforward analysis-of-covariance (ANCOVA) 
fashion modeling post-treatment levels as a function of pre-treatment levels with factors 
corresponding to INCB024360 (yes/no) and DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) 
with adjuvant poly-ICLC (yes/no).
Similarly, for the exploratory cohort at Roswell site only, the secondary analysis of continuous 
immunological response endpoints [antibody titres; NY-ESO-1 specific CD8+ and CD4+ 
frequency and function (IFN-γ ELISPOT and tumor recognition by CTL)] will be analyzed in a 
straightforward analysis-of-covariance (ANCOVA) fashion modeling post-treatment levels as a 
function of pre-treatment levels with factors corresponding to sirolimus (yes/no) and 
DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) with adjuvant poly-ICLC (yes/no).
11.3 Toxicity
All patients enrolled in this study will be eligible for the analysis of toxicity.
The toxicity rate will be estimated using a one-sided, 95%, exact binomial confidence interval 
(Clopper-Pearson). The lower one sided limit will be used.
11.4 Immune Response
Patients that complete 2 or more cycles of treatment will be eligible for the analysis of immune 
response.
Due to the early stage of this study and the feasibility considerations, the sample size for this study 
will be restricted. The analysis of continuous immunological response endpoints (e.g., antibody 
titers; NY-ESO-1 specific CD8+ and CD4+ frequency and function; frequency of memory T cell 
populations; TCR avidity) will be analyzed via an analysis-of-covariance (ANCOVA) model with 
post-treatment levels modeled as a function pre-treatment levels and main effects to the parallel 
design.
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11.5 Interim Analysis and Criteria for Early Termination of the Study
All patients enrolled in this study will eligible for the analysis of safety.
Drug safety will be monitored and evaluated weekly throughout the study including a 30 day safety 
follow-up period by obtaining, reviewing and analyzing data on AEs, changes in laboratory values, 
vital signs, and physical examination findings. If the committee views the toxicity as unacceptable, 
the trial will be stopped early.
In the phase 2 portion of the study, the Roswell Park Data Safety Monitoring Committee will 
assess the progress of the study, the safety data, and critical efficacy endpoints.  The DSMC will 
review the study annually and will make recommendations that include but not limited to; (a) 
continuation of the study, (b) modifications to the design (c) or termination of the study.
12 CORRELATIVE DATA ANALYSIS
12.1 Pharmacokinetic or Pharmacokinetic/Pharmacodynamic Analysis
A population pharmacokinetic model will be developed utilizing the pharmacokinetic timepoints 
collected, and then used to estimate individual AUCs or CL of INCB024360 in combination with 
DEC205mAb-NY-ESO-1 fusion protein (CDX-1401) with adjuvant poly-ICLC vaccine. The 
effect of patient factors on INCB024360 pharmacokinetics will be evaluated by the model, along 
with other patient factors that may explain the inter-patient variability in pharmacokinetics. 
INCB024360 AUC, as well as the observed Cmax, will then be tested for association changes in 
various immunological biomarkers and the relationship between tryptophan and kynurenine. If an 
observable trend exists among changes in any of these biomarkers and pharmacodynamic 
endpoints, a pharmacokinetic/pharmacodynamic model will be developed to evaluate the 
exposure-response relationship between the time course of INCB024360 exposure (e.g., AUC, 
Cmax) in relation to changes to these immunological biomarkers. Demographic and clinical data 
(i.e., ethnicity, current age, age at diagnosis, ECOG status) will be utilized to assess interpatient 
variability in the model.
13 ETHICAL AND REGULATORY STANDARDS
13.1 Ethical Principles
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC). Each patient (or legal guardian) shall read, understand, and sign an 
instrument of informed consent prior to performance of any study-specific procedure. It is the 
responsibility of the Investigator to ensure that the patient is made aware of the investigational 
nature of the treatment and that informed consent is given.
The Investigator is responsible for the retention of the patient log and patient records; although 
personal information may be reviewed by authorized persons, that information will be treated as 
strictly confidential and will not be made publicly available. The Investigator is also responsible 
for obtaining patient authorization to access medical records and other applicable study specific 
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information according to Health Insurance Portability and Accountability Act regulations (where 
applicable).
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the patient is treated, in accordance with the Declaration of 
Helsinki, Good Clinical Practice, and according to the guidelines in this protocol, including 
attached appendices.
13.2 Informed Consent
The Investigator is responsible for obtaining written consent from each patient or the patient's 
legally authorized representative in accordance with ICH-GCP guidelines using the approved 
informed consent form, before any study specific procedures (including screening procedures) are 
performed. The informed consent form acknowledges all information that must be given to the 
patient according to ICH-GCP, including the purpose and nature of the study, the expected efficacy 
and possible side effects of the treatment(s), and specifying that refusal to participate will not 
influence further options for therapy. Any additional information that is applicable to the study 
must also be included. Additional national or institutionally mandated requirements for informed 
consent must also be adhered to. The patient should also be made aware that by signing the consent 
form, processing of sensitive clinical trial data and transfer to other countries for further processing 
is allowed.
The Investigator shall provide a copy of the information sheet and of the signed consent form to 
the patient and the signed original shall be maintained in the Investigator File. A copy of the signed 
consent form must be filed in the patient file. At any stage, the patient may withdraw from the 
study and such a decision will not affect any further treatment options.
14 STUDY RESPONSIBILITIES
14.1 Data Collection
Data entry into the database is to be completed in a timely fashion (approximately within 28 days) 
after the patient’s clinic visit. If an AE is considered serious it is captured on both the Adverse 
Event page and the Serious Adverse Event Form, which is handled in an expedited fashion.
Data management activities will be performed using EXPeRT. EXPeRT is a suite of software tools 
that enables the collection, cleaning and viewing of clinical trial data. CRS data management will 
design the study-specific database and facilitate its development by the EXPeRT Information 
Technology team. Once the database design is approved by the Investigator, Statistician, and 
Clinical Research Coordinator, the database will be put into production and data entry can begin. 
Data can be entered and changed only by those with the rights to do so into the eCRFs. EXPeRT 
is compliant with all relevant technical aspects of relevant GCP guidelines.

The system can generate accurate copies of stored data and audit trail information in human 
readable form.

System access is limited to authorized individuals through the controlled assignment of unique 
ID and password combinations.
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
The system is designed to periodically force users to change their passwords and verifies that 
user ID and password combinations remain unique.

The system automatically generates a permanent time-stamped audit trail of all user 
interactions.
When data entry is complete, data management will review the data and will query any missing, 
incomplete, or invalid data points for resolution by the CRC and Investigator. Once all queries 
have been resolved, the data can be released to the statistician for analysis.
14.2 Monitoring
It is understood that Roswell Park appointed  personnel may contact the Investigators, and that 
they will be allowed direct access to source data/documents for trial related monitoring, audits, 
IRB Committee review, and regulatory inspection. Direct access is defined as permission to 
examine, analyze, verify, and reproduce any records and reports that are important to evaluation 
of a clinical trial. All reasonable precautions within the constraints of the applicable regulatory 
requirement(s) to maintain the confidentiality of patients’ identities and sponsor’s proprietary 
information will be exercised. (Section 5.15.1 and 1.21, respectively: Guideline for Good Clinical 
Practice, ICH Harmonized Tripartite Guideline [CPMP/ICH/135/95, adopted July 1996])
It is the appointed personnel’s responsibility to inspect the eCRFs at regular intervals throughout 
the trial to verify adherence to the protocol, the completeness, accuracy and consistency of the 
data, and adherence to Good Clinical Practice guidelines. The appointed personnel should have 
access to patient charts, laboratory reports and other patient records needed to verify the entries on 
the case report forms.
Where local rules do not allow direct access to the source data, the appointed personnel will verify 
entries in the eCRF by asking direct questions of a person or persons with authorized access to the 
source data. The Investigator agrees to cooperate with the appointed personnel to ensure that any 
problems detected during the course of these monitoring visits are resolved.
14.3 Maintenance of Study Documents
Essential documents should be retained per Roswell Park’s policy for 6 years from the study 
termination date. These documents could be retained for a longer period, however, if required by 
the applicable local regulatory requirements or by an agreement with Roswell Park. It is the 
responsibility of Roswell Park to inform the Investigator/ institution as to when these documents 
no longer need to be retained. If, for any reason, the Investigator desires to no longer maintain the 
study records, they may be transferred to another institution, another Investigator, or to Roswell 
Park upon written agreement between the Investigator and Roswell Park.
15 ADMINISTRATIVE RULES
15.1 Revisions to the Protocol
Roswell Park may make such changes to the protocol as it deems necessary for safety reasons or 
as may be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to 
the CRS/SRC/IRB for written approval before implementation.
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15.2 Termination of the Study
It is agreed that, for reasonable cause, the Investigators or Roswell Park may terminate this study, 
provided a written notice is submitted within the time period provided for in the Clinical Trial 
Agreement. In addition, Roswell Park may terminate the study at any time upon immediate notice 
if it believes termination is necessary for the safety of patients enrolled in the study.
15.3 Confidentiality
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry will 
be done using PIDs only. Information will not be released without written authorization of the 
participant.
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16 APPENDICES
Appendix A. ECOG Performance Status Scores
Description
Status
Fully active, able to carry on all pre-disease performance without restriction.
0
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light housework, office work.
1
Ambulatory and capable of all self-care but unable to carry out any work activities.
2
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
4
Dead
5
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Appendix B
Sirolimus Drug Interaction List
1. Ketoconazole 
2. Posaconazole 
3. Voriconazole
4. Itraconazole
5. Erythromycin
6. Clarithromycin
7. Telithromycin
8. Rifampicin
9. Rifabutin
10. Cyclosporine
11. Bromocriptine
12. Diltiazem
13. Metoclopramide
14. Nicardipine
15. Troleandomycin
16. Verapamil
17. Carbamazepine
17. Phenobarbital
18. Phenytoin
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102
Appendix C. Diary for Medication (Poly-ICLC Subcutaneous Injection)
Protocol #: __________________________
Patient Name: ____________________________
Drug Name: _________________________
Medical Record #: __________________
Cycle (circle one):
1
2
3
4
5
Study Medication (Poly-ICLC Subcutaneous Injection) Calendar for Cohort -2, Cohort -1, Cohort 1, Cohort 2b
Please complete this calendar on a daily basis. Fill in the date for each day in the 1st row and write the time that you give your injection 
each day in the 2nd row. You should give your injection about 24 hours (±6 hour) from your injection that was given in the clinic.
On days you do not give yourself an injection; please write “NA” in date and time boxes.
Start Date: ________________
Day(s) After Vaccine
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Date
Time
No injection 
will be 
given on 
this day.
No injection will be given on these days.
Day(s) After Vaccine
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Date
Time
No injection will be given on these days.
Day(s) After Vaccine
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Date
Time
No injection will be given on these days.
Day(s) After Vaccine
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Date
Time
No injection will be given on these days.
If you missed an injection please comment:_________________________________________________________________________
____________________________________________________________________________________________________________
Please remember to bring this calendar and your pill bottle (including any unused pills) with you to your next clinic appointment.
____________________________________________________________________________________________________________
Coordinator’s Use Only
Patient Signature: _________________________________________
Date: ____________
CRC Signature: __________________________________________
Date: ____________
Clinical Research Services
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Appendix D. Diary for Medication (INCB024360)
Protocol #: __________________________
Patient Name: ____________________________
Drug Name: _________________________
Medical Record #: __________________
Cycle (circle one):
1
2
3
4
5
6
7
Study Medication (INCB024360) Calendar for Cohort -2, Cohort -1, Cohort 1, Cohort 2b
Please complete this calendar on a daily basis. Fill in the date for each day in the 1st row, write the drug dose that you take each day in 
the 2nd row, and write the total number of pills you take each day in the 3rd row. You should take your pills in the morning and in the 
evening, about 12 hours apart and at least 2 hours after a meal and not have any food for 1 hour after you take your pills.
On days you do not take any study drug; please write “0” in drug dose box. If your dose changes record the new dose level.
Start Date: ________________
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day(s) After Vaccine
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Date
Time
Dose
Number of pills taken
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day(s) After Vaccine
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Date
Time
Dose
Number of pills taken
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Day(s) After Vaccine
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Date
Time
Dose
Number of pills taken
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Day(s) After Vaccine
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Date
Time
Dose
Number of pills taken
If you missed a dose please comment:____________________________________________________________________________
Please remember to bring this calendar and your pill bottle (including any unused pills) with you to your next clinic appointment.
___________________________________________________________________________________________________________
Coordinator’s Use Only
% 𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒=(
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑃𝑖𝑙𝑙𝑠 𝐷𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑‒ 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑃𝑖𝑙𝑙𝑠 𝑅𝑒𝑡𝑢𝑟𝑛𝑒𝑑
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑃𝑖𝑙𝑙𝑠 𝑆𝑐ℎ𝑒𝑑𝑢𝑙𝑒𝑑
) × 100
Patient Signature: _________________________________________
_____% 𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒=  (
                          ‒                         
 
) × 100
Date: ____________
CRC Signature: __________________________________________
Date: ____________
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Clinical Research Services
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Appendix E
Diary for Medication (Sirolimus)
Study No.: I 248613
Patient Name: _____________________________________
Drug Name: Sirolimus
Medical Record No.: _________________________
Cycle (circle one):
1
2
3
4
Study Medication (Sirolimus) Calendar for Exploratory Cohort
Please complete this calendar on a daily basis immediately after you take your tablets. Fill in the date for each day in the 1st row, write 
the time of day that you take each day in the 2nd row (circle AM or PM), and write the total number of tablets you take that day in the 
3rd row.
On days you do not take any study drug; please write “0” in the “Number of tablets taken” box. 
Day(s):After Vaccine
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Date
Time
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Number of tablets taken
Day(s):After Vaccine
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Date
Time
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
AM
PM
Number of tablets taken
Day(s):After Vaccine
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Date
Time
Number of tablets taken
No Drug Should Be Taken On These Days.
Day(s) :After Vaccine
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Date
Time
Number of tablets taken
No Drug Should Be Taken On These Days.
If 
you 
missed 
a 
dose 
please 
comment: 
_______________________________________________________________
Please remember to bring this calendar and your tablet bottle (including any unused tablets) with you to your next clinic appointment.
Coordinator’s Use Only
% 𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒=(
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑃𝑖𝑙𝑙𝑠 𝐷𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑‒ 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑃𝑖𝑙𝑙𝑠 𝑅𝑒𝑡𝑢𝑟𝑛𝑒𝑑
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑃𝑖𝑙𝑙𝑠 𝑆𝑐h𝑒𝑑𝑢𝑙𝑒𝑑
) × 100
_____% 𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒=  (
               ‒                 
        
) × 100
Patient Signature: __________________________________________
Date: ____________
CRC signature: ____________________________________________
Date: ____________
Investigator signature: ______________________________________
Date: ____________
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Appendix F. Immunohistochemistry to Determine NY-ESO-1 Tumor Expression
1.
Adhere 5 m paraffin sections to charged slides (Fisherbrand Superfrost/Plus Slides). 
Five sections are required.
2.
Heat slides in 60C oven for 2 hours.
3.
Deparaffinize slides in xylene and bring to water through graded alcohols.
4.
Antigen Retrieval: Steam heat slides by immersing slides in a 90C, 1:10 solution of 
DAKO’s Target Retrieval Solution High pH for 15 minutes.
5.
Cool at room temperature for 30 minutes.
6.
Perform IHC; Block tissue with 5% BSA/PBS solution for 30 minutes at room 
temperature.
7.
Apply primary antibody (in this case ES121 [2.5 g/mL]) overnight, 4C.
8.
Rinse with PBS.
9.
Apply secondary; (Vector, Burlingame, CA) Horse anti mouse, 1:200; 30 minutes at 
room temperature.
10.
Rinse with PBS.
11.
Block endogenous peroxidase with a 1% H2O2 solution for 20 minutes at room 
temperature.
12.
Rinse with PBS.
13.
Apply avidin-biotin-complex system (Vector) for 30 minutes at room temperature.
14.
Rinse with PBS.
15.
Develop with diaminobenzidine tetrahydrochloride (DAB, Biogenex, San Ramon, CA).
16.
Counterstain with hematoxylin solution.
17.
Dehydrate and cover slip.
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Appendix G. Nucleic Acid Determination of NY-ESO-1 and LAGE-1 Tumor Expression
Determination of NY-ESO-1 and LAGE-1 tumor expression by reverse transcription (RT) of total 
RNA and polymerase chain reaction (PCR) amplification of cDNA 
RT-PCR Reagents:
25 mM MgCl2 Solution (Perkin Elmer-Cetus)
10 x PCR Buffer II, pH 8.3 (Perkin Elmer-Cetus)
dNTPs:
dGTP, 10 mM ]
dATP, 10 mM ]
Mix 1:1:1:1 before use (Perkin Elmer-Cetus)
dTTP, 10 mM ]
dCTP, 10 mM ]
RNasin RNAse Inhibitor (40 µg/mL) (Promega)
M-MLV Reverse Transcriptase (200 µg/L) (Gibco BRL)
Random Hexamer (400 ng/L) (Promega)
Primers:
ESO1A and ESO1B primers (each at a concentration of 200 ng/L)
5' primer ESO1-A1: CAGGGCTGAATGGATGCTGCAGA
3' primer ESO1-B1: GCGCCTCTGCCCTGAGGGAGG
Anticipated size of PCR amplified product = 329 bp.
For LAGE-1 typing, the primer sequences are
5' primer LAGE-1A: CTGCGCAGGATGGAAGGTGCCCC
3' primer LAGE-1B: GCGCCTCTGCCCTGAGGGAGC
Anticipated size of PCR amplified product = 332 bp.
Amplitaq Gold DNA Polymerase (5 µg/L) (Perkin Elmer-Cetus)
Nuclease-Free Water (Promega)
Mineral Oil (Perkin Elmer-Cetus)
Other Supplies:
0.5 mL sterile microcentrifuge tubes
Barrier or Aerosol Resistant Pipet Tips
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Reverse Transcriptase (RT) Protocol
1.
Set up each RT sample in a sterile 0.5 mL microcentrifuge tube. Use only Aerosol Resistant 
Pipet Tips, changing tips after each use to prevent cross-contamination. A master mix 
consisting of all the above reagents minus the RNA can be made and then aliquotted 
appropriately.
Component
Initial Concentration
Volume
Final Concentration
MgCl2
25 mM
4 L
5 mM
PCR Buffer II
10X
2 L
1X
DNTP 
Mix (1:1:1:1)
8 L
1 mM each of: dGTP, dATP, 
dTTP, CTP
RNAse Inhibitor
40 ng/L
1 L
2 ng (per 20 L)
M-MLV Reverse Transcriptase
1 L
10 g (per 20 L)
Random Hexamer
1 L
400 ng (per 20 L)
Total RNA in Nuclease Free 
Water
3 L
2 g (per 20 L)
Final
20 L
2.
Overlay the above RT sample mix with mineral oil to reduce evaporation or refluxing. 
Incubate the RT sample mix at room temperature for 10 minutes for the random hexamer 
to anneal and begin reverse transcription of the RNA.
3.
Place a drop of mineral oil into each well of the thermal cycler that is to be used. This will 
ensure even heating and cooling of each sample during the RT cycle. Incubate all tubes in 
a thermal cycler according to the following parameters:
Step Cycle
Segment 1
42°C
60 minutes
Stable annealing of the random hexamer for reverse 
transcription
Segment 2
99°C
5 minutes
Inactivation of M-MLV Reverse Transcriptase
Segment 3
5°C
5 minutes
Cycle Count 1
Link to
Soak Cycle
4°C
Polymerase Chain Reaction (PCR) Protocol
1.
Set up each PCR sample in a sterile 0.5 mL microcentrifuge tube. Use only Aerosol 
Resistant Tips, changing tips after each use to prevent cross-contamination. A negative 
control (without cDNA) should be run with each PCR panel to ensure the purity of the 
reagents. A master mix of all reagents, minus the cDNA, can be prepared when running 
several PCR samples at once.
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Component
Initial Concentration
Volume
Final Concentration or 
Amount
MgCl2
25 mM
2 L
2 mM
PCR Buffer II
10X
2.5 L
1X
DNTP 
Mix (1:1:1:1)
2 L
0.2 mM
ESO-1A1a
200 ng/L
0.25 L
50 ng (per 25 L)
ESO-1B1a
200 ng/L
0.25 L
50 ng (per 25 L)
Amplitaq Gold DNA 
Polymerase 
5 µg/L
0.125 L
0.625 g (per 25 L)
Nuclease Free Water
12.875 L
—
CDNA
5 L
0.5 g
Final
25 L
a For LAGE-1 methods, replace ESO-1A1 and ESO-1B1 with LAGE-1A and LAGE-1B, 
respectively.
2.
Overlay the above PCR sample mix with sterile mineral oil to reduce evaporation or 
refluxing.
3
Place a drop of mineral oil into each well of the thermal cycler. This will ensure even 
heating and cooling of each sample during the PCR cycle. Incubate tubes in a thermal 
cycler according to the following parameters:
Time Delay Cycle
95°C
10 min
Initial heatup for Activation of Amplitaq 
Gold DNA polymerase
Cycle count 1
Link to
Step cycle
Segment 1
94°C
1 minute
Denaturation of cDNA
Segment 2
60°C
1 minute
Primer annealing
Segment 3
72°C
1 minute
Primer extension
Cycle Count 35
Link to
Time Delay Cycle
72°C
6 minute
Final Primer extension
Link to
Soak Cycle
4°C
Gel Electrophoresis
Use 15 L of the 25 L PCR product, analyze by 1.2% to 1.5% agarose gel (ethidium bromide in 
the gel).
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GENERAL COMMENTS
1.
RNA Preparation
Guanidium thiocyanate/CsCl gradient method is used to prepare RNA. Other RNA protocols, such 
as Trizol, should give comparable results. The RNA preparations should be quantitated by 
measuring absorbance at 260 nm.
Absorbance at 260 x dilution factor x 40 mcg/mL = concentration (µg/mL)
Confirm the RNA and cDNA quality by control trans-intron primers for any housekeeping gene, 
preferentially with anticipated PCR product > 350 bp – 400 bp. Usually a faint background smear 
on the gel is visible even when the RNA being analyzed is NY-ESO-1 negative In the case of an 
absolutely clean gel on electrophoresis it may signify a poor PCR, probably due to poor RNA 
template or poor RT.
2.
RT-PCR
Perform the RT reaction with 2 mcg RNA per 20 mL reaction Mixture. Use 5 L of this RT 
product for 25 L PCR reaction, corresponding to 0.5 mcg total RNA. Use 15 L of the PCR 
product for electrophoresis.
For PCR reaction, AmpliTaq Gold gave more consistent results than other Taq polymerase and 
should be used.
Since some RNA preparations generate a nonspecific band slightly smaller than the NY-ESO-1 
product comparison with a positive control is necessary. Testicular RNA or RNA from a known 
NY-ESO-1 positive line is an appropriate positive control. Using the above protocol 1 L cDNA 
prepared from testicular RNA should give a clear positive signal.
3.
Gel Electrophoresis
Short run for 1 to 3 hours provides better results than overnight gel at low voltage, particularly for 
weaker positives.
Results are considered positive if a 332 bp band is noted for NY-ESO-1 and 338 bp is noted 
LAGE-1.
As a positive internal control all PCR reactions are done using testicular RNA.
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Appendix H. Shipping Information for HLA Testing
HLA specimen collection kit containing 3 ten ml EDTA purple top tubes provided by Roswell 
Park.
Collect should occur at baseline if HLA typing has not already performed.
Specimens should be shipped via Prime Time Courier, ambient on the same day of collection, with 
enclosed Immco specimen requisition.  This will be handled by Roswell Park Lab medicine 
department and shipped to:
Immco Diagnostics
640 Ellicott Street
Buffalo, NY 14203
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Appendix I.
Assessment of T cell Responses
CD4+ and CD8+ cells will be enriched from PBMCs by magnetic cell sorting using miniMACS 
(Miltenyi Biotec Inc., Bergisch Gladbach, Germany) and stimulated with irradiated autologous 
APCs in the presence of NY-ESO-1 peptide pool (each 2 µM; NeoMPS Inc., San Diego, CA), 
rhIL-2 (10 IU/mL), and rhIL-7 (10 ng/mL). At Day 8, cultures will be tested for intracellular IFN- 
secretion after stimulation, during 4 hours, and in the absence or presence of the peptide pool or of 
individual peptides. Response will be considered significant if the frequency of T cells detected in 
at least one post vaccine sample exceeded by 3-fold that found in the baseline sample.
For ex vivo assessments, cryopreserved total PBMCs will be thawed, rested overnight, and 
stimulated for 7 hours in the absence or presence of the NY-ESO-1 peptide pool. Brefeldin A will 
be added 2 hours after the beginning of the incubation. At the end of the incubation, cells will be 
stained with antibodies directed against surface markers (CD3, CD4, CD8, CD45RA, and CCR7), 
fixed, permeabilized, and stained with cytokine-specific antibodies. 
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Appendix J.
 Instructions for Network Sites
1.  CONTACT INFORMATION
All questions related to the protocol or study implementation should be directed to:
Roswell Park
CRS Network Office
ASB K 104
Buffalo, New York 14263
Telephone:
Monday - Friday; 7:00 AM to 4:00 PM EST
716-845-8084
After hours, weekends, and holidays request the Roswell Park Investigator
716-845-2300
Fax: 716-845-8743
1. INFORMED CONSENT

Informed consent must be obtained by the site Investigator from any subjects wishing to 
participate, prior to any procedures or change in treatment.

An informed consent template is provided by Roswell Park and can be amended to reflect 
institutional requirements.

All consent changes must be reviewed by Roswell Park Network Office prior to 
submission to the site IRB.

The informed consent must be IRB approved.

Always check that the most up to date version of the IRB approved consent is being used.

Within 5 business days, notify the Roswell Park Network Office of all participant 
withdrawals or consent to limited study participation and appropriately document the 
discontinuation and the reason (s) why.
2. SUBJECT REGISTRATION
The subject completes the Gender, Race, and Ethnicity Form and this is placed in the study 
binder.
Roswell Park does not grant exceptions to eligibility criteria.
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Phase 2 Protocol Registration Instructions
The Subject Enrollment Log must be faxed or emailed to the Roswell Park Network Office within 
24 hours of the date the subject is consented. Once the Investigator has determined that eligibility 
has been met, complete the Subject Registration Form and fax or email it to the Roswell Park 
Network Monitor at 716-845-8743.
3. STUDY DEVIATIONS

If a deviation has occurred to eliminate hazard, this must be reported to the Roswell Park 
Network, site IRB and any other regulatory authority involved in the trial.

All study deviation will be recorded on the Study Deviation Log.

Subjects inadvertently enrolled with significant deviation(s) from the study-specified 
criteria will be removed from the study.
4. STUDY DOCUMENTATION

Study documents must be filled out completely and correctly. Ditto marks are not allowed.

If an entry has been documented in error put a single line through the entry and initial and 
date the change. The Roswell Park Network Monitor must be able to read what has been 
deleted.
o
Do NOT use white-out, magic marker, scratch-outs.
o
Do NOT erase entries.

Use only black ink for documentation on the accountability form and any other study 
forms.
5. DRUG ACCOUNTABILITY
Drug accountability must be strictly maintained.

Responsibility rests solely with the Investigator but can be delegated as appropriate (e.g., to 
pharmacy personnel).

A drug accountability record form (DARF) will record quantities of study drug received, 
dispensed to subjects and wasted, lot number, date dispensed, subject ID number and 
initials, quantity returned, balance remaining, manufacturer, expiration date, and the 
initials of the person dispensing the medication.

Study drug supply will only be used in accordance with the IRB approved study.

Drug accountability forms are protocol and agent specific, they are study source documents 
and will be used to verify compliance with the study.
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
An inventory count must be performed with each transaction. Any discrepancies shall be 
documented and explained.

Drug accountability forms must be stored with study related documents.

Each medication provided for this study and each dosage form and strength must have its 
own DARF.

Dispensing the wrong study supply is considered a medication error.
o
NEVER replace investigational agents with commercial product.
o
Do NOT “transfer”, “borrow” or “replace” supplies between studies.
6. SERIOUS ADVERSE EVENT REPORTING
The site Investigator or designated research personnel will report all SAEs, whether related or 
unrelated to the investigational agent(s) to the IRB in accordance with their local institutional 
guidelines. The site will notify the Roswell Park Network Monitor within 1 business day of being 
made aware of the SAE. A preliminary written report must follow within 24 hours (1 business day) 
of the first notification using the following forms:

Roswell Park SAE report form

MedWatch 3500A 
Investigators MUST report (within 1 business day), upon becoming aware, to Incyte, Sentrx, or 
Celldex ANY SAEs, whether or not they are considered related to the investigational 
agent(s)/intervention.
Sentrx
Overlook at Great Notch
150 Clove Road
Little Falls, NJ 07424
SAE Facsimile Number: Sentrx: 866-726-9234
Sentrx Helpdesk Phone (Helpdesk support available 8am – 8 pm EST):
866-278-6759 (toll free in US)
973-812-7575 Ext: 250
Incyte Pharmacovigilance
Route 141 and Henry Clay Road
Wilmington, DE 19880
Phone:  302-498-6727
All SAE reports are to be sent via e-mail to:  PhVpHVOpsIST@incyte.com
Celldex Therapeutics, Inc.
SAE Reporting
Fax No:  781-644-6434
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E-mail:  SAE@celldex.com
A complete follow-up report must be sent to the Roswell Park Network Monitor within 10 working 
days.
7. UNANTICIPATED PROBLEM REPORTING
An unanticipated problem (UP) is any incident, experience, or outcome that meets all of the criteria 
in Section 9.3
For all adverse events occurring that are unanticipated and related or possibly related to the 
research drug, biologic or intervention, the participating physician or delegated research staff from 
each site will notify their local IRB in accordance with their local institutional guidelines. The 
site must also notify the Roswell Park Network Monitor within 24 hours of being made aware of 
the Unanticipated Problem by completing the Roswell Park Reportable New Information Form 
and faxing or emailing it to the Roswell Park Network Monitor.
8. LAB INFORMATION
Baseline Tumor Tissue Requirements 

Evaluation of all other biomarkers will occur in the Pathology Network Shared Resource 
at Roswell Park.
o
8 unstained sections (5μm thick) on plus glass
Send samples, along with the sponsor-provided shipping log, using study-specific subject ID number 
and tissue accession number to Roswell Park Pathology Network Shared Resource (Attn: Protocol Lab 
Team). The 
Shipping label should read as follows:
Roswell Park 
Correlative Sciences Pathology Office, S-636
Attn:  Protocol Lab Team – I 248613 Samples
Elm & Carlton Streets
Buffalo, NY  14263
(716) 845-8917
Email:  CRSLabPathTeam@RoswellPark.org and the network monitor
NY-ESO-1 Tissue Testing for Eligibility at baseline
•
Pathologist at the institution where the patient had surgery should choose a block of 
representative tumor with sufficient tumor nuclei and little necrosis.
•
Either send the block or cut:
•
5 unstained slides at 4-5 um on charged glass slides, air dried and
•
8 tissue curls- cut with molecular precautions at 10 um and placed in a tube or on non-
charged slides)
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•
If there is not enough material for both the 4-5 um and the 10 um curls, please send just the 
slides and we test by IHC only. The slides and curls can be sent with a cold pack
•
Label the samples with patient ID, patient initials and study number
•
Complete the OmniSeq Order Requisition form and provide a copy of the pathology report 
(de-identified with patient initial and study ID #)
•
Specimen Packing Sheet needs to be filled out and sent with samples.
•
Tissue must be shipped from Magee Hospital – U Pitt
Shipping of NY-ESO-1 Tissue Testing for Eligibility at baseline
Ship samples Monday – Thursday (not on a holiday) using standard overnight delivery
OmniSeq, LLC
700 Ellicott Street 
Buffalo NY  14203
Receiving phone is 716-898-8654
Notify via email:  specimenreceiving@omniseq.com and jennifer.ventola@roswellpark.org with Site 
name, FedEx tracking # and Study #, Pathology Report and OmniSeq Req.
HLA Typing

HLA specimen 3 (10mL) Lavender Top blood at Screening. 

Ship whole blood ambient same day of collection priority overnight through FedEx
IMMCO Diagnostics
Immunogenetics Laboratory
640 Ellicott Street
Buffalo, NY 14203

Roswell Park Research requisition should be included with sample for each patient.  This form 
is called Immco_HLA_testing

These will be collected and shipped only Monday- Thursday (no holidays):
Notify via email:  Ckillion@immco.com and Network Monitor (jennifer.ventola@roswellpark.org )
Include the FedEx #, patient ID, and Study Number (see “Immco_HLA_Testing” form for shipping 
address)
Immunological Response:
70 mL of blood for immunological analysis will be collected using 6 green top and 1 red top. 
Collected on visits:
Cycle 1 Day 1
Cycle 2 Day 1
Cycle 3 Day 1
Cycle 4 Day 1
Cycle 5 Day 1
Treatment Discontinuation
3 month, 6 month, 12 month after last vaccine or dose of INCB
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Overnight ship the samples at room temp to:
Immune Analysis Facility
Cancer Cell Center, Room 416
Roswell Park
Elm and Carlton Streets
Buffalo, NY 14263
Attn: Junko Matsuzaki, PhD 
**When shipping samples make sure to include the shipping log.
NOTIFY via email Junko ( junko.matsuzaki@roswellpark.org ) and jennifer.ventola@roswellpark.org 
the FedEx #, patient ID, Time point, and Study number
Correlative studies
Whole blood samples for pharmacokinetic analysis of INCB024360 levels will be collected via 
venipuncture using (2) 2 mL purple-top EDTA collection tube per time point. (Make sure they are 
draw one right after each other)
Cycle 1 Day 15: predose and 2 hours postdose of INCB024360
Cycle 2 Day 1: trough, prior to vaccination
-Plasma will be separated by centrifugation at 4°C from whole blood within 30 minutes following the 
extraction and aliquoted into (2) cryovials per time-point.
-The tube will be labeled with the participant’s number, patient’s initials, clinical study number, 
protocol time point, dose, and protocol day. 
The samples will be immediately frozen at    -70ºC or below until analyzed. 
Samples will be processed in Roswell Park’s Bioanalytics, Metabolomics & Pharmacokinetics Core 
Facility.
Shipping of Samples will occur at least once a year or 50% of the site accrual is met.
***Ship Monday – Thursday for next day delivery (Not on a holiday) 
**When shipping samples make sure to include the shipping log.
Address: 
Roswell Park
Bioanalytics, Metabolomics & Pharmacokinetics Core Facility, 
Center for Genetics and Pharmacology, Room L1-140, 
Study # I 248613, 
Elm & Carlton Streets, 
Buffalo, New York 14262, 
Notify via email: PKPDCore@RoswellPark.org  and jennifer.ventola@roswellpark.org : with Your site 
name, FedEx # and study #
APPROVED RPCI IRB
5/13/2021


Roswell Park Study No.: I 248613
PRIVATE AND CONFIDENTIAL INFORMATION OF ROSWELL PARK
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102
Correlative studies … cont’d
Whole blood samples for pharmacokinetic analysis of tryptophan and kynurenine levels will be 
collected via venipuncture using (2) 2 mL purple-top EDTA collection tube per time point. (Make sure 
they are draw one right after each other)
Cycle 1 Day 15: predose and 2 hours postdose of INCB024360
Cycle 2 Day 1: trough, prior to vaccination
Plasma will be separated by centrifugation at 4°C from whole blood within 30 minutes following the 
extraction and aliquotted into (2) cryovials per time-point.
-The tube will be labeled with the participant’s number, patient’s initials, clinical study number, 
protocol time point, dose, and protocol day. 
The samples will be immediately frozen at    -70ºC or below until analyzed. 
Samples will be processed in Roswell Park’s Bioanalytics, Metabolomics & Pharmacokinetics Core 
Facility.
Shipping of Samples will occur at least once a year or 50% of the site accrual is met.
***Ship Monday – Thursday for next day delivery (Not on a holiday) 
**When shipping samples make sure to include the shipping log.
Address: 
Roswell Park
Bioanalytics, Metabolomics & Pharmacokinetics Core Facility, 
Center for Genetics and Pharmacology, Room L1-140, 
Study #: I 248613, 
Elm & Carlton Streets, 
Buffalo, New York 14262, 
Notify via email: PKPDCore@RoswellPark.org  and jennifer.ventola@roswellpark.org : with Your site 
name, FedEx # and study #
APPROVED RPCI IRB
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Roswell Park Study No.: I 248613
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APPROVED RPCI IRB
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APPROVED RPCI IRB
5/13/2021